Note: Descriptions are shown in the official language in which they were submitted.
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 322
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VOLUME
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CONTAINING PAGES 1 TO 322
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
CA 03099605 2020-11-06
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DIHYDROPYRIMIDINE DERIVATIVES AND USES THEREOF IN THE
TREATMENT OF HBV INFECTION OR OF HBV-INDUCED DISEASES
BACKGROUND
Chronic hepatitis B virus (HBV) infection is a significant global health
problem,
affecting over 5% of the world population (over 350 million people worldwide
and
1.25 million individuals in the U.S.).
Despite the availability of a prophylactic HBV vaccine, the burden of chronic
HBV
infection continues to be a significant worldwide medical problem, due to
suboptimal
treatment options and sustained rates of new infections in most parts of the
developing world.
Current treatments do not provide a cure and are limited to only two classes
of
agents (interferon alpha and nucleoside analogues/inhibitors of the viral
polymerase); drug resistance, low efficacy, and tolerability issues limit
their impact.
The low cure rates of HBV are attributed at least in part to the fact that
complete
suppression of virus production is difficult to achieve with a single
antiviral agent.
However, persistent suppression of HBV DNA slows liver disease progression and
helps to prevent hepatocellular carcinoma. Current therapy goals for HBV-
infected
patients are directed to reducing serum HBV DNA to low or undetectable levels,
and
to ultimately reducing or preventing the development of cirrhosis and
hepatocellular
carcinoma.
The HBV capsid protein plays essential functions during the viral life cycle.
HBV
capsid/core proteins form metastable viral particles or protein shells that
protect the
viral genome during intercellular passage, and also play a central role in
viral
replication processes, including genome encapsidation, genome replication, and
virion morphogenesis and egress.
Capsid structures also respond to environmental cues to allow un-coating after
viral
entry.
Consistently, the appropriate timing of capsid assembly and dis-assembly, the
appropriate capsid stability and the function of core protein have been found
to be
critical for viral infectivity.
Background references on dihydropyrimidine derivatives in the treatment of HBV
infection include WO 2014/029193, CN103664899, CN103664925, and CN103664897.
There is a need in the art for therapeutic agents that can increase the
suppression of
virus production and that can treat, ameliorate, or prevent HBV infection.
Administration of such therapeutic agents to an HBV infected patient, either
as
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monotherapy or in combination with other HBV treatments or ancillary
treatments,
will lead to significantly reduced virus burden, improved prognosis,
diminished
progression of the disease and enhanced seroconversion rates.
SUMMARY
Provided, in one aspect, is a compound of formula (I)
R4
R5
0 R6
R3
'0
YI 3 N RI
A
Y
0 2
,
Y4
P
(I)
including the deuterated isomers, stereoisomers and the tautomeric forms
thereof,
wherein
Yi represents a bond or CR7R8;
wherein
Y2 represents a bond or CR7R8, wherein R7 and R8 are independently selected
from hydrogen and C1-C4 alkyl, and A represents CH or N; or
Y2 is CR9 and A is C thus forming a C=C bond, wherein R9 is hydrogen or Ci-C4
alkyl;
wherein Y3 represents CH;
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or Y1 and Y2 represent a bond, and a further -CH2- is present directly
connecting A
and Y3 to form a bridged 5-membered cyclic hydrocarbon;
wherein Y4 represents OH, OR14 or R14 wherein R14 is Cl-C4 alkyl;
wherein Q represents a bond or a 5- to 6- membered aromatic ring,
wherein said 5- to 6- membered aromatic ring optionally comprises 1-3
heteroatoms,
wherein said 5- to 6- membered aromatic ring is optionally substituted with
one or
more substituents each independently selected from the group consisting of
Cl-C4 alkyl,
halogen,
OR13 wherein R13 is H or C1-C4 alkyl,
NR1OR11 where Rth and RH are independently selected from H and Cl-C4 alkyl,
or Rth and RH form a C4, C5 or C6 membered ring,
Cl-C4 alkyl substituted with one or more halogen,
Cl-C4 alkyl substituted with OR12 wherein each R12 is H or C1-C4 alkyl;
wherein if Q represents a bond, Y4 is selected from the group consisting of
phenyl,
pyrazolyl,
isoxazolyl,
thiadiazolyl,
phenyl substituted with Cl-C4 alkyl,
pyrazolyl substituted with Cl-C4 alkyl,
isoxazolyl substituted with Cl-C4 alkyl, and
thiadiazolyl substituted with Cl-C4 alkyl;
wherein Ll is selected from the group consisting of
a bond,
Cl-C4 alkyl, and
Cl-C4 alkyl substituted with one or more substituents each independently
selected from the group consisting of
Cl-C4 alkyl,
halogen,
oxo,
OR7 wherein R7 independently is hydrogen or C1-C4 alkyl, and
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Ci-C4 alkyl substituted with one or more halogen;
wherein L2 is selected from the group consisting of
a bond,
Ci-C4 alkyl, and
a 3-7 membered saturated ring optionally containing one or more
hetereoatom(s), the heteroatom being a nitrogen
wherein each of said Cl-C4 alkyl and said 3-7 membered saturated ring are
optionally substituted with one or more substituents each independently
selected
from the group consisting of
Ci-C4 alkyl,
halogen,
OR15 wherein R15 independently is hydrogen or Cl-C4 alkyl, and
Cl-C4 alkyl substituted with one or more halogen;
wherein p is an integer selected from 0 and 1, more particularly 1;
wherein R4 is selected from the group consisting of thiazolyl, pyridyl,
thiazolyl
substituted with one or more halogen and pyridyl substituted with one or more
halogen;
wherein R3 is Cl-C3 alkyl; and
wherein R4, R5 and R6 each independently are selected from the group
consisting
of hydrogen, Cl-C3 alkyl and halogen;
or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect, provided herein is a pharmaceutical composition
comprising at least one compound of Formula I, or a pharmaceutically
acceptable
salt thereof, together with a pharmaceutically acceptable carrier.
In another aspect, provided herein is a pharmaceutical composition
comprising at least one disclosed compound, together with a pharmaceutically
acceptable carrier. In another aspect, provided herein is a method of treating
an
HBV infection in an individual in need thereof, comprising administering to
the
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individual a therapeutically effective amount of a compound of Formula I or a
pharmaceutically acceptable salt thereof.
In yet a further aspect, provided herein is a product comprising a first
compound and a second compound as a combined preparation for simultaneous,
separate or sequential use in the prevention or treatment of an HBV infection
or of
an HBV-induced disease in mammal in need thereof, wherein said first compound
is
different from said second compound, wherein said first compound is the
compound
of any one of claims 1-8 or the pharmaceutical composition of claim 9, and
wherein
said second compound is an HBV inhibitor which is chosen from among:
- cytokines having HBV replication inhibition activity,
- antibodies having immune checkpoint modulation activity,
- substituted pyrimidines having HBV capsid assembly inhibition activity or
having TLR agonist activity,
- antiretroviral nucleoside analogues, and
- the combinations thereof.
In another aspect, provided herein is a method of inhibiting or reducing the
formation or presence of HBV DNA-containing particles or HBV RNA-containing
particles in an individual in need thereof, comprising administering to the
individual a therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
In an embodiment, any of the methods provided herein can further comprise
administering to the individual at least one additional therapeutic agent
selected
from the group consisting of an HBV polymerase inhibitor, immunomodulatory
agents, interferon, viral entry inhibitor, viral maturation inhibitor, capsid
assembly
modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-
agonist, an HBV vaccine, and any combination thereof.
In a still further aspect, a process is provided for producing the compound of
formula I, wherein p is 1, and A is CH, the processing comprising:
reacting an activated acyl compound of formula III-1,
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0
yi y3 OH
Li =
)) y2
0
y)L2
Q
= 4
iii-1
with R3-malonate into an intermediate of formula IV-1,
0 0
R3
yi Y3
)
Li Y2
0
)L Q
= 4 2
Y4
iV-1 =
subjecting the compound of formula IV-1 with compounds of general formula
V and VI, i.e.,
R4
R5
NH
R6
0 H H2N R1
V VI ,
and
to a multiple component reaction in the presence of a base in order to provide
an intermediate of formula VII
R4
R5
0
R6
R3,0
I
Y1 Y3 N R1
) H
Li Y2
0
)L Q
= 4 2
Y4
Vii =
6
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subjecting the intermediate of formula VII to ester hydrolysis in order to
provide a compound of formula I.
Alternatively, another process is provided for producing the compound of
formula I, wherein p is 1, and A is N, and wherein the compound produced is a
compound satisfying formula II, the processing comprising:
reacting an activated acyl compound of formula 111-2,
0
)L0H
Y1 Y3
P Y2
P is protecting group
I I I -2
with R3-malonate into an intermediate of formula IV-2,
0 0
'R3
0
Y1 Y3
)
P Y2
P is protecting group
IV-2
subjecting the compound of formula IV-2 with compounds of general formula
V and VI, i.e.,
R4,
+,,R5
NH
R6
0 H H2N R1
V VI
and
to a multiple component reaction in the presence of a base in order to provide
an intermediate of formula VIII,
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R4
R5
0
R6
R3
I
Yi Y3 N R1
) H
P- Y2 P is protecting group
VIII
subjecting the compound of formula VIII with the deprotection reaction to
provide an intermediate of formula IX,
R4
R5
0
R5
R3
-0
I JL
Yi Y3 N R1
41,v) H
2
IX
subjecting the compound of formula IX with a coupling reaction to provide an
intermediate of formula XI,
R4
R5
0
R
R3 6
Yi Y3 N R1
) H
Y2
0
L
4 2
XI
subjecting the intermediate of formula XI to ester hydrolysis in order to
provide a compound of formula II (here formula II equals formula I).
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R4
R5
0
R
R3 6
I
Yi Y3 N R1
) H
14 Y2
0
HO 2
DETAILED DESCRIPTION
The application provides compounds of formula (I),
R4
R6
0
R6
R3
'0
YI 3 N R1
A, )
L' Y2
0 1 2
,
4 _ 1-2
P
(I)
including the deuterated isomers, stereoisomers and the tautomeric forms
thereof,
wherein
Yi represents a bond or CR7R8;
wherein
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Y2 represents a bond or CR7R8, wherein R7 and R8 are independently selected
from hydrogen and C1-C4 alkyl, and A represents CH or N; or
Y2 is CR9 and A is C thus forming a C=C bond, wherein R9 is hydrogen or C1-C4
alkyl;
wherein Y3 represents CH;
or Y1 and Y2 represent a bond, and a further -CH2- is present directly
connecting A
and Y3 to form a bridged 5-membered cyclic hydrocarbon;
wherein Y4 represents OH, OR14 or R14 wherein R" is C1-C4 alkyl;
wherein Q represents a bond or a 5- to 6- membered aromatic ring,
wherein said 5- to 6- membered aromatic ring optionally comprises 1-3
heteroatoms,
wherein said 5- to 6- membered aromatic ring is optionally substituted with
one or
more substituents each independently selected from the group consisting of
Ci-C4 alkyl,
halogen,
OR13 wherein R13 is H or C1-C4 alkyl,
NR1OR11 where Rth and RH are independently selected from H and C1-C4
alkyl, or Rth and RH form a C4, C5 or C6 membered ring,
CI-GI alkyl substituted with one or more halogen,
CI-GI alkyl substituted with OR12 wherein each R12 is H or CI-GI alkyl;
wherein if Q represents a bond, Y4 is selected from the group consisting of
phenyl,
pyrazolyl,
isoxazolyl,
thiadiazolyl,
phenyl substituted with C1-C4 alkyl,
pyrazolyl substituted with C1-C4 alkyl,
isoxazolyl substituted with Cl-C4 alkyl, and
thiadiazolyl substituted with Cl-C4 alkyl;
wherein Ll is selected from the group consisting of
a bond,
Cl-C4 alkyl, and
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Ci-C4 alkyl substituted with one or more substituents each independently
selected from the group consisting of
Ci-C4 alkyl,
halogen,
oxo,
OR7 wherein R7 independently is hydrogen or Ci-C4 alkyl, and
C1-C4 alkyl substituted with one or more halogen;
wherein L2 is selected from the group consisting of
a bond,
Ci-C4 alkyl, and
a 3-7 membered saturated ring optionally containing one or more
hetereoatom(s), the heteroatom being a nitrogen
wherein each of said Ci-C4 alkyl and said 3-7 membered saturated ring are
optionally substituted with one or more substituents each independently
selected
from the group consisting of
Ci-C4 alkyl,
halogen,
OR15 wherein R15 independently is hydrogen or Ci-C4 alkyl, and
Ci-C4 alkyl substituted with one or more halogen;
wherein p is an integer selected from 0 and 1, more particularly 1;
wherein R1 is selected from the group consisting of thiazolyl, pyridyl,
thiazolyl
substituted with one or more halogen and pyridyl substituted with one or more
halogen;
wherein R3 is Ci-C3 alkyl; and
wherein R4, R5 and R6 each independently are selected from the group
consisting
of hydrogen, Ci-C3 alkyl and halogen;
or a pharmaceutically acceptable salt or a solvate thereof.
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Provided herein are compounds, e.g., the compounds of formula (I), or
pharmaceutically acceptable salts thereof, that are useful in the treatment
and
prevention of HBV infection in subject.
Without being bound to any particular mechanism of action, these compounds
are believed to modulate or disrupt HBV assembly and other HBV core protein
functions necessary for HBV replication or the generation of infectious
particles
and/or may disrupt HBV capsid assembly leading to empty capsids with greatly
reduced infectivity or replication capacity. In other words, the compounds
provided
herein may act as capsid assembly modulators.
The compounds provided herein have potent antiviral activity, exhibit
favorable metabolic properties, tissue distribution, safety and pharmaceutical
profiles, and are suitable for use in humans. Disclosed compounds may modulate
(e.g., accelerate, delay, inhibit, disrupt or reduce) normal viral capsid
assembly or
disassembly, bind capsid or alter metabolism of cellular polyproteins and
precursors.
The modulation may occur when the capsid protein is mature, or during viral
infectivity. Disclosed compounds can be used in methods of modulating the
activity
or properties of HBV cccDNA, or the generation or release of HBV RNA particles
from within an infected cell.
In one embodiment, the compounds described herein are suitable for
monotherapy and are effective against natural or native HBV strains and
against
HBV strains resistant to currently known drugs. In another embodiment, the
compounds described herein are suitable for use in combination therapy.
Definitions
Listed below are definitions of various terms used to describe this invention.
These definitions apply to the terms as they are used throughout this
specification
and claims, unless otherwise limited in specific instances, either
individually or as
part of a larger group.
Unless defined otherwise, all technical and scientific terms used herein
.. generally have the same meaning as commonly understood by one of ordinary
skill
in the art to which this invention belongs. Generally, the nomenclature used
herein
and the laboratory procedures in cell culture, molecular genetics, organic
chemistry,
and peptide chemistry are those well-known and commonly employed in the art.
As used herein, the articles "a" and "an" refer to one or to more than one
(i.e.
to at least one) of the grammatical object of the article. By way of example,
"an
element" means one element or more than one element. Furthermore, use of the
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term "including" as well as other forms, such as "include", "includes," and
"included,"
is not limiting.
As used herein, the term "about" will be understood by persons of ordinary
skill in the art and will vary to some extent on the context in which it is
used. As
used herein when referring to a measurable value such as an amount, a temporal
duration, and the like, the term "about" is meant to encompass variations of
20% or
10%, including 5%, 1%, and 0.1% from the specified value, as such
variations
are appropriate to perform the disclosed methods.
As used herein, the term "capsid assembly modulator" refers to a compound
that disrupts or accelerates or inhibits or hinders or delays or reduces or
modifies
normal capsid assembly (e.g., during maturation) or normal capsid disassembly
(e.g.,
during infectivity) or perturbs capsid stability, thereby inducing aberrant
capsid
morphology and function. In one embodiment, a capsid assembly modulator
accelerates capsid assembly or disassembly, thereby inducing aberrant capsid
morphology. In another embodiment, a capsid assembly modulator interacts (e.g.
binds at an active site, binds at an allosteric site, modifies or hinders
folding and the
like) with the major capsid assembly protein (CA), thereby disrupting capsid
assembly or disassembly. In yet another embodiment, a capsid assembly
modulator
causes a perturbation in structure or function of CA (e.g., ability of CA to
assemble,
disassemble, bind to a substrate, fold into a suitable conformation, or the
like),
which attenuates viral infectivity or is lethal to the virus.
As used herein, the term "treatment" or "treating" is defined as the
application or administration of a therapeutic agent, i.e., a disclosed
compound
(alone or in combination with another pharmaceutical agent), to a patient, or
application or administration of a therapeutic agent to an isolated tissue or
cell line
from a patient (e.g., for diagnosis or ex vivo applications), who has an HBV
infection,
a symptom of HBV infection or the potential to develop an HBV infection, with
the
purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve
or affect
the HBV infection, the symptoms of HBV infection, or the potential to develop
an
.. HBV infection. Such treatments may be specifically tailored or modified,
based on
knowledge obtained from the field of pharmacogenomics.
As used herein, the term "prevent" or "prevention" means no disorder or
disease development if none had occurred, or no further disorder or disease
development if there had already been development of the disorder or disease.
Also
considered is the ability of one to prevent some or all of the symptoms
associated
with the disorder or disease.
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As used herein, the term "patient," "individual" or "subject" refers to a
human
or a non-human mammal. Non-human mammals include, for example, livestock
and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
Preferably, the patient, subject, or individual is human.
As used herein, the terms "effective amount," "pharmaceutically effective
amount," and "therapeutically effective amount" refer to a nontoxic but
sufficient
amount of an agent to provide the desired biological result. That result may
be
reduction or alleviation of the signs, symptoms, or causes of a disease, or
any other
desired alteration of a biological system. An appropriate therapeutic amount
in any
individual case may be determined by one of ordinary skill in the art using
routine
experimentation.
As used herein, the term "pharmaceutically acceptable" refers to a material,
such as a carrier or diluent, which does not abrogate the biological activity
or
properties of the compound, and is relatively non-toxic, i.e., the material
may be
administered to an individual without causing undesirable biological effects
or
interacting in a deleterious manner with any of the components of the
composition
in which it is contained.
As used herein, the term "pharmaceutically acceptable salt" refers to
derivatives of the disclosed compounds wherein the parent compound is modified
by
converting an existing acid or base moiety to its salt form. Examples of
pharmaceutically acceptable salts include, but are not limited to, mineral or
organic
acid salts of basic residues such as amines; alkali or organic salts of acidic
residues
such as carboxylic acids; and the like. The pharmaceutically acceptable salts
of the
present invention include the conventional non-toxic salts of the parent
compound
formed, for example, from non-toxic inorganic or organic acids. The
pharmaceutically acceptable salts of the present invention can be synthesized
from
the parent compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting the free
acid or
base forms of these compounds with a stoichiometric amount of the appropriate
base
or acid in water or in an organic solvent, or in a mixture of the two;
generally, non-
aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
are
preferred. Lists of suitable salts are found in Remington's Pharmaceutical
Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of
Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by
reference in its entirety.
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As used herein, the term "composition" or "pharmaceutical composition"
refers to a mixture of at least one compound useful within the invention with
a
pharmaceutically acceptable carrier. The pharmaceutical composition
facilitates
administration of the compound to a patient or subject. Multiple techniques of
administering a compound exist in the art including, but not limited to,
intravenous,
oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
As used herein, the term "pharmaceutically acceptable carrier" means a
pharmaceutically acceptable material, composition or carrier, such as a liquid
or
solid filler, stabilizer, dispersing agent, suspending agent, diluent,
excipient,
thickening agent, solvent or encapsulating material, involved in carrying or
transporting a compound useful within the invention within or to the patient
such
that it may perform its intended function. Typically, such constructs are
carried or
transported from one organ, or portion of the body, to another organ, or
portion of
the body. Each carrier must be "acceptable" in the sense of being compatible
with
the other ingredients of the formulation, including the compound useful within
the
invention, and not injurious to the patient. Some examples of materials that
may
serve as pharmaceutically acceptable carriers include: sugars, such as
lactose,
glucose and sucrose; starches, such as corn starch and potato starch;
cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and
cellulose
acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter
and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower
oil, sesame
oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol;
polyols, such
as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate
and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and
aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water;
isotonic
saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and
other non-
toxic compatible substances employed in pharmaceutical formulations.
As used herein, "pharmaceutically acceptable carrier" also includes any and
all coatings, antibacterial and antifungal agents, and absorption delaying
agents,
and the like that are compatible with the activity of the compound useful
within the
invention, and are physiologically acceptable to the patient. Supplementary
active
compounds may also be incorporated into the compositions. The
"pharmaceutically
acceptable carrier" may further include a pharmaceutically acceptable salt of
the
compound useful within the invention. Other additional ingredients that may be
included in the pharmaceutical compositions used in the practice of the
invention are
known in the art and described, for example in Remington's Pharmaceutical
Sciences
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(Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated
herein
by reference.
As used herein, the term "alkyl," by itself or as part of another substituent
means, unless otherwise stated, a straight or branched chain hydrocarbon
having the
number of carbon atoms designated (i.e., Ci-C3alkyl means an alkyl having one
to
three carbon atoms, C1-C4alkyl means an alkyl having one to four carbon) and
includes straight and branched chains. Examples include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl. Embodiments of alkyl include, but are
not
limited to, Ci-Cio alkyl, such as C1-C6 alkyl, such as C1-C4 alkyl.
As used herein, the term "halo" or "halogen" alone or as part of another
substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or
iodine
atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or
chlorine.
As used herein, the term "3-7 membered saturated ring" refers to a mono
cyclic non-aromatic saturated radical, wherein each of the atoms forming the
ring
(i.e., skeletal atoms) is a carbon atom, unless such ring contains one or more
heteroatoms if so further defined. 3-7 Membered saturated rings include groups
having 3 to 7 ring atoms. Monocyclic 3-7 membered saturated rings include, but
are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
As used herein, 3-7 membered saturated ring optionally comprising one or
more heteroatoms refers to a heteroalicyclic group containing one or more,
more in
particular, one, two or three, even more in particular, one or two, and most
particular,
one ring heteroatoms each selected from 0, S, and N. In one embodiment, each
heterocyclyl group has from 3 to 7 atoms in its ring system, with the proviso
that the
ring of said group does not contain two adjacent 0 or S atoms. The
heterocyclic
.. system may be attached to the remainder of the molecule, unless otherwise
stated, at
any heteroatom or carbon atom that affords a stable structure.
An example of a 3-membered heterocyclyl group includes, and is not limited to,
aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not
limited to, azetidine and a beta lactam. Examples of 5-membered heterocyclyl
.. groups include, and are not limited to, pyrrolidine, oxazolidine and
thiazolidinedione.
Examples of 6-membered heterocycloalkyl groups include, and are not limited
to,
piperidine, morpholine, and piperazine.
Other non-limiting examples of heterocyclyl groups include monocyclic groups
such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane,
pyrrolidine,
pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, tetrahydrofuran,
thiophane,
piperidine, piperazine, morpholine, thiomorpholine.
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As used herein, the term "aromatic" refers to a carbocycle or heterocycle with
one or more polyunsaturated rings and having aromatic character, i.e., having
(4n +
2) delocalized ri (pi) electrons, where n is an integer.
As used herein, the term "aryl," employed alone or in combination with other
terms, means, unless otherwise stated, a carbocyclic aromatic system
containing one
or more rings (typically one, two, or three rings), wherein such rings may be
attached
together in a pendent manner, such as a biphenyl, or may be fused, such as
naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl.
Preferred examples are phenyl (e.g., C6-aryl) and biphenyl (e.g., C12-aryl).
In some
.. embodiments, aryl groups have from six to sixteen carbon atoms. In some
embodiments, aryl groups have from six to twelve carbon atoms (e.g., C6-C12-
aryl).
In some embodiments, aryl groups have six carbon atoms (e.g., C6-aryl).
As used herein, the term "heteroaryl" or "heteroaromatic" refers to a
heterocycle having aromatic character. Heteroaryl substituents may be defined
by
the number of carbon atoms, e.g., C1-C9-heteroaryl indicates the number of
carbon
atoms contained in the heteroaryl group without including the number of
heteroatoms. For example, a C1-C9-heteroaryl will include an additional one to
four
heteroatoms. A polycydic heteroaryl may include one or more rings that are
partially saturated. Non-limiting examples of heteroaryls include pyridyl,
pyrazinyl,
pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl,
furyl,
pyrrolyl (including, e.g., 2-pyrroly1), imidazolyl, thiazolyl, oxazolyl,
pyrazolyl
(including, e.g., 3- and 5-pyrazoly1), isothiazolyl, 1,2,3 -triazolyl, 1,2,4-
triazolyl,
1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-
thiadiazoly1 and
1,3,4-oxadiazolyl.
Non-limiting examples of polycyclic heterocycles and heteroaryls include
indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indoly1), indolinyl, quinolyl,
tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinoly1),
1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including, e.g., 2-
and
5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-
benzodioxanyl,
co umarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (including, e.g., 3-
, 4-, 5-,
6- and 7-benzofury1), 2,3-dihydrobenzofuryl, 1,2 -benzisoxazolyl, benzothienyl
(including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl,
benzothiazolyl
(including, e.g., 2-benzothiazoly1 and 5-benzothiazoly1), purinyl,
benzimidazolyl
(including, e.g., 2-benzimidazoly1), benzotriazolyl, thioxanthinyl,
carbazolyl,
carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.
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As used herein, the term "substituted" means that an atom or group of atoms
has replaced hydrogen as the substituent attached to another group.
As used herein, the terminology "selected from..." (e.g., "R4 is selected from
A,
B and C") is understood to be equivalent to the terminology "selected from the
group
consisting of..." (e.g., "R4 is selected from the group consisting of A, B and
C").
In an embodiment of the compound of formula (I), Y4 is OH, methoxyl or
ethoxyl.
In an embodiment of the compound of formula (I), R3 is methyl or ethyl.
In an embodiment of the compound of formula (I), R4, R5 and R6 each
independently are chosen from among CH3, F, Cl and Br, more particularly from
F
and Cl.
In an embodiment of the compound of formula (I), Q is selected from the
group consisting of oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyridyl, pyrazolyl, imidazoyl, thiazolyl, thiadiazolyl, and
phenyl.
In an embodiment of the compound of formula (I), Yi, Y2, and Y3 are CH.
In an embodiment of the compound of formula (I), L2 is methylene, ethylene,
isobutylene, or cyclobutylene.
All combinations of the foregoing embodiments are expressly included.
In embodiment, the compound of formula (I) is selected from the compounds
satisfying the following formulae:
0 oa a
so 1 0 1 trans so
1 NN
H 1\11)
0 trans H N\ 1 j
0 0 ter HLi
0 0
Compound 1-1-C Compound 1-2-D 0\
Compound 1-4-B
OH OH OH
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F F
F F
0 0 CI 0
. CI
0 N 0 N
,,,, I so I Ks 0 1 NS ' N
N
el 11 -() go H \ j H-\
0 N 0
5¨IN 5¨IN --IN
0\ Compound I-6-B 0\ Compound I-9-B 0
Compound I-13-C
OH OH OH Compound I-13-D
F F F
F
e
I. F l
0 CI 0 CI 0 Cl
0 N 0 N 0 N
j
_.1
S S S
40 N e le ENi I\
trans H \ _..) H T\ j N =
0 N 0 õ,= N ==
------IN \ N µµ
0 Compound I-14-B OH 0 Compound I-16-B 0 Compound
I-17-A
HO HO
F
el F
el F
0
0 Br 0 = Br CI
0 N 0 N 0 N
I I )s
S S
. N h let N 1,
H 11 j H II) te N--r j
N -
es,, N 0 õ, N =
\ N INsµ
0 Compound I-18-A 0 Compound 1-19-B 0 Compound I-20-B
HO HO HO
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F F F
ill F F F
0 CI CI 0 i CI
0
/c) N 1 0 N 0 1
I
N
S
',,, N,,S S
trans H Tl_.) trans H 1 j (el I j
0 õ,= N 0 N
\ N \ IN \ N
Compound 1-24
o Compound I-23-B Compound I-
25-B
Compound I-24-A
HO 0 0
OH OH
F
F
F F
IIIIF
le F CI
0 CI
0
0 N 1 1\1
S 0 N
01
1 j
trans N \ j ' N S
N N / trans H
trans H TI s , N
N N i H
NO 'N N
jN, _
s".
1\I
N
HO
n HO Compound I-28-B 0 Compound I-32-B Compound I-33-C
OH
F F F
F F
0 *
0 CI 0 0 N
1 Ks
0
II 0 N N
1 I 1 H \\ j
= 's N" S N 1, S\ N,rN N
trans H 1 j H 11_2 1
N, .9---.._,.---- N N,r N N
N
4j 0 1
0 Compound I-38-B HO NCompound II-1-B 0 OH
Compound II-2-B
OH
F
F F
0
0 * 0 *
õ.õ-----,0
N 0
I N
''0 N
N ,
N H N1 j N 1,
H 1' j
N
1 1 0 NyN N
0 NyN
N
HO"N
HO)"N
0 OH
Compound II-3-B Compound II-5-B Compound
II-6-B
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F F
0 CI 0 CI
F
0 CI
0 N 0 N
0 N 1 1
I s
N S S
,, ,,
)
N H ) N 11) H
H \ 1 .._) N,N IN 0 SN N
N,N N
1 I
1 I N HO N
N
Compound II-8-B 0 OH Compound II-9-B Compound
II-1 0-B
0 OH
F F F
0 CI 0 CI 0 CI
0 N
0 N 0 N 1
1 1 N ) S
S
N 1,s N
N 11_)
H N N H
\ \ _.) H N" j NyN N
Ny N
0 Y
I N li 1.1
HON H0 N
0
0 OH Compound II-14-A Compound II-15-A Compound
II-16-B
F F F
0 CI 0 CI 0 CI
IIIIL
0 N 0 N 0 I N
1 1 s
S S
N N
NH) i H 11) H 11)
O N 0 sõN N N,N N
$¨IN )'\----c_li
HO N 1 I
N
HO--t
0 Compound II-18-B Compound II-19-A Compound II-
20-B
0 OH
F F
F
F F
O a
0 a 0 a
0 N
1 s 0 N 0 N
N 1
H li j N S 1 N N
N N N H \ \ _.) (I)
1 Y NN N N H S
N HO 1 1 1 Y
1\1 N
0 OH
Compound II-22-B
ir Compound II-24-B 0 OH
Compound II-27-B
0
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F F F
F F F
O ci 0 a 0 a
N 0 N 0 N
1 1 NIN 1 S N S
1,
N
H \ -) N N H ril 0 H 11 j
N
0 NN N 0
11 HO>\----IN
HO" Compound II-28-B HO Compound II-29-B
Compound II-30-B
F F F
F F F
0 CI L 0 CI 0 CI
0 N 0 N 0 N
1 1 1
S N S S
HO
N N
H I \ ) H 1\ j
0_,N N \ \ j
1\1 N N N N HN
1 ----____II
0 N HO NI I
H
Compound II-41-B Compound 11-50-BO Compound II-
55-B
HO 0
OH
F F F
F F F
0
* CI 0 CI 0 CI
0 1 !\I 0
I N 0 N
I S )i-1 S S
N
11Kr /)
N---, N ,
11_1
Ny N 1\1 N H 1 j N 1\1 N N
1 Y 1 HY
N N N
Compound II-58-B Compound II-59-B
Compound II-60-B
0 OH HO 0 HO 0
F F F
F F F
1 0 * CI 0 CI 0 CI
0 N 0 N 0 N
I N s I Ks I s
N
H 11 j H \ \ j H
N N N N, N N 1\1, N N N
I I I Y 1 Y
Cl N N N
Compound II-61-B
0 OH OOH Compound II-63B HOO Compound II-65-B
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F F
F F F
F
0 CI CI
0 N N
0 N 1 1 jls 0
1 s N ,, N I,
S
N H 11 j H
11 j
H \\ j 1\*N N ON N
1\1N N
r_r_1
0 1 rj
Compound II-66-B Compound II-67-B Compound II-68-
B
0
OH 0 OH OH
F F
F
F F
F
0 . CI 0 CI
0 CI
0 N 0 N
I 1 0 N
S S 1
js
N N
H \\ ) H
, N ON N 11)
1 Ny N HN
0 HOOC N
00H Compound II-69-B OH Compound II-70-B
Compound II-74-B
F F F
F F F
0 Cl 0 CI 0 Br
0 N
1 1 js 1
S S
N N N 1,
H \ ___1 H 11)
1\1,..,N N sN N 0s .,,N N
HO/ \`--N
0 Compound II-78-B HO¨ Compound II-80-B
Compound II-82-B
OH 0
F F
F F
o a o a
0 Br c) N
1 0 N
0 N 1 1 _
S N ,, S
S
NH 11 j N
N 0.õ._
N N N
0 1
N H
\\ ,s
---__
HON ' N o HON
OH 0
Compound II-84-B Compound II-86-B
Compound II-17-B
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The disclosed compounds may possess one or more stereocenters, and each
stereocenter may exist independently in either the R or S configuration. The
stereochemical configuration may be assigned at indicated centers as (*) when
the
absolute stereochemistry is undetermined at the stereocenter although the
compound itself has been isolated as a single stereoisomer and is
enatiomerically/diastereomerically pure. In one embodiment, compounds
described
herein are present in optically active or racemic forms. It is to be
understood that
the compounds described herein encompass racemic, optically-active,
regioisomeric
and stereoisomeric forms, or combinations thereof that possess the
therapeutically
useful properties described herein.
Preparation of optically active forms is achieved in any suitable manner,
including by way of non-limiting example, by resolution of the racemic form
with
recrystallization techniques, synthesis from optically-active starting
materials,
chiral synthesis, or chromatographic separation using a chiral stationary
phase. In
one embodiment, a mixture of one or more isomer is utilized as the disclosed
compound described herein. In another embodiment, compounds described herein
contain one or more chiral centers. These compounds are prepared by any means,
including stereoselective synthesis, enantioselective synthesis or separation
of a
mixture of enantiomers or diastereomers. Resolution of compounds and isomers
thereof is achieved by any means including, by way of non-limiting example,
chemical processes, enzymatic processes, fractional crystallization,
distillation, and
chromatography.
When the absolute R or S stereochemistry of a compound cannot be
determined, it can be identified by the retention time after chromatography
under
particular chromatographic conditions as determined by chromatography column,
eluent etc.
In one embodiment, the disclosed compounds may exist as tautomers. All
tautomers are included within the scope of the compounds presented herein.
Compounds described herein also include isotopically-labeled compounds
wherein one or more atoms is replaced by an atom having the same atomic
number,
but an atomic mass or mass number different from the atomic mass or mass
number
usually found in nature. Examples of isotopes suitable for inclusion in the
compounds described herein include and are not limited to 211, 3H, iic, 13C,
14C, 36C1,
18F, 1231, 1251, 13N, 15N, 150, 170, 180, 32p, and 355. In one embodiment,
isotopically-
labeled compounds are useful in drug or substrate tissue distribution studies.
In
another embodiment, substitution with heavier isotopes such as deuterium
affords
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greater metabolic stability (for example, increased in vivo half-life or
reduced dosage
requirements).
In yet another embodiment, substitution with positron emitting isotopes, such
as 11C, 18F, 150 and 13N, is useful in Positron Emission Topography (PET)
studies for
examining substrate receptor occupancy. Isotopically-labeled compounds are
prepared by any suitable method or by processes using an appropriate
isotopically-
labeled reagent in place of the non-labeled reagent otherwise employed.
In one embodiment, the compounds described herein are labeled by other
means, including, but not limited to, the use of chromophores or fluorescent
moieties,
bioluminescent labels, or chemiluminescent labels.
The compounds described herein, and other related compounds having
different substituents are synthesized using techniques and materials
described
herein and techniques known to a person skilled in the art. General methods
for the
preparation of compound as described herein are modified by the use of
appropriate
reagents and conditions, for the introduction of the various moieties found in
the
formula as provided herein.
Compounds described herein are synthesized using any suitable procedures
starting from compounds that are available from commercial sources, or are
prepared using procedures described herein.General synthesis schemes are given
in
the Examples below.
Accordingly, a process is provided for producing the compound of formula (I),
wherein said process comprises
reacting an activated acyl compound of formula III- 1,
0
yiVy3).LOH
)
Li Y2
0
Q
T 4
Ill-i
,
with R3-malonate into an intermediate of formula IV- 1,
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0 0
1 R3
J_____
,
)(1 ;)' -C)
)
Li Y2
0
Q
)\---L2
Y4
IV-1 =
,
subjecting the compound of formula IV-1 with compounds of general formula
V and VI, i.e.,
R4
R
NH
x
R6 *1
0 H H2N R1
V vi
and ,
5 to a multiple component reaction in the presence of a base in order to
provide
an intermediate of formula VII
R4
R5
0
R6
R3,
0 N
I *
Y 1 Y3 N 1
) H
Li Y2 R
0
Q
T 4 VII =
,
subjecting the intermediate of formula VII to ester hydrolysis in order to
provide a compound of formula I.
In an other embodiment a process is provided for producing the compound of
formula (I), wherein p is 1, and A is N, and wherein the compound produced is
a
compound satisfying formula II, the processing comprising:
reacting an activated acyl compound of formula III-2,
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0
)LoH
Y1 Y3
)
P Y2
P is protecting group
III-2
with R3-malonate into an intermediate of formula IV-2,
)2L)L0 cyR3
7õ
3
ID' 12
P is protecting group
IV-2 =
subjecting the compound of formula IV-2 with compounds of general formula
V and VI, i.e.,
R4,
NH
R6
0 H H2N R1
V VI ,
and
to a multiple component reaction in the presence of a base in order to provide
an intermediate of formula VIII,
R4
R5
0
R5
R3
I
Y1 Y3 N R1
) H
P- Y2 P is protecting group
VIII =
subjecting the compound of formula VIII with the deprotection reaction to
provide an intermediate of formula IX,
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R4
R5
0
R6
R3
'0 N
I *
Yi Y3 N R1
HN,Y2) H
IX =
,
subjecting the compound of formula IX with a coupling reaction to provide an
intermediate of formula XI,
R4
R5
0
R
R3 6
'0 N
I *s,7
Y 1 Y3 N R1
H
14 Y2
0
v 0
L
. 4 2 XI =
,
subjecting the intermediate of formula XI to ester hydrolysis in order to
provide a compound of formula II:
R4
R5
0
R
R3 6
'0 N
I
Yi Y3 N R1
H
l_i Y2
0
HO)LL2 Q
II .
Methods
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Provided herein is a method of treating an HBV infection in an individual in
need thereof, comprising administering to the individual a therapeutically
effective
amount of a disclosed compound.
Also provided herein is a method of eradicating an HBV infection in an
individual in need thereof, comprising administering to the individual a
therapeutically effective amount of a disclosed compound.
Provided herein is a method of reducing viral load associated with an HBV
infection in an individual in need thereof, comprising administering to the
individual a therapeutically effective amount of a disclosed compound.
Further, provided herein is a method of reducing reoccurrence of an HBV
infection in an individual in need thereof, comprising administering to the
individual a therapeutically effective amount of a disclosed compound.
Provided herein is a method of inhibiting or reducing the formation or
presence of HBV DNA-containing particles or HBV RNA-containing particles in an
individual in need thereof, comprising administering to the individual a
therapeutically effective amount of a disclosed compound.
In certain aspects, the methods and/or compositions described herein are
effective for inhibiting or reducing the formation or presence of HBV-
associated
particles in vitro or in vivo (e.g., in a cell, in a tissue, in an organ
(e.g., in the liver),
in an organism or the like). HBV-associated particles may contain HBV DNA
(i.e.,
linear and/or covalently closed circular DNA (cccDNA)) and/or HBV RNA (i.e.,
pre-
genomic RNA and/or sub-genomic RNA). Accordingly, HBV-associated particles
include HBV DNA-containing particles or HBV RNA-containing particles.
As used herein, "HPV-asociated particles" refer to both infectious HBV virions
(i.e., Dane particles) and non-infectious HBV subviral particles (i.e., HBV
filaments
and/or HBV spheres). HBV virions comprise an outer envelope including surface
proteins, a nucleocapsid comprising core proteins, at least one polymerase
protein,
and an HBV genome. HBV filaments and HBV spheres comprise HBV surface
proteins, but lack core proteins, polymerase and an HBV genome. HBV filaments
and HBV spheres are also known collectively as surface antigen (HBsAg)
particles.
HBV spheres comprise middle and small HBV surface proteins. HBV filaments also
include middle, small and large HBV surface proteins.
HBV subviral particles can include the nonparticulate or secretory HBeAg,
which serves as a marker for active replication of HBV.
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Provided herein is a method of reducing an adverse physiological impact of an
HBV infection in an individual in need thereof, comprising administering to
the
individual a therapeutically effective amount of a disclosed compound.
Also provided herein is a method of reducing, slowing, or inhibiting an HBV
infection in an individual in need thereof, comprising administering to the
individual a therapeutically effective amount of a disclosed compound.
Provided herein is a method of inducing reversal of hepatic injury from an
HBV infection in an individual in need thereof, comprising administering to
the
individual a therapeutically effective amount of a disclosed compound.
Provided herein is a method of reducing the physiological impact of long-term
antiviral therapy for HBV infection in an individual in need thereof,
comprising
administering to the individual a therapeutically effective amount of a
disclosed
compound.
Provided herein is a method of prophylactically treating an HBV infection in
an individual in need thereof, wherein the individual is afflicted with a
latent HBV
infection, comprising administering to the individual a therapeutically
effective
amount of a disclosed compound.
In one embodiment, the individual is refractory to other therapeutic classes
of
HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry
inhibitors, viral
maturation inhibitors, literature-described capsid assembly modulators,
antiviral
compounds of distinct or unknown mechanism, and the like, or combinations
thereof). In another embodiment, the disclosed method reduces viral load in an
individual suffering from an HBV infection to a greater extent or at a faster
rate
compared to the extent that other therapeutic classes of HBV drugs reduce
viral
load in the individual.
In one embodiment, the administering of a disclosed compound, or a
pharmaceutically acceptable salt thereof, allows for administering of the at
least one
additional therapeutic agent at a lower dose or frequency as compared to the
administering of the at least one additional therapeutic agent alone that is
required
to achieve similar results in prophylactically treating an HBV infection in an
individual in need thereof.
In one embodiment, the administering of a disclosed compound, or a
pharmaceutically acceptable salt thereof, reduces the viral load in the
individual to
a greater extent or at a faster rate compared to the administering of a
compound
selected from the group consisting of an HBV polymerase inhibitor, interferon,
viral
entry inhibitor, viral maturation inhibitor, distinct capsid assembly
modulator,
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antiviral compounds of distinct or unknown mechanism, and any combination
thereof.
In one embodiment, the disclosed method reduces viral load in an individual
suffering from an HBV infection, thus allowing lower doses or varying regimens
of
combination therapies to be used.
In one embodiment, the disclosed method causes a lower incidence of viral
mutation or viral resistance compared to other classes of HBV drugs, thereby
allowing for long term therapy and minimizing the need for changes in
treatment
regimens.
In one embodiment, the administering of a compound the invention, or a
pharmaceutically acceptable salt thereof, causes a lower incidence of viral
mutation
or viral resistance than the administering of a compound selected from the
group
consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor,
viral
maturation inhibitor, distinct capsid assembly modulator, antiviral compounds
of
distinct or unknown mechanism, and combination thereof.
In one embodiment, the disclosed method increases the seroconversion rate
from HBV infected to non-HBV infected or from detectable HBV viral load to non-
detectable HBV viral load beyond that of current treatment regimens. As used
herein, "seroconversion" refers to the period of time during which HBV
antibodies
develop and become detectable.
In one embodiment, the disclosed method increases or normalizes or restores
normal health, elicits full recovery of normal health, restores life
expectancy, or
resolves the viral infection in the individual in need thereof.
In one embodiment, the disclosed method eliminates or decreases the number
of HBV RNA particles that are released from HBV infected cells thus enhancing,
prolonging, or increasing the therapeutic benefit of the disclosed compounds.
In one embodiment, the disclosed method eradicates HBV from an individual
infected with HBV, thereby obviating the need for long term or life-long
treatment,
or shortening the duration of treatment, or allowing for reduction in dosing
of other
antiviral agents.
In another embodiment, the disclosed method further comprises monitoring
or detecting the HBV viral load of the subject, and wherein the method is
carried out
for a period of time including until such time that the HBV virus is
undetectable.
Accordingly, in one embodiment, provided herein is a method of treating an
HBV infection in an individual in need thereof, comprising administering to
the
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individual a therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
Accordingly, in one embodiment, provided herein is a method of treating an
HBV infection in an individual in need thereof, comprising administering to
the
individual a therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
In another embodiment, provided herein is a method of treating an HBV
infection in an individual in need thereof, comprising administering to the
individual a therapeutically effective amount of a compound of Table 1, or a
pharmaceutically acceptable salt thereof.
In an embodiment of any of the methods provided herein, the method can
further comprise monitoring the HBV viral load of the subject, wherein the
method
is carried out for a period of time such that the HBV virus is undetectable.
Combination Therapies
The disclosed compounds may be useful in combination with one or more
additional compounds useful for treating HBV infection. These additional
compounds may comprise other disclosed compounds and/or compounds known to
treat, prevent, or reduce the symptoms or effects of HBV infection. Such
compounds
include, but are not limited to, HBV polymerase inhibitors, interferons, viral
entry
inhibitors, viral maturation inhibitors, literature-described capsid assembly
modulators, reverse transcriptase inhibitors, immunomodulatory agents, TLR-
agonists, and other agents with distinct or unknown mechanisms that affect the
HBV life cycle or affect the consequences of HBV infection.
In non-limiting examples, the disclosed compounds may be used in
combination with one or more drugs (or a salt thereof) selected from the group
comprising:
HBV reverse transcriptase inhibitors, and DNA and RNA polymerase
inhibitors including, but not limited to, lamivudine (3TC, Zeffix, Heptovir,
Epivir,
and Epivir-HBV), entecavir (Baraclude, Entavir), adefovir dipivoxil (Hepsara,
Preveon, bis-POM PMEA), tenofovir disoproxil fumarate (Viread, TDF or PMPA);
interferons including, but not limited to, interferon alpha (IFN-a),
interferon
beta (IFN-W, interferon lambda (IFN-A), and interferon gamma (IFN-y);
viral entry inhibitors;
viral maturation inhibitors;
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literature-described capsid assembly modulators, such as, but not limited to,
BAY 41-4109;
reverse transcriptase inhibitors;
immunomodulatory agents such as TLR-agonists; and
agents of distinct or unknown mechanisms, such as but not limited to
AT-61 ((E) -N- (1- chloro- 3 - oxo- 1-phenyl- 3- (pip eridin- 1-yl)prop - 1-en-
2 -yl)benzamide),
AT-130 ((E)-N-(1-bromo-1-(2-methoxypheny1)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-
y1)-
4-nitrobenzamide), and similar analogs.
In one embodiment, the additional therapeutic agent is an interferon.
The term "interferon" or "IFN" refers to any member of the famly of highly
homologous species-specific proteins that inhibit viral replication and
cellular
proliferation and modulate immune response. Human interferons are grouped into
three classes: Type I, which includes interferon-alpha (IFN-a), interferon-
beta (IFN-
6), and interferon-omega (IFN-co), Type II, which includes interferon-gamma
(IFN-y),
and Type III, which includes interferon-lambda (IFN-A). Recombinant forms of
interferons that have been developed and are commercially available are
encompassed by the term "interferon" as used herein. Subtypes of interferons,
such
as chemically modified or mutated interferons, are also encompassed by the
term
"interferon" as used herein. Chemically modified interferons may include
pegylated
interferons and glycosylated interferons. Examples of interferons also
include, but
are not limited to, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-
n 1,
interferon-beta- la, interferon-beta- lb, interferon-lamda-1, interferon-lamda-
2, and
interferon-lamda-3. Examples of pegylated interferons include pegylated
interferon-
alpha-2a and pegylated interferon alpha-2b.
Accordingly, in one embodiment, the compounds of Formula I can be
administered in combination with an interferon selected from the group
consisting
of interferon alpha (IFN-a), interferon beta (IFN-6), interferon lambda (IFN-
A), and
interferon gamma (IFN-y). In one specific embodiment, the interferon is
interferon-
alpha-2a, interferon-alpha-2b, or interferon-alpha-nl. In another specific
embodiment, the interferon-alpha-2a or interferon-alpha-2b is pegylated. In a
preferred embodiment, the interferon-alpha-2a is pegylated interferon-alpha-2a
(PE GASYS).
In another embodiment, the additional therapeutic agent is selected from
immune modulator or immune stimulator therapies, which includes biological
.. agents belonging to the interferon class.
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Further, the additional therapeutic agent may be an agent of distinct or
unknown mechanism including agents that disrupt the function of other
essential
viral protein(s) or host proteins required for HBV replication or persistence.
In another embodiment, the additional therapeutic agent is an antiviral agent
that blocks viral entry or maturation or targets the HBV polymerase such as
nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors. In a
further
embodiment of the combination therapy, the reverse transcriptase inhibitor or
DNA
or RNA polymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA,
Stavudine,
Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine,
ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir,
Tenofovir,
Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.
In an embodiment, the additional therapeutic agent is an immunomodulatory
agent that induces a natural, limited immune response leading to induction of
immune responses against unrelated viruses. In other words, the
immunomodulatory agent can effect maturation of antigen presenting cells,
proliferation of T-cells and cytokine release (e.g., IL-12, IL-18, IFN-alpha, -
beta, and
-gamma and TNF-alpha among others),
In a further embodiment, the additional therapeutic agent is a TLR
modulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist. In
further
embodiment of the combination therapy, the TLR-7 agonist is selected from the
group consisting of SM360320 (9-benzy1-8-hydroxy-2-(2-methoxy-ethoxy)adenine)
and AZD 8848 (methyl [3-(1[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-911-purin-9-
yl)propyl][3-(4-morpholinyl)propyllaminolmethyl)phenyli acetate).
In any of the methods provided herein, the method may further comprise
administering to the individual at least one HBV vaccine, a nucleoside HBV
inhibitor, an interferon or any combination thereof. In an embodiment, the HBV
vaccine is at least one of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-
B, or SHANVAC B.
In one embodiment, the methods described herein further comprise
administering at least one additional therapeutic agent selected from the
group
consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion
inhibitors, and
any combination of these or other antiviral mechanisms.
In another aspect, provided herein is method of treating an HBV infection in
an individual in need thereof, comprising reducing the HBV viral load by
administering to the individual a therapeutically effective amount of a
disclosed
compound alone or in combination with a reverse transcriptase inhibitor; and
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further administering to the individual a therapeutically effective amount of
HBV
vaccine. The reverse transcriptase inhibitor may be at least one of
Zidovudine,
Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine,
Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,
valacyclovir,
ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz,
Nevirapine, Delavirdine, or Etravirine.
In another aspect, provided herein is a method of treating an HBV infection
in an individual in need thereof, comprising reducing the HBV viral load by
administering to the individual a therapeutically effective amount of a
disclosed
compound alone or in combination with a antisense oligonucleotide or RNA
interference agent that targets HBV nucleic acids; and further administering
to the
individual a therapeutically effective amount of HBV vaccine. The antisense
oligonucleotide or RNA interference agent possesses sufficient complementarity
to
the the target HBV nucleic acids to inhibit replication of the viral genome,
transcription of viral RNAs, or translation of viral proteins.
In another embodiment, the disclosed compound and the at least one
additional therapeutic agent are co-formulated. In yet another embodiment, the
disclosed compound and the at least one additional therapeutic agent are co-
administered.
For any combination therapy described herein, synergistic effect may be
calculated, for example, using suitable methods such as the Sigmoid-E.
equation
(Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of
Loewe
additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-
326)
and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:
27-
55). Each equation referred to above may be applied to experimental data to
generate a corresponding graph to aid in assessing the effects of the drug
combination. The corresponding graphs associated with the equations referred
to
above are the concentration-effect curve, isobologram curve and combination
index
curve, respectively.
In an embodiment of any of the methods of administering combination
therapies provided herein, the method can further comprise monitoring or
detecting
the HBV viral load of the subject, wherein the method is carried out for a
period of
time including until such time that the HBV virus is undetectable.
Administration/Dosage/Formulations
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In another aspect, provided herein is a pharmaceutical composition
comprising at least one disclosed compound, or a pharmaceutically acceptable
salt
thereof, together with a pharmaceutically acceptable carrier.
Actual dosage levels of the active ingredients in the pharmaceutical
compositions of this invention may be varied so as to obtain an amount of the
active
ingredient that is effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration, without being
toxic to
the patient.
In particular, the selected dosage level will depend upon a variety of factors
.. including the activity of the particular compound employed, the time of
administration, the rate of excretion of the compound, the duration of the
treatment,
other drugs, compounds or materials used in combination with the compound, the
age, sex, weight, condition, general health and prior medical history of the
patient
being treated, and like factors well, known in the medical arts.
A medical doctor, e.g., physician or veterinarian, having ordinary skill in
the
art may readily determine and prescribe the effective amount of the
pharmaceutical
composition required. For example, the physician or veterinarian could begin
administration of the pharmaceutical composition to dose the disclosed
compound at
levels lower than that required in order to achieve the desired therapeutic
effect and
.. gradually increase the dosage until the desired effect is achieved.
In particular embodiments, it is especially advantageous to formulate the
compound in dosage unit form for ease of administration and uniformity of
dosage.
Dosage unit form as used herein refers to physically discrete units suited as
unitary
dosages for the patients to be treated; each unit containing a predetermined
.. quantity of the disclosed compound calculated to produce the desired
therapeutic
effect in association with the required pharmaceutical vehicle. The dosage
unit
forms of the invention are dictated by and directly dependent on (a) the
unique
characteristics of the disclosed compound and the particular therapeutic
effect to be
achieved, and (b) the limitations inherent in the art of
compounding/formulating
such a disclosed compound for the treatment of HBV infection in a patient.
In one embodiment, the compositions of the invention are formulated using
one or more pharmaceutically acceptable excipients or carriers. In one
embodiment,
the pharmaceutical compositions of the invention comprise a therapeutically
effective amount of a disclosed compound and a pharmaceutically acceptable
carrier.
In some embodiments, the dose of a disclosed compound is from about 1 mg to
about 2,500 mg. In some embodiments, a dose of a disclosed compound used in
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compositions described herein is less than about 10,000 mg, or less than about
8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less
than
about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or
less
than about 500 mg, or less than about 200 mg, or less than about 50 mg.
Similarly,
in some embodiments, a dose of a second compound (i.e., another drug for HBV
treatment) as described herein is less than about 1,000 mg, or less than about
800
mg, or less than about 600 mg, or less than about 500 mg, or less than about
400 mg,
or less than about 300 mg, or less than about 200 mg, or less than about 100
mg, or
less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or
less
than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less
than
about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than
about 1
mg, or less than about 0.5 mg, and any and all whole or partial increments
thereof.
In one embodiment, the present invention is directed to a packaged
pharmaceutical composition comprising a container holding a therapeutically
effective amount of a disclosed compound, alone or in combination with a
second
pharmaceutical agent; and instructions for using the compound to treat,
prevent, or
reduce one or more symptoms of HBV infection in a patient.
Routes of administration of any of the compositions of the invention include
oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
The
compounds for use in the invention may be formulated for administration by any
suitable route, such as for oral or parenteral, for example, transdermal,
transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral,
vaginal (e.g.,
trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical,
intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous,
intramuscular, intradermal, intra-arterial, intravenous, intrabronchial,
inhalation,
and topical administration.
Suitable compositions and dosage forms include, for example, tablets,
capsules, caplets, pills, gel caps, troches, dispersions, suspensions,
solutions, syrups,
granules, beads, transdermal patches, gels, powders, pellets, magmas,
lozenges,
creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for
nasal or oral
administration, dry powder or aerosolized formulations for inhalation,
compositions
and formulations for intravesical administration and the like. It should be
understood that the formulations and compositions that would be useful in the
present invention are not limited to the particular formulations and
compositions
that are described herein.
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For oral application, particularly suitable are tablets, dragees, liquids,
drops,
suppositories, or capsules, caplets and gelcaps. The compositions intended for
oral
use may be prepared according to any method known in the art and such
compositions may contain one or more agents selected from the group consisting
of
inert, non-toxic pharmaceutically excipients that are suitable for the
manufacture of
tablets. Such excipients include, for example an inert diluent such as
lactose;
granulating and disintegrating agents such as cornstarch; binding agents such
as
starch; and lubricating agents such as magnesium stearate. The tablets may be
uncoated or they may be coated by known techniques for elegance or to delay
the
release of the active ingredients. Formulations for oral use may also be
presented as
hard gelatin capsules wherein the active ingredient is mixed with an inert
diluent.
For parenteral administration, the disclosed compounds may be formulated
for injection or infusion, for example, intravenous, intramuscular or
subcutaneous
injection or infusion, or for administration in a bolus dose or continuous
infusion.
Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally
containing other formulatory agents such as suspending, stabilizing or
dispersing
agents may be used.
Those skilled in the art will recognize, or be able to ascertain using no more
than routine experimentation, numerous equivalents to the specific procedures,
embodiments, claims, and examples described herein. Such equivalents were
considered to be within the scope of this invention and covered by the claims
appended hereto. For example, it should be understood, that modifications in
reaction conditions, including but not limited to reaction times, reaction
size/volume,
and experimental reagents, such as solvents, catalysts, pressures, atmospheric
conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-
recognized alternatives and using no more than routine experimentation, are
within
the scope of the present application.
It is to be understood that wherever values and ranges are provided herein,
all values and ranges encompassed by these values and ranges, are meant to be
encompassed within the scope of the present invention. Moreover, all values
that
fall within these ranges, as well as the upper or lower limits of a range of
values, are
also contemplated by the present application.
The following examples further illustrate aspects of the present invention.
However, they are in no way a limitation of the teachings or disclosure of the
present invention as set forth herein.
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EXAMPLES
EXAMPLE 1:
General Scheme 1
R4
O 0 0
R3 R5
NH
v1 y3 )'LOH ,,,----,
Y 1 , 3 0 )-)-L '
1
Rb *
1 ) 1 ) 0 H H2N R1
-1 Y2 ¨1 Y2 V VI
Method A 24---L Method B
Y4 2 Y4 2
III-1 IV-1
R4 R4
R5 R5
0 0
R6 R6
R3, R3,
0 N 0 N
I * I *
-------- --------
Yi Y3 N RI Yi Y3 N R1
) H _______________________________ ).- ) H
Li Y2 Method C Li Y2
0 0 0 0
)\--L 4 Ho )\--L2
Y2
VII I
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General Scheme 2
R4
R5
o )CUtto, R3 NH
*
7)OH ------, 0 1:11 6 H2N Ri
,
Yi . 3 Yi Y3 V VI
IV, ) ________ y IV,v)
P- Y2 Method A P- ' 2 Method B
P is protecting group P is protecting group
III-2 IV-2
Li x
C\)\ do
R4 R4 /'---- L2
Y4
R5 R5
0 R3 R3 0 __ X = OH or halides
R6 R6
X
I * I * ,,,------- Method D s,..-----,
Y 1 Y3 N R1 Y 1 Y3 N R1 Method E
H 141, ) H
P Y2 Y2
P is protecting group
VIII IX
R4 R4
R5 R
0 0
R6 R6
R3
'o N R3,0 N
I * I *
------, -----,
Y1 Y3 N RI Y1 Y3 N R
11, ) 14 Y H ____________ w- 11, ) H
0 Y
Method C 0\ 2
0
14 )\_...L 2 0
7-- L2
Y4 2 HO
XI II
The general synthesis of final compound of general formula I is described in
general
scheme 1. Compound of general formula IV-1 can be synthesized with Method A.
As
described in Method A, an acid of general formula III-1 is activated, e.g.
into an acyl
imidazole, and coupled with methyl (or ethyl) potassium malonate under basic
condition to generate an intermediate which in turn undergoes decarboxylation
to
yield the ketoester of general formula IV-1. The compound of general formula
VII
can be synthesized through a chemical methodology of multiple component
reaction
(Method B) with compounds of general formula IV-1, V and VI in the presence of
base (but not limited to sodium acetate Na0Ac) in solvent of choice (but not
limited
to ethanol). The final product of general formula I can be synthesized through
an
ester hydrolysis reaction (Method C).
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The general synthesis of final compound of general formula II is described in
general
scheme 2. Compound of general formula IV-2 can be synthesized with Method A.
As
described in Method A, an acid of general formula 111-2 is converted by
reacting with
N,N-carbonyldiimidazole CDI to an activated ester which then couples with
methyl
(or ethyl) potassium malonate under basic condition to generate an
intermediate
which in turn undergoes decarboxylation to yield the ketoester of general
formula
IV-2. The compound of general formula VIII can be synthesized through a
chemical
methodology of multiple component reaction (Method B) with compounds of
general
formula IV-2, V and VI in the presence of base (but not limited to sodium
acetate
Na0Ac) in solvent of choice (but not limited to ethanol). The free amine of
general
formula IX can be synthesized by a deprotection reaction (Method D). Compound
of
general formula II can be synthesized from general formula IX and general
formula
X, through SNAr reaction (Method E), and then followed by an ester hydrolysis
reaction (Method C). Some of final compounds of general formula II were
synthesized through forming the ketoester intermediates and then multiple
component reaction procedure.
Method A
0 0
yi y3 OH
3
) )
L Y2 L Y
001 ____________________________________________ > 0012
)L-2 1L Method A ,)LL2
14 4
Ill-1 1V-1
0 }00 0,R3
Yl Yi 3 Yl Y3
N,
ID' Y2 Method A P- 2
111-2 1V-2
To a solution of the acid of general formula III-1 or 111-2 (1 equivalent) in
acetonitrile was added N,N'-carbonyldiimidazole (1.1-2 equivalents) at room
temperature. The mixture was stirred at room temperature under nitrogen
atmosphere for 2 hours (mixture A). To a suspension of methyl potassium
malonate
(2-2.1 equivalents, R3 is methyl) or ethyl potassium malonate (2-2.1
equivalents, R3
is ethyl) in acetonitrile was added magnesium chloride (2.1-2.5 equivalents)
and
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triethylamine (3-3.2 equivalents) at room temperature. After stirred under
nitrogen
atmosphere for 2 hours, the resulting mixture was added mixture A and stirring
continued at 80 - 100 C in a range of three hours to overnight. It was then
cooled
down to room temperature and concentrated to give a residue, which was
purified by
silica gel column chromatography to afford the ketoester of general formula IV-
1 or
IV-2.
Method B
R4
R4 R5
0 0 0
,R3 R5 R6
NH R3
0
T I 3
-1 Y
R6
) 0 H H2N RI Y1 Y3
N R1
I
2
0)\___ 0
) H
L2 Method B L1 Y2
Y4 L
Y4 2
IV-1 VII
R4 R4
R5 R5
0 0 NH
0' R3
R6 I I
0
R6
0 H H2N R1
) V VI I
P- Y2 Y 1 Y3 N R1
Method B H
P is protecting group
P- Y2 P is
protecting group
IV-2 VIII
To a solution of the ketoester of general formula IV-1 or IV-2 (1 equivalent)
in
ethanol was added the aldehyde of general formula V (1 equivalent), the
carboxamidine hydrochloride of general formula VI (1 equivalent) and sodium
acetate (1 ¨ 1.2 equivalents). The mixture was brought up to 70 ¨ 100 C and
stirred
under nitrogen atmosphere from sixteen hours to overnight. After cooled down
to
room temperature, it was concentrated to dryness. The residue was extracted
from
dichloromethane, washed with water, brine, dried over anhydrous Na2SO4 and
filtered. The filtrate was concentrated under reduced pressure to give a
residue,
which was purified by silica gel column chromatography to afford the
.. dihydropyrimidine product of general formula VII, or general formula VIII.
When
applicable, the stereoisomers of the dihydropyrimidine product of general
formula
VII or general formula VIII were isolated and purified using chiral
chromatography.
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Method C
R4 R4
R5 R5
0 0
R6 R6
R3 R3
I I
Yi Y3 N R1 Yi Y3 N RI
) H ) H
0
L1 Y2 Method C 0 Li Y2
Oh Oh
L2 W.
H0)\ -- 1_2 WV
Y4
VII
R4 R4
R5 R5
0 0
R6 R3 R3 R6
I I
Yi Y3 N R1 Yi Y3 N R1
) H
N. __________________________________ > ) H
N.
1_<1 Y2 14 Y2
0 AN Method C 0 AN
L2 L W.
H0)\ 2 Wir
Y4 XIII
To a solution of the ester of general formula VII (1 equivalent), or formula
XE (1
equivalent), in the solvents of tetrahydrofuran : methanol : water 2:2:1 was
added
lithium hydroxide hydrate (2 equivalent) at 0 C. After stirred at 0 C for 2
hours,
the mixture was added with water, and concentrated at room temperature under
reduced pressure to remove volatiles. The residue was acidified with 1 M
hydrochloride aqueous solution and purified by silica gel column
chromatography to
afford the final compound of general formula I, or II, respectively. When
applicable,
the stereoisomers of the dihydropyrimidine product of general formula I and II
were
isolated and purified using chiral chromatography.
Method D
To a solution of general formula VIII (1 equivalent) in dichloromethane was
added
trifluoroacetic acid (80 equivalent) at room temperature. After stirred at
room
temperature for 0.5 hour, the mixture was concentrated under reduced pressure
to
give a residue, which was dissolved in ethyl acetate and washed with saturated
sodium bicarbonate aqueous solution for three times, water for three times,
and
brine for three times, dried over Na2SO4(s) and filtered. The filtrate was
concentrated
under reduced pressure to give the final compound of general formula IX.
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Method E
To a solution of general formula IX (1 equivalent) and general formula X (1
equivalent) in solvent (such as 1,4-dioxane, DMF) was added base (such as
triethylamine, N,N-Diisopropylethylamine, or potassium carbonate, 5
equivalent) at
room temperature. After stirred at 100 C under nitrogen atmosphere for 5
hours
and cooled down to room temperature, the mixture was diluted with water and
extracted with ethyl acetate twice. The combined organic layers were washed
with
brine, dried over Na2SO4(s) and filtered. The filtrate was concentrated under
reduced
pressure to give a residue, which was purified by C18 column to give the
product of
.. general formula XL When applicable, the stereoisomers of the
dihydropyrimidine
products of general formula XI were isolated and purified using chiral
chromatography.
Part I: Preparation of Acids of general formula Ill-1 and 111-2
Acid 1: 4(4-(methoxycarbonyl)oxazol-2-yl)cydohexane- 1-carboxylic acid (Al)
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Ph
Ph-P-Ph
+1
o
0 0 Cl-
BnBr (1.2 eq)
(1'6 eq)
A1-3 K2CO3 (2.0 eq) 6N HCI (3.0 eq)
DMF, r.t., 2 d. t-BuOK (1.6 eq), THF THF, 0 C-25 C, 2 h
CO2H CO2Bn
CO2Bn
A1-1 A1-2 A1-4
Bn0 0
0
C)
NH2HCI (1 '1 eq)
A1-6 K2CO3 (1.2 eq), NBS (1.2 eq)
_______________________________ P" 0 N
DABCO (3.0 eq), NCS (1.1 eq) \
CO2Bn DCM, 0-20 C, 2 h 0 DCE, reflux, 0.5 h
A1-5 ¨0
A1-7
Bn0 0 HO 0
Pd/C, H2 balloon
0 N N
rt 16 h 0 N
0 0
¨0
A1-8 Al
Intermediate A1-2:
Benzyl 4-oxocydohexanecarboxylate
To a solution of 4-oxocyclohexanecarboxylic acid A1-1 (20.0 g, 0.141 mol),
potassium
carbonate (38.9 g, 0.282 mol) in N,N-dimethylformamide (100 mL) was added
(bromomethyl)benzene (28.8 g, 0.169 mol). The mixture was stirred at room
temperature for 2 days. The reaction mixture was poured into water (450 mL),
extracted with ethyl acetate (200 mL) for three times. The combined organic
layers
were washed with water (100 mL), brine (100 mL), dried over Na2SO4(s),
filtered and
concentrated to give the crude product, which was purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 10 1 to 5 1) to give the title
compound (30.0 g, 92 % yield) as yellow oil. 111 NMR (300 MHz, DMSO-d6) 6 7.37
-
7.26 (m, 511), 5.12 - 5.05 (m, 211), 2.91 - 2.79 (m, 111), 2.41 - 2.31 (m,
211), 2.23 - 2.08
(m, 411), 1.87 - 1.72 (m, 211).
Intermediate A1-4:
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Benzyl 4-(methoxymethylene)cyclohexanecarboxylate
To a mixture of (methoxymethyl)triphenylphosphonium chloride A1-3 (54.8 g,
0.160
mol) in tetrahydrofuran (350 mL) was added potassium tert-butoxide (17.9 g,
0.160
mol) at 0 C slowly to keep inner temperature below 5 C. After stirring at
this
temperature for 1 hour, a solution of benzyl 4-oxocyclohexanecarboxylate A1-2
(23.7
g, 0.100 mol) in tetrahydrofuran (50 mL) was added into the mixture. The
mixture
was warmed up to 25 C slowly and stirred at 25 C for 16 hours. The reaction
mixture was diluted with water (500 mL). The organic phase was separated. The
aqueous layer was extracted with ethyl acetate (100 mL) for three times. The
combined organic layers were washed with brine (100 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated to give a residue, which was purified
by silica
gel column chromatography (petroleum ether: ethyl acetate = 200 : 1 to 50 :1)
to
give the title compound (19.1 g, 72 % yield) as colorless oil. 111 NMR (300
MHz,
CDC13) 67.38 - 7.29 (m, 511), 5.77 (s, 111), 5.11 (s, 211), 3.53 (s, 311),
2.76 - 2.71 (m,
111), 2.51 - 2.43 (m, 111), 2.13 - 2.08 (m, 111), 2.01 - 1.87 (m, 311), 1.79 -
1.71 (m, 111),
1.56 - 1.45 (m, 211).
Intermediate A1-5:
Benzyl 4-formylcyclohexanecarboxylate
To a mixture of benzyl 4-(methoxymethylene)cyclohexane-1-carboxylate A1-4
(19.1 g,
73.5 mmol) in tetrahydrofuran (160 mL) was added 6 M hydrochloride aqueous
solution (38.2 mL, 229 mmol) at 0 C. After stirred at 25 C for 2 hours, the
reaction
mixture was quenched with brine (300 mL). The organic layer was separated out.
The aqueous layer was extracted with ethyl acetate (200 mL) for three times.
The
combined organic layers were washed with brine (200 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated to give the title compound (17.6 g, 98
% yield)
as yellow oil. 1H NMR (400 MHz, CDC13) 6 9.65 (s, 0.411), 9.63 (s, 0.611),
7.37 - 7.31
(m, 511), 5.12 (s, 1.211), 5.11 (s, 0.811), 2.51 - 2.48 (m, 0.311), 2.35 -
2.22 (m, 1.511),
2.15 - 2.04 (m, 2.711), 1.99 - 1.93 (m, 0.511), 1.79 - 1.75 (m, 111), 1.71 -
1.66 (m, 111),
1.56 - 1.47 (m, 1.511), 1.34 - 1.26 (m, 1.511).
Intermediate A1-7:
Methyl 2-(4-((benzyloxy)carbonyl)cydohexyl)-2,5-dihydrooxazole-4-carboxylate
To a mixture of (R)-methyl 2-amino-3-hydroxypropanoate hydrochloride A1-6
(12.2 g,
78.7 mmol) in dichloromethane (350 mL) was added 1,4-diazabicyclo[2.2.2ioctane
(24.1 g, 215 mmol). After stirring at 25 0C under nitrogen atmosphere for 20
minutes,
the mixture was added a solution of benzyl 4-formylcyclohexanecarboxylate A1-5
(17.6 g, 71.5 mmol) in dichloromethane (350 mL). The mixture was stirred at 25
C
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under nitrogen atmosphere for 30 minutes. To the mixture was added N
chlorosuccinimide (10.5 g, 78.7 mmol) at 0 C and the resulting mixture was
stirred
at 0 C for 2 hours. The reaction mixture was quenched with saturate sodium
metabisulfite aqueous solution (300 mL). The organic phase was separated. The
aqueous layer was extracted with dichloromethane (100 mL) for three times. The
combined organic layers were washed with brine (100 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated to give a residue, which was purified
by silica
gel column chromatography (petroleum ether ethyl acetate = 20 1 to 5 1) to
give
the title compound (18.4 g, 74 % yield) as colorless oil. 111 NMR (400 MHz,
CDC13) 6
7.38 - 7.30 (m, 511), 5.72 - 5.67 (m, 111), 5.14- 5.11 (m, 211), 4.86 - 4.71
(m, 211), 3.92
(s, 311), 2.68 - 2.66 (m, 0.211), 2.35 - 2.31 (m, 0.811), 2.28 - 2.19 (m,
0.611), 2.16 - 2.06
(m, 1.611), 1.94- 1.91 (m, 0.811), 1.84- 1.69 (m, 211), 1.62 - 1.40 (m, 311),
1.26 - 1.17
(m, 111).
Intermediate A1-8:
Methyl 2-4-((benzyloxy)carbonyl)cydohexyl)oxazole-4-carboxylate
A mixture of methyl 2-(4-((benzyloxy)carbonyl)cyclohexyl)-2,5-dihydrooxazole-4-
carboxylate A1-7 (5.00 g, 14.5 mmol), potassium carbonate (2.30 g, 17.4 mmol)
in
1,2-dichloroethane (150 mL) was stirred at 25 C under nitrogen atmosphere for
30
minutes. /V-Bromosuccinimide (3.13 g, 17.4 mmol) was added into the mixture.
After
refluxing for 30 minutes, the reaction mixture was cooled down to room
temperature,
quenched with saturate sodium sulfite aqueous solution (50 mL), saturate
sodium
bicarbonate aqueous solution (50 mL) and separated. The aqueous layer was
extracted with ethyl acetate (50 mL) for three times. The combined organic
layers
were washed with brine (50 mL), dried over Na2SO4(s) and filtered. The
filtrate was
concentrated to give a residue, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 10 1 to 3 2) to give the title
compound (3.30 g, 66 % yield) as white solids. LC-MS (ESI): RT = 1.823 min,
mass
calcd. for C191121N05 343.1, m/z found 344.1 [M+11] . 1H NMR (400 MHz, CDC13)
6
8.15 (s, 111), 7.39 - 7.31 (m, 511), 5.13 (s, 211), 3.90 (s, 311), 3.03 - 2.97
(m, 0.211), 2.87 -
2.79 (m, 0.811), 2.64 - 2.58 (m, 0.211), 2.45 - 2.37 (m, 0.811), 2.23 - 2.14
(m, 411), 1.98 -
1.85 (m, 111), 1.75 - 1.69 (m, 111), 1.63 - 1.52 (m, 211).
Acid 1:
444-(4ethoxycarbonyl)oxazol-2-yl)cydohexanecarboxylic acid
To a mixture of methyl 2-(4-((benzyloxy)carbonyl)cyclohexyl)oxazole-4-
carboxylate
A1-8 (3.30 g, 9.60 mmol) in ethyl acetate (60 mL) was added 10 % palladium on
charcoal wt.(660 mg) under nitrogen atmosphere. The mixture was stirred at
room
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temperature under hydrogen atmosphere (112 balloon) for 16 hours. The reaction
mixture was filtered and the filtrate was concentrated to give the title
compound
(1.30 g, 54% yield) as red solids. 11-1 NMR (400 MHz, CDC13) 6 8.16 (s, 111),
3.91 (s,
311), 3.05 - 2.97 (m, 0.411), 2.88 - 2.79 (m, 0.611), 2.67 - 2.59 (m, 0.411),
2.43 - 2.33 (m,
0.611), 2.24- 2.16 (m, 211), 2.10 - 2.02 (m, 211), 1.95 - 1.87 (m, 111), 1.76 -
1.50 (m, 311).
Acid 2: 3-(4-(methoxycarbonyl)oxazol-2-yl)bicydo[1.1.1]pentane-1-carboxylic
acid (A2)
0 DMAP (1.1 eq.),
0< 0
0 OH
Boc20 (2.0 eq.) LiOH
v.-
0 THF/H20
t-BuOH, 50 C, 20 h
0
0 0
0
A2-1 A2-2 A2-3
0
0
B2H6 (1.6 eq), THF OH
DMSO (2.4 eq.), Et3N x0y1I)H
0 (5.0 eq.),-78 oC to -60 oC
1.5h 0
A2-4 A2-5
0 0 0
K2
NH2 HCI CO3 (1.2 eq),
A1-6 (1.1 eq. i NBS (1.2 eq),
DABCO (3.0 eq.),NCS 0 DCE, reflux, 0.5 h 0
(1.1 eq.), DCM, 0 C for 0 0
1h, 20 C for 2h A2-6 / A2
Intermediate A2-2:
1-(tert-butyl) 3-methyl bicydo[1.1.1]pentane-1,3-dicarboxylate
To a solution of 3-(methoxycarbonyObicyclo[1.1.1ipentane-1-carboxylic acid A2-
1
(1.94 g, 11.2 mmol,) and di- tert-butyl dicarbonate (4.98 g, 22.8 mmol,) in
tert-butanol
(32 mL) was added N,N-dimethylpyridin-4-amine (1.53 g, 12.5 mmol) at room
temperature. After stirred at 50 C for 20 hours, the reaction mixture was
concentrated under reduced pressure to remove the volatile and dissolved in
ethyl
acetate (100 mL). The resulting solution was washed with water (50 mL), 0.2 M
hydrochloride aqueous solution (70 mL), saturated sodium bicarbonate aqueous
solution (60 mL), water (50 mL) and brine (50 mL), dried over Na2SO4(s) and
filtered.
The filtrate was concentrated under reduced pressure to give the title
compound
(2.55 g, 90 % purity from 11-1 NMR, 91 % yield) as white solids. 11-1 NMR (400
MHz,
CDC13) 6 3.67 (s, 311), 2.45 (s, 611), 1.43 (s, 911).
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Intermediate A2-3:
3-(tert-Butoxycarbonyl)bicydo[ 1. 1.1]pentane- 1-carboxylic acid
To a solution of 1- tert-butyl 3-methyl bicyclo[1.1.1ipentane-1,3-
dicarboxylate A2-2
(2.55 g, 90 % purity, 10.1 mmol) in tetrahydrofuran (30 mL) and water (10 mL)
was
added lithium hydroxide monohydrate (651 mg, 15.5 mmol) at 0 C. After stirred
at
0 C for 2.5 hours, the reaction mixture was concentrated under reduced
pressure to
give a residue, which was diluted with water (10 mL) and extracted with ethyl
acetate (20 mL). Then the aqueous was acidified to pH 3 - 4 with 0.2 M
hydrochloride aqueous solution and extracted with ethyl acetate (40 mL) for
three
times. The combined organic layers were washed with brine (40 mL), dried over
Na2SO4(s) and filtered. The filtrate was concentrated under reduced pressure
to give
the title compound (2.10 g, 90 % purity from 111 NMR, 88 % yield) as white
solids. 111
NMR (300 MHz, DMSO-d6) 6 12.53 (br s, 111), 2.13 (s, 611), 1.39 (s, 911).
Intermediate A2-4:
tert-Butyl 3-(hydroxymethyl)bicydo[ 1. 1.1]pentane-1-carboxylate
To a solution of 3-(tert-butoxycarbonyObicyclo[1.1.1ipentane-1-carboxylic acid
A2-3
(2.10 g, 90 % purity, 8.91 mmol) in tetrahydrofuran (33 ml) was added 10 M
borane-
dimethylsulfide complex (1.4 mL, 14.0 mmol) in tetrahydrofuran (7 ml) at -70
C
under nitrogen atmosphere. After allowed to warm to room temperature and
stirred
.. for 2 hours under nitrogen atmosphere, the reaction mixture was quenched
with
water (15 mL) and saturated sodium bicarbonate aqueous solution (15 mL) at 0
C
and extracted with ethyl acetate (40 mL) for three times. The combined organic
layers were washed with brine (40 mL), dried over Na2SO4(s) and filtered. The
filtrate was concentrated under reduced pressure to give title compound (1.95
g, 90 %
.. purity from 11-1 NMR, 99 % yield) as colorless oil. 111 NMR (300 MHz,
CDC13) 6 3.61
(s, 211), 1.93 (s, 611), 1.43 (s, 911).
Intermediate A2-5:
tert-Butyl 3-formylbicydo[1.1.1]pentane-1-carboxylate
To a solution of dimethylsulfoxide (1.68 g, 21.5 mmol) in dichloromethane (80
ml)
was slowly added oxalyl chloride (1.38 g, 10.9 mmol) at -78 C under nitrogen
atmosphere. The reaction mixture was allowed to warm to -60 C and stirred for
15
minutes at the same temperature. After a solution of methyl 3-
(hydroxymethyl)bicyclo[1.1.1ipentane-1-carboxylate A2-4 (1.95 g, 90 % purity,
8.85
mmol) in dichloromethane (15 ml) was added at - 60 C, the mixture was stirred
at -
60 C for 30 minutes. After triethylamine (4.52 g, 44.3 mmol) was added at -
60 C,
the reaction mixture was stirred at -60 C for 30 minutes. The reaction
mixture was
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quenched with water (20 ml) at - 60 C and warmed to room temperature. The
organic layer was separated. The aqueous layer was extracted with
dichloromethane
(50 ml) twice. The combined organic layers were washed with 0.3 M
hydrochloride
aqueous solution (150 ml), water (80 mL) and brine (80 mL), dried over
Na2SO4(s)
and filtered. The filtrate was concentrated under reduced pressure to give the
title
compound (1.84 g, 90 % purity from 111 NMR, 95 % yield) as white solids. 111
NMR
(300 MHz, DMSO-d6) 69.53 (s, 111), 2.17 (s, 611), 1.40 (s, 911).
Intermediate A2-6:
Methyl-2(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan- 1-0-2,3-dihydrooxazole-4-
carboxylate
To a suspension of D-serine methyl ester hydrochloride A1-6 (1.47 g, 9.45
mmol) in
dichloromethane (60 mL) was added 1,4-diazabicyclo[2.2.2ioctane (2.90 g, 25.8
mmol)
at room temperature. After stirred at room temperature for 30 minutes under
nitrogen atmosphere, the mixture was added the solution of tert-butyl 3-
formylbicyclo[1.1. lipentane-l-carboxylate A2-5 (1.84 g, 90% purity, 8.44
mmol) in
dichloromethane (40 mL) and stirring continued at room temperature for 30
minutes under nitrogen atmosphere. Then 1-chloropyrrolidine-2,5-dione (1.27 g,
9.32
mmol) was added at 0 C and the mixture was stirred at 0 C under nitrogen
atmosphere for 2 hours. Then it was quenched with saturated sodium pyrosulfite
aqueous solution (20 mL) and water (20 mL). The aqueous layer was extracted
with
dichloromethane (50 mL) for three times. The combined organic layers were
washed
with saturated sodium bicarbonate aqueous solution (50 mL) and brine (50 mL),
dried over Na2SO4(s) and filtered. The filtrate was concentrated under reduced
pressure to give a residue, which was purified by silica gel column
chromatography
(dichloromethane to petroleum ether ethyl acetate = 100 % to 3 1) to give the
title
compound (1.33 g, 90 % purity from 11-1 NMR, 48 % yield) as white solids. LC-
MS
(EST): RT = 1.55 min, mass calcd. for Ci51121N05 295.1, m/z found 296.2 [M+111
. 11-1
NMR (400 MHz, DMSO-d6) 6 5.83 (dd, J= 6.4, 4.8 Hz, 111), 4.79 - 4.68 (m, 211),
3.81
(s, 311), 1.87 (s, 611), 1.40 (s, 911).
Acid 2:
344-(Methoxycarbonyl)oxazol-2-yl)bicydo[1.1.1]pentane- 1-carboxylic acid
To a solution of methyl 2-(3-(tert-butoxycarbonyl)bicyclo[1.1.1ipentan-1-y1)-
2,3-
dihydrooxazole-4-carboxylate A2-6 (1.33 g, 90 % purity, 4.05 mmol) in 1,2-
dichloroethane (32 mL) was added 4A molecular sieve and potassium carbonate
(672
mg, 4.86 mmol) at room temperature. After stirred at room temperature for 30
minutes, the mixture was added 1-bromopyrrolidine-2,5-dione (865 mg, 4.86
mmol),
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heated to reflux for 20 minutes, then cooled to 0 C. It was quenched with the
addition of saturated sodium thiosulfate aqueous solution (6 mL) and saturated
sodium bicarbonate aqueous solution (10 mL). The resulting mixture was
filtered
and the filtrate was separated. The aqueous layer was extracted with
dichloromethane (30 mL) for three times, then acidified to pH 2 ¨ 3 with 0.5 M
hydrochloride aqueous solution. It was extracted with ethyl acetate (30 mL)
for
three times. The combined ethyl acetate layers were washed brine (30 mL),
dried
over Na2SO4(s) and filtered. The filtrate was concentrated under reduced
pressure to
give the title compound (550 mg, 90 % purity from 111 NMR, 51 % yield) as
white
solids. LC-MS (EST): RT = 0.29 min, mass calcd. for C11lInN05 237.1, m/z found
238.2 [M+111 . 111 NMR (300 MHz, CDC13) 68.17 (s, 111), 3.91 (s, 311), 2.55
(s, 611).
Acid 3: 4-(4-(ethoxycarbonypoxazol-2-yl)cydohex-3-enecarboxylic acid (A3)
0 H OTf
Boc20 (3 eq) PhNTf2 (1.1 eq),
DMAP (1.4 eq) KHMDS (1.25 eq)
t-BuOH, r.t. THF, -78 C, 0.5h;
overnight 0 0-
0 OH r.t., 1.5h
0 0
A1-1 A3-1 A3-2
0
\_-0, 0- / Q -0 II
No
B-B' (1.5 eq)
/o O CI--<0 I (1.2 eq)
\--\
Pd(dppf)Cl2 (0.05 eq) Pd(PPh3)4 (0.05 eq)
CH3COOK (2.5 eq) K2CO3 (3 eq)
1,4-dioxane, 70 C, overnight 0 0 DMF, 100 C, overnight
A3-3
0 0
0< OH
0 0
DCM/TFA
rt., lh
0
0 0
A3-4 A3
Intermediate A3-1:
tert-Butyl 4- oxocydohexanecarboxylate
To a solution of 4-oxocyclohexanecarboxylic acid A1-1 (10.2 g, 98 % purity,
70.3
mmol) in tert-butanol (100 mL) was added N,N-dimethylpyridin-4-amine (12.7 g,
95 %
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purity, 98.5 mmol) and di- tert-butyldicarbonate (46.5 g, 99 % purity, 211
mmol). The
reaction mixture was stirred at room temperature under nitrogen atmosphere
overnight. It was then concentrated in vacuo and the obtained residue was
purified
by silica gel column chromatography (petroleum : ethyl acetate = 10 :1) to
give the
title compound (13.3 g, 99 % purity, 94 % yield) as colorless oil. 111 NMR
(300 MHz,
DMSO-d6) 6 2.74- 2.64(m, 111), 2.44 -2.33 (m, 21I), 2.26- 2.18(m, 21I), 2.11-
2.03(m,
21I), 1.83 - 1.70 (m, 211), 1.41 (s, 91I).
Intermediate A3-2:
tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)cydohex-3-enecarboxylate
To the solution of tert-butyl 4-oxocyclohexanecarboxylate A3-1 (2.00 g, 95 %
purity,
9.58 mmol,) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)
methanesulfonamide (3.84 g, 10.5 mmol) in dry tetrahydrofuran (30 mL) was
added
1.0 M potassium bis(trimethylsilyl)amide in tetrahydrofuran (12 mL, 12.0 mmol)
dropwise over 10 minutes at -78 C. After addition, the mixture was stirred at
-78 C
for 30 minutes. Then the mixture was stirred at room temperature for 1.5
hours.
The mixture was diluted with water (50 mL) and extracted with ethyl acetate
(40
mL) three times. The combined organic layers was washed with brine (100 mL),
dried with Na2SO4(s) and filtered. The filtrate was concentrated and purified
by
silica gel chromatography (petroleum ether : ethyl acetate = 100 : 1 to 50 :1)
to give
the title compound (2.4 g, 95 % purity from HNMR, 72 % yield) as colorless
oil. 11I
NMR (400 MHz, DMSO-d6) 6 5.89 (s, 111), 2.58 - 2.52 (m, 111), 2.43 - 2.28 (m,
41I),
2.01 - 1.94 (m, 111), 1.85 - 1.76 (m, 111), 1.40 (s, 91I).
Intermediate A3-3:
tert-butyl 444,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y0cydohex-3-
enecarboxylate
The suspension of tert-Butyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-
enecarboxylate A3-2 (2.4 g, 6.90 mmol, 95 % purity), bis(pinacolato)diboron
(2.68 g,
10.35 mmol), [1, U-Bis(diphenylphosphino)ferroceneldichloropalladium(II) (258
mg,
0.345 mmol) and potassium acetate (1.73 g, 17.3 mmol) in 1,4-dioxane (25 mL)
was
stirred at 70 C under nitrogen atmosphere overnight. The mixture was cooled
down
and diluted with water (50 mL). The resulting solution was extracted with
ethyl
acetate (50 mL) for three times. The combined organic layers were washed with
brine (100 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated and
purified by silica gel chromatography (petroleum ether : ethyl acetate = 100 :
1 to 40 :
1) to give the title compound (1.05 g, 95 % purity from HNMR, 47 % yield) as
white
solids. LC-MS (ESI): RT = 1.71 min, mass calcd. for Ci71129B04 308.2, m/z
found
326.3 [M+N114i . 1H NMR (400 MHz, CDC13) 6 6.54 (s, 111), 2.45 - 2.37 (m,
111), 2.29 -
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2.24 (m, 311), 2.14 - 2.06 (m, 111), 2.00 - 1.94 (m, 111), 1.58 - 1.50 (m,
111), 1.44 (s, 911),
1.26 (s, 1211).
Intermediate A3-4:
Ethyl 2-(4-(tert-butoxycarbonyl)cydohex-1-en-1-y1)oxazole-4-carboxylate
.. The suspension of tert-butyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
y1)
cyclohex-3-enecarboxylate A3-3 (950 mg, 95 % purity, 2.93 mmol,), ethyl 2-
chlorooxazole-4-carboxylate (629 mg, 3.51 mmol), tetrakis(triphenylphosphine)
palladium (172 mg, 0.15 mmol) and potassium carbonate (1.24 g, 8.78 mmol) in
N,N-Dimethylformamide (30 mL) was stirred at 100 C under nitrogen atmosphere
overnight. After cooled down, the mixture was diluted with water (100 mL) and
extracted with ethyl acetate (100 mL) twice. The combined organic layers were
washed with water (100 mL), and then brine (100 mL), dried over Na2SO4(s) and
filtered. The filtrate was concentrated and purified by silica gel
chromatography
(petroleum ether : ethyl acetate = 10 :1) to give the title compound (630 mg,
95 %
purity from HNMR, 64 % yield) as white solids. LC-MS (ESI): RT = 1.73 min,
mass
calcd. for C171123N05 321.2, m/z found 322.3 [M+11] . 11-1 NMR (400 MHz,
CDC13) 6
8.12 (s, 111), 6.85 (s, 111), 3.39 (q, J= 7.2 Hz, 211), 2.76 - 2.72 (m, 111),
2.54- 2.48 (m,
411), 2.15 - 2.09 (m, 111), 1.81 - 1.72 (m, 111), 1.46 (s, 911), 1.38 (t, J=
7.2 Hz, 311).
Acid 3:
4-(4-(ethoxycarbonyl)oxazol-2-371)cydohex-3-enecarboxylic acid
To the solution of ethyl 2-(4-(tert-butoxycarbonyl)cyclohex-1-en-1-yl)oxazole-
4-
carboxylate A3-4 (630 mg, 95 % purity, 1.86 mmol) in dichloromethane (2.5 mL)
was
added trifluoroacetic acid (2.5 mL). After stirred at room temperature for 1
hour, the
mixture was concentrated to give the title compound (540 mg, 90 % purity from
HNMR, 98 % yield) as light yellow solids. LC-MS (ESI): RT = 1.08 min, mass
calcd.
for Ci311i5N05 265.1, m/z found 266.2 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 6
8.77
(s, 111), 6.78 (s, 111), 4.28 (q, J= 7.2 Hz, 211), 2.60 - 2.53 (m, 211), 2.47 -
2.33 (m, 311),
2.08 - 2.03 (m, 111), 1.72 - 1.62 (m, 111), 1.28 (t, J= 7.2 Hz, 311).
Acid 4: 4-(4-(1VIethoxycarbony1)-5-methyloxazol-2-ypcydohexanecarboxylic acid
(A4)
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NH2
COOMe 0 O.
HCI
0 OH 0 OH
A4-3 (1.6 eq)
BnBr (0.95 eq), EDCI (1.2 eq), PPh3 (1.3 eq),
K2CO3 (0.95 eql, HOBt (1.2 eq) DIPEA (1.4 eq)
DMF, 60-80 C, TEA (3 eq), DMF 0 NH CCI4 (1.3
eq),
overnight ,Bn r.t., overnight CH3CN/DCM
0 OH 0 0 HO .õ
COOMe r.t., overnight
A4-1 A4-2 A4-4
Bn,0 0
Bn,0 0 HO 0
DBU (1.1 eq)
BrCCI3 (1.1 eq) Pd/C, H2
DCM, r.t., overnight Et0Ac, 30 C,
0 N 0 N overnight 0 N
)-(
COOMe COOMe COOMe
A4-5 A4-6 A4
Intermediate A4-2:
4-((Benzyloxy)carbonyl)cydohexanecarboxylic acid
To a solution of cyclohexane-1,4-dicarboxylic acid A4-1 (10.5 g, 60.0 mmol) in
NN
dimethylformamide (50 mL) was added poassium carbonate (7.96 g, 57.0 mmol)
under nitrogen atmosphere. The mixture was stirred at 60 C for 1 hour, then
(bromomethyl)benzene (9.85 g, 57.0 mmol) was added. The mixture was stirred at
80
C overnight. After cooling down to room temperature, the mixture was acidified
to
pH 6 with 1 M hydrochloride aqueous solution and extracted with ethyl acetate
(100
mL) twice. The separated organic layers were washed with water (200 mL) twice,
dried over anhydrous Na2SO4(s), filtered and concentrated to give the title
compound
(3.4 g, 23 % yield) as white solids. 111 NMR (300 MHz, DMSO-d6) 6 12.03 (br s,
111),
7.38 - 7.29 (m, 511), 5.06 (s, 211), 2.34- 2.26 (m, 111), 2.18 - 2.11 (m,
111), 1.96 - 1.87
(m, 411), 1.42 - 1.24 (m, 411).
Intermediate A4-4:
Benzyl 4-0(21i 31)-3-hydroxy-1-methoxy-1-oxobutan-2-yOcarbamoyl)cyclohex
anecarboxylate
To a solution of 4-((benzyloxy)carbonypcyclohexanecarboxylic acid A4-2 (4.00
g, 14.4
mmol), (2R, 3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride A4-3 (4.00 g,
23.2 mmol) and 1-hydroxybenzotriazole (2.40 g, 17.4 mmol) in /V,/V-
dimethylformamide (50 mL) was added triethylamine (4.50 g, 43.4 mmol). The
resulting solution was cooled to 0 C and then /V1-((ethylimino)methylene)-
N3,N3-
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dimethylpropane-1,3-diamine hydrochloride (3.40 g, 17.4 mmol) was added. After
stirring at room temperature overnight, the reaction mixture was poured into
water
(200 mL) and extracted with ethyl acetate (400 mL) twice. The combined organic
layers were washed with water (200 mL), brine (200 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated to give the title compound (4.00 g, 70
% yield)
as colorless oil. LC-MS (ESI): RT = 1.42 min, mass calcd. for C20H27N06 377.2,
m/z
found 378.4 [M+111 . 11-1 NMR (300 MHz, CDC13) 6 7.37 - 7.35 (m, 5H), 6.34 (d,
J=
8.7 Hz, 1H), 5.13 - 5.08 (m, 2H), 4.61 - 4.56 (m, 1H), 4.38 - 4.32 (m, 1H),
3.76 - 3.73
(m, 3H), 2.37 - 1.98 (m, 7H), 1.53 - 1.42 (m, 4H), 1.21 - 1.16 (m, 3H).
Intermediate A4-5:
Methyl 244- ((benzyloxy)carbonyl)cydohexyl)-5-methyl-4,5-dihydrooxazole-4-car
boxylate
To a solution of benzyl 4-(((2R,30-3-hydroxy-1-methoxy-1-oxobutan-2-yl)carbamo
yl)cyclohexanecarboxylate A4-4 (4.00 g, 10.6 mmol) in acetonitrile (40 mL) and
dichloromethane (15 mL) was added triphenylphosphine (3.60 g, 13.8 mmol) and
/V,/V-diisopropylethylamine (1.90 g, 14.8 mmol). After carbon tetrachloride
(2.10 g,
13.8 mmol) was added dropwise slowly, the reaction mixture was stirred at room
temperature overnight. The reaction mixture was cooled to 0 C and diluted in
ethyl
acetate (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL).
After stirring for 10 minutes, the organic layer was seperated and washed with
brine (100 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated and
purified by silica gel chromatography (petroleum ether : ethyl acetate = 10 :
1 to 4 :1)
to give the title compound (3.80 g, 39 % yield) as colorless oil. LC-MS (ESI):
RT =
1.63 min, mass calcd. for C20H25N05 359.2, m/z found 360.3 [M+111 . 11-1 NMR
(300
MHz, CDC13) 67.38 - 7.29 (m, 5H), 5.12 - 5.10 (m, 2H), 4.87 - 4.71 (m, 2H),
3.75 -
3.71 (m, 3H), 2.57 - 2.51 (m, 0.5H), 2.40 - 2.29 (m, 1.5H), 2.13 - 1.92 (m,
4H), 1.76 -
1.66 (m, 1H), 1.52 - 1.46 (m, 3H), 1.27 - 1.23 (m, 3H).
Intermediate A4-6:
Methyl 244- ((benzyloxy)carbonyl)cydohexyl)-5-methyloxazole-4-carboxylate
To a solution of methyl 2-(4-((benzyloxy)carbonyl)cyclohexyl)-5-methyl-4,5-
dihydro
oxazole-4-carboxylate A4-5 (1.00 g, 2.80 mmol) in dichloromethane (10 mL) was
added dry 1,8-diazabicyclo[5.4.0iundec-7-ene (471 mg, 3.10 mmol) dropwise at 0
C
followed by bromotrichloromethane (608 mg, 3.10 mmol). After stirring at room
temperature overnight, the mixture was poured in saturated ammonium chloride
aqueous solution (20 mL) and extracted with dichloromethane (20 mL) twice. The
combined organic layers were dried over Na2SO4(s) and filtered. The filtrate
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concentrated and purified by silica gel chromatography (petroleum ether ethyl
acetate = 8 1 to 5 1) to give the title compound (450 mg, 45 % yield) as white
solids.
LC-MS (ESI): RT = 1.70 min, mass calcd. for C201123N05 357.2, miz found 358.3
[M+11] . 111 NMR (400 MHz, CDC13) 6 7.39 - 7.31 (m, 511), 5.12 (s, 211), 3.89
(s, 311),
2.95 - 2.90 (m, 0.311), 2.78 - 2.72 (m, 0.711), 2.65 - 2.62 (m, 0.311), 2.59
(s, 311), 2.42 -
2.36 (m, 0.711), 2.20 - 1.98 (m, 411), 1.90 - 1.83 (m, 0.511), 1.76 - 1.70 (m,
0.511), 1.60 -
1.55 (m, 311).
Acid 4:
444-(Methoxycarbony1)-5-methyloxazol-2-y1)cydohexanecarboxylic acid
To a solution of methyl 2-(4-((benzyloxy)carbonyl)cyclohexyl)-5-methyloxazole-
4-ca
rboxylate A4-6 (1.42 g, 90 % purity, 3.58 mmol) in ethyl acetate (35 mL) was
added
10 % palladium on charcoal wt. (420 mg). The mixture was stirred at 30 C
under
hydrogen atmosphere (balloon) overnight. The reaction mixture was filtered and
the
filtrate was concentrated to give the title compound (1.00 g, 90 % purity, 94
% yield)
as white solids. LC-MS (EST): RT = 0.30 min, mass calcd. for C131117N05 267.1,
miz
found 268.2 [M411+. 111 NMR (300 MHz, CDC13) 6 3.89 (s, 311), 2.81 - 2.73 (m,
111),
2.59 (s, 311), 2.42 - 2.35 (m, 111), 2.23 - 2.14 (m, 411), 1.70 - 1.48 (m,
411).
Acid 5: 4-04-(Methoxycarbonypoxazol-2-yl)methyl)cyclohexanecarboxylic acid
(A5)
0
Ph 0Bn
ci Cl- P+Ph OBn
Ph 0
(0.4eq)
07N Ph3P (1.0eq) or\I A1-2
toluene
'
t-BuOK (0.3eq) 0 N
0 85 C overnight
-78 C, 111
-0 -0 r.t., 16h 0
A5-1 A5-2 0 A5-3
0
OH
Pd/C, H2 balloon),
Me0H 0 N
C, overnight \
0
0\ A5
20 Intermediate A5-2:
04-(Methoxycarbonyl)oxazol-2-yl)methyl)triphenylphosphonium chloride
To a solution of methyl 2-(chloromethyl)oxazole-4-carboxylate A5-1 (5.00 g,
28.2
mmol) in dry toluene (30 mL) was added triphenylphosphine (7.50 g, 28.2 mmol)
at
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room temperature. After stirred at 85 C under nitrogen atmosphere overnight,
the
reaction mixture was cooled down to room temperature and filtered to give the
title
compound (5.60 g, 99 % purity from 1H NMR, 45 % yield) as yellow solids. 1H
NMR
(300 MHz, CDC13) 6 8.06 - 8.05 (m, 1H), 7.94 - 7.87 (m, 6H), 7.80 - 7.75 (m,
3H), 7.69
- 7.62 (m, 6H), 6.26 (d, J= 15.3 Hz, 2H), 3.81 (s, 311).
Intermediate A5-3:
Methyl 2-04-((benzyloxy)carbonyl)cydohexylidene)methyl)oxazole-4-carboxylate
To a solution of ((4-(methoxycarbonyl)oxazol-2-yl)methyl)triphenylphosphonium
chloride A5-2 (6.50 g, 99 % purity, 14.7 mmol) in dry dichloromethane (45 mL)
was
added potassium 2-methylpropan-2-olate (1.70 g, 6.03 mmol) at - 78 C. After
stirring at - 78 C under nitrogen atmosphere for 1 hour, a solution of benzyl
4-
oxocyclohexanecarboxylate A1-2 (1.06 g, 4.50 mmol) in dichloromethane (5 mL)
added slowly. After stirred at room temperature under nitrogen atmosphere for
16
hours, the mixture was diluted with dichloromethane (60 mL). The resulting
.. solution was washed with water (100 mL), and then brine (100 mL), dried
over
Na2SO4(s) and filtered. The filtrate was concentrated to give a residue, which
was
purified by silica gel column chromatography (petroleum ether ethyl acetate =
10
1 to 3:1) to give the title compound (1.00 g, 98 % purity, 31 % yield) as
yellow oil.
LC-MS (ESI): RT = 1.71 min, mass calcd. for C201121N05 355.1, m/z found 356.2
[M+111 . 1H NMR (300 MHz, DMSO-d6) 6 8.79 - 8.75 (m, 1H), 7.45 - 7.31 (m, 5H),
6.17 (s, 1H), 5.32 (s, 1H), 5.11 (s, 1H), 3.81 (s, 1.5H), 3.61 (s, 1.5H), 3.56
- 3.49 (m,
1H), 2.73 - 2.64 (m, 1H), 2.46 - 2.42 (m, 1H), 2.35 - 2.26 (m, 2H), 2.09 -
1.99 (m, 2H),
1.62 - 1.46 (m, 2H).
Acid 5:
44(4-(4ethoxycarbonyl)oxazol-2-yl)methyl)cydohexanecarboxylic acid
To the solution of methyl 2-((4-
((benzyloxy)carbonyl)cyclohexylidene)methyl)oxazole-
4- carboxylate A5-3 (1.60 g, 98 % purity, 4.41 mmol) in methanol (25 mL) was
added
10 % palladium on charcoal wt. (353 mg). The mixture was stirred at 25 C
under
hydrogen atmosphere of balloon overnight. Then the mixture was filtered off
and the
filtrate was concentrated to give the title compound (1.30 g, 90 % purity, 99
% yield)
as light-yellow solids. LC-MS (ESI): RT = 1.14 min, mass calcd. for Ci3Hi7N05
267.1,
m/z found 266.1 [M-Ht. 1H NMR (400 MHz, DMSO-d6) 6 11.86 (br s, 1H), 8.75 (s,
1H), 3.79 (s, 3H), 2.72 - 2.67 (m, 2H), 2.48 - 2.43 (m, 0.6H), 2.15 - 2.07 (m,
0.4H), 1.93
- 1.81 (m, 2.5H), 1.71 - 1.68 (m, 1H), 1.54 - 1.45 (m, 2.5H), 1.30 - 1.17 (m,
2H), 1.11 -
0.98 (m, 1H).
Acid 6: 4-(4-(2-ethoxy-2-oxoethyl)oxazol-2-y1)cydohexane-1-carboxylic acid
(A6)
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0 0
0 NH2
COOBn COI (1.5 eq), Et0Ac A6-2 (2.0 eq)
HO NH3H20 r.t., lh dioxane/toluene(1/1)
A4-2 120 C, overnight
0 OBn
A6-1
OBn OH
Pd/C, H2 ballon
0 N r/
EA, r.t., overnight 0 )--A
r0
A6-3 A6
Intermediate A6-1:
Benzyl 4-carbamoylcydohexanecarboxylate
To a solution of 4-((benzyloxy)carbonyl)cyclohexanecarboxylic acid A4-2 (9.20
g, 35.1
mmol) in ethyl acetate (100 mL) was added N,N'-carbonyldiimidazole (7.39 g,
52.6
mmol) at room temperature. After stirring at room temperature for 1 hour,
ammonia
solution (20 mL) was added. The mixture was stirred at room temperature for 20
minutes. Then the mixture was diluted with water, acidified with 1 M
hydrochloride
aqueous solution (55 mL), and extracted with ethyl acetate (100 mL) twice. The
separated organic layers were washed with bicarbonate aqueous solution (100
mL),
dried over anhydrous Na2SO4(), filtered and concentrated to give the title
compound
(10.0 g, 99 % yield) as yellow solids. LC-MS (ESI): RT = 0.61 min, mass calcd.
for
C151119NO3 261.1, m/z found mass 262.3 [M+111 .
Intermediate A6-3:
Benzyl 4(442-ethoxy-2-oxoethyl)oxazol-2-y1)cydohexanecarboxylate
To a solution of benzyl 4-carbamoylcyclohexanecarboxylate A6-1 (6.00 g, 16.1
mmol)
in toluene (50 mL) and 1,4-dioxane (50 mL) was added ethyl 4-chloro-3-
oxobutanoate A6-2 (5.40 g, 32.2 mmol). The reaction mixture was heated to 120
C
and stirred at 120 C under nitrogen atmosphere overnight. After cooling down
to
room temperature, the mixture was concentrated and purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 10 1 to 7 1) to give the title
compound (5.30 g, 80 % yield) as light yellow oil. LC-MS (ESI): RT = 1.87 min,
mass
calcd. for C211125N05 371.2, m/z found 372.0 [M+11] . 111 NMR (400 MHz, CDC13)
6
7.54 - 7.53 (m, 111), 7.39 - 7.31 (m, 511), 5.12 (s, 211), 4.25 - 4.13 (m,
211), 3.58 (s,
0.611), 3.57 (s, 1.411), 2.98 - 2.92 (m, 0.311), 2.78 - 2.72 (m, 0.711), 2.61 -
2.56 (m, 0.311),
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2.43 - 2.35 (m, 0.711), 2.20 - 1.95 (m, 411), 1.88 - 1.73 (m, 111), 1.60 -
1.42 (m, 311),
1.32 - 1.24 (m, 311).
Add 6:
444-(2-Ethoxy-2-oxoethyl)oxazol-2-y0cyclohexanecarboxylic acid
To a solution of benzyl 4-(4-(2-ethoxy-2-oxoethyl)oxazol-2-yl)cyclohexanecarbo
xylate
A6-3 (3.00 g, 1.25 mmol, 90 % purity) in ethyl acetate (50 mL) was added 10 %
palladium on charcoal wt. (1.00 g). The mixture was stirred at room
temperature
under hydrogen atmosphere overnight. 10 % palladium on charcoal was filtered
off
and the filtrate was concentrated to give the title compound (2.10 g, 98 %
yield) as
light white solids. 11-1 NMR (400 MHz, DMSO-d6) 6 12.09 (hr s, 111), 7.83 -
7.82 (m,
111), 4.09 (q, J= 7.2 Hz, 211), 3.56 (d, J= 1.2 Hz, 0.611), 3.54 (d, J= 0.8
Hz, 1.411),
2.97 - 2.91 (m, 0.311), 2.78 - 2.70 (m, 0.711), 2.27 - 2.17 (m, 111), 2.05 -
2.02 (m, 111),
1.97 - 1.94 (m, 111), 1.85 - 1.71 (m, 211), 1.68 - 1.60 (m, 111), 1.49 - 1.41
(m, 311), 1.20 -
1.17 (m, 311).
Acid 7: 4(442-Ethoxy-2-oxoethyl)-5-methyloxazol-2-y1)cyclohexanecarboxylic
acid
(A7)
Br
H2N 0 OBn OH
0 0
0 OBn \ I \ I
A6-1 (1.0 eq) N Pd/C,H2 N
0 0
THF/toluene (1.1) 0 EA, rt, overnight 0
A7-1 120 C, overnight 0 0
A7-2 A7
Intermediate A7-2:
Benzyl 4(442-ethoxy-2-oxoethyl)-5-methyloxazol-2-y1)cydohexanecarboxylate
To a solution of ethyl 4-bromo-3-oxopentanoate A7-1 (2.000 g, 80 % purity,
6.123
mmol) in 1,4-dioxane (60 mL) and toluene (60 mL) was added benzyl 4-
carbamoylcyclohexanecarboxylate A6-1 (1.710 g, 80 % purity, 6.133 mmol) at
room
temperature under nitrogen atmosphere. After refluxed at 120 C overnight, the
reaction mixture was allowed to cool down to room temperature and concentrated
under reduced pressure to afford the residue, which was purified by silica gel
column chromatography (petroleum ether ethyl acetate = 10 1 to 5 1) to afford
the product (360 mg, 80 % purity from 11-1 NMR, 12 % yield) as colorless oil.
LC-MS
(ESI): RT = 1.925 min, mass calcd. for C221127N05 385.2, miz found 386.1
[M411+. 11-1
NMR (400 MHz, CDC13) 6 7.37 - 7.32 (m, 511), 5.12 (s, 211), 4.16 (q, J= 7.2
Hz, 211),
3.44 (s, 211), 2.90 -2.88 (m, 0.211), 2.71 - 2.67 (m, 0.711), 2.60 - 2.57 (m,
0.311), 2.40 -
2.35 (m, 0.811), 2.23 (s, 2.311), 2.18 (s, 0.711), 2.16 - 2.12 (m, 311), 2.02 -
1.97 (m, 111),
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1.86 - 1.81 (m, 0.7H), 1.72 - 1.69 (m, 0.3H), 1.58 -1.53 (m, 3H), 1.26 (t, J=
7.2 Hz,
3H).
Acid 7:
4-(4-(2-Ethoxy-2-oxoethyl)-5-methyloxazol-2-y0cydohexanecarboxylic acid
To a solution of benzyl 4-(4-(2-ethoxy-2-oxoethyl)-5-methyloxazol-2-
yl)cyclohexanecarboxylate A7-2 (460 mgõ 85 % purity 1.01 mmol) in ethyl
acetate
(10 mL) was added 10 % palladium on charcoal wt. (55 mg). The mixture was
stirred
at room temperature under hydrogen atmosphere overnight. Then the catalyst was
filtered off and the filtrate was concentrated to give the title compound (310
mg, 80 %
.. purity from 11-1 NMR, 83 % yield) as yellow oil. 11-1 NMR (400 MHz, CDC13)
6 9.56
(hr s, 1H), 4.19 - 4.12 (m, 2H), 3.47 (s, 2H), 2.90 - 2.86 (m, 0.2H), 2.75 -
2.69 (m,
0.7H), 2.61 - 2.59 (m, 0.3H), 2.38 - 2.33 (m, 0.8H), 2.24 (s, 2.3H), 2.19 (s,
0.7H), 2.16 -
2.12 (m, 3H), 2.02 - 1.96 (m, 1H), 1.88 - 1.84 (m, 0.5H), 1.72 - 1.67 (m,
0.5H), 1.60 -
1.53 (m, 3H), 1.26 (t, J= 7.2 Hz, 3H).
Acid 8: 1-(4-(tert-Butoxycarbonyl)phenyl)piperidine-4-carboxylic acid (A8)
o)
HN 0
0 A8-2 (1 eq) LiOH (3 eq)
K2CO3(3 eq), DMSO, Me0H/H20 4/1
______ 0
120 C,16 h 0 rt,16h
A8-1 A8-3
HO
0
0
A8
Intermediate A8-3:
Ethyl 1-(4-(tert-butoxycarbonyl)phenyl)piperidine-4-carboxylate
To a mixture of tert-butyl 4-fluorobenzoate A8-1 (589 mg, 3.00 mmol) and ethyl
.. piperidine-4-carboxylate A8-2 (472 mg, 3.00 mmol) in dimethyl sulfoxide (3
mL) was
added potassium carbonate (1.24 g, 9.00 mmol) at room temperature. After
stirred at
120 C 16 hours, the mixture was poured into water (20 mL) and extracted with
ethyl acetate (30 mL) for three times. The combined organic layers were washed
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with water (30 mL), dried over Na2SO4(s) and concentrated to give a residue,
which
was purified by silica gel column chromatography (petroleum ether ethyl
acetate =
50 1 to 10 1) to afford the title compound (480 mg, 48 % yield) as white
solids. 11-1
NMR (400 MHz, CDC13) 6 7.86 (d, J= 8.8 Hz, 2H), 6.85 (d, J= 8.8 Hz, 2H), 4.15
(q, J
= 7.2 Hz, 2H), 3.82 - 3.77 (m, 2H), 2.96 - 2.89 (m, 211), 2.54 - 2.46 (m, 1H),
2.04 - 1.99
(m, 2H), 1.88 - 1.78 (m, 2H), 1.57 (s, 9H), 1.27 (t, J= 7.2 Hz, 3H).
Acid 8:
1-(4-(tert-Butoxycarbonyl)phenyDpiperidine-4-carboxylic acid
To a solution of ethyl 1-(4-(tert-butoxycarbonyOphenyl)piperidine-4-
carboxylate A8-3
(480 mg, 1.40 mmol) in methanol (6 mL) and water (1.5 mL) was added lithium
hydroxide monohydrate (176 mg, 4.20 mmol) under nitrogen atmosphere. After
stirring at room temperature 16 hours, the solvent was removed and the residue
was diluted with water (10 mL), acidified with 1 M hydrochloride aqueous
solution
to pH 4, then extracted with ethyl acetate (30 mL) for three times. The
combined
organic layers were dried over Na2SO4(s) and concentrated to afford the title
compound (400 mg, 94 % yield) as white solids. 11-1 NMR (400 MHz, CDC13) 6
7.90 (d,
J= 8.8 Hz, 2H), 6.90 (d, J= 8.8 Hz, 2H), 3.86 - 3.82 (m, 2H), 3.02 - 2.96 (m,
2H), 2.64
- 2.57 (m, 1H), 2.11 - 2.07 (m, 2H), 1.95 - 1.85 (m, 2H), 1.61 (s, 9H).
Acid 9: 4-(4-(3-methoxy-3-oxopropyl)oxazol-2-y0cydohexane-1-carboxylic acid
(A9)
0
H2i\i COOBn
0 0 - -
Br2 (1.0 eq), Me0H A6-1 (0.67 eq)
OH _______________________ > >
0 C-reflux DMF,120 C,
overnight
0 Br 0
A9-1 A9-2
OC OBn OC OH
N)Cr Pd/C, H2 Na
-0 -0
\ 0 THF, 50 psi, r.t., overnight \ 0
0
A9-3 A9
Intermediate A9-2:
Methyl 5-bromo-4-oxopentanoate
To a solution of 4-oxopentanoic acid A9-1 (10.0 g, 84.4 mmol) in methanol (86
mL)
was added bromine (13.6 g, 84.4 mmol) at 0 C. After stirred at room
temperature
for 1 hour under nitrogen atmosphere, the reaction mixture was diluted with
water
(20 mL) and extracted with dichloromethane (100 mL) twice. The separated
organic
layers were washed with saturated sodiun bicarbonate aqueous solution (20 mL),
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dried over anhydrous Na2SO4(s), filtered and concentrated to give a residue,
which
was purified by silica gel column chromatography (petroleum ether : ethyl
acetate =
: 1) to give the title compound (4.70 g, 27 % yield) as yellow oil. 11-1 NMR
(300 MHz,
DMSO-d6) 6 4.36 - 4.33 (m, 211), 3.57 - 3.52 (m, 311), 2.85 - 2.79 (m, 211) ,
2.51 - 2.45
5 (m, 211).
Intermediate A9-3:
Benzy14-(4-(3-methoxy-3-oxopropyl)oxazol-2-yl)cydohexanecarboxylate
To a solution of benzyl 4-carbamoylcyclohexanecarboxylate A6-1 (500 mg, 1.91
mmol)
in /V,/V-dimethylformamide (5 mL) was added methyl 5-bromo-4-oxopentanoate A9-
2
(599 mg, 2.87 mmol). After stirred at 120 C overnight, the mixture was
diluted with
water (20 mL) and extracted with dichloromethane (20 mL) twice. The separated
organic layers were washed with saturated sodiun bicarbonate aqueous solution
(20
mL), dried over anhydrous Na2SO4(s), filtered and concentrated to give a
residue,
which was purified by silica gel column chromatography (petroleum ether :
ethyl
acetate = 10: 1 to 5 :1) to give the title compound (1.20 g, 32 % yield) as
yellow oil.
11-1 NMR (300 MHz, DMSO-d6) 6 7.64 (s, 111), 7.35 - 7.29 (m, 511), 5.06 (s,
211), 3.55 (s,
311), 2.73 - 2.66 (m, 111), 2.67 - 2.62 (m, 211), 2.57 - 2.52 (m, 211), 2.42 -
2.33 (m, 111),
2.01 - 1.95 (m, 411), 1.52 - 1.36 (m, 411).
Add 9:
4-(4-(3-Methoxy-3-oxopropypoxazol-2-yl)cydohexanecarboxylic acid
To a solution of benzy14-(4-(3-methoxy-3-oxopropyl)oxazol-2-y1)
cyclohexanecarboxylate A9-3 (1.43 g, 3.89 mmol) in tetrahydrofuran (150 mL)
was
added 10 % palladium on charcoal wt. (2.00 g). The reaction mixture was
stirred at
room temperature under hydrogen atmosphere (50 psi) overnight. The completed
reaction mixture was filtered and the filtrate was concentrated to give the
crude
product (980 mg, 91 % yield) as white solids. 'H NMR (300 MHz, DMSO-d6) 6
12.06
(br s, 111), 7.64 (d, J= 3.0 Hz, 111), 3.57 - 3.55 (m, 311), 2.70 - 2.67 (m,
111), 2.65 - 2.62
(m, 211), 2.48 - 2.37 (m, 211), 2.24- 2.12 (m, 111), 2.01 - 1.91 (m, 411),
1.50 - 1.33 (m,
411).
Acid 10: 4-(4-(3-ethoxy-2,2-dimethy1-3-oxopropyl)oxazol-2-yl)cydohexane-1-
carboxylic acid (A10)
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CI (1 ecI=) NBS(1.2 eq.) 0 Br
LDA (1.2 eq.) CI 0 water, r.t., 2h
0 -78 C¨r.t.,THF 0
A10-1 overnight A10-2 A10-3
0 0
Bn0 NH2 0
0
A6-1 (0.67 eq.) o\ Pd/C(1.5 eq.), H2(balloon)
1,4-dioxane/toluene(1/1) Bn0 /
ethyl acetate
0
120 C, overnight r.t., overnight
A10-4
0
0
HO /
0
Al o
Intermediate A10-2:
Ethyl 4-chloro-2,2-dimethylpent-4-enoate
To a solution of ethyl isobutyrate A10-1 (10.0 g, 86.1 mmol) in
tetrahydrofuran (40
mL) was added 2 M lithium diisopropylamide in tetrahydrofuran (52 mL, 104
mmol)
at -78 C under nitrogen atmosphere. After stirred at -78 C for 1 hour, 2,3-
dichloroprop-1-ene (9.60 g, 86.5 mmol) was added at -78 C. Then the mixture
was
warmed up slowly to room temperature and stirred overnight. And then it was
quenched with saturated ammonium chloride aqueous solution (50 mL) and
extracted with ethyl acetate (50 mL) twice. The combined organic layers were
washed with brine (30 mL), dried over Na2SO4(s), filtered and concentrated to
give a
residue, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 10 :1) to give the desired compound (13.0 g, 90 % purity from
11-1
NMR, 71 % yield) as colourless oil. 11-1 NMR (300 MHz, CDC13) 6 5.22 (s, 1H),
5.11 (s,
1H), 4.11 (q, J= 6.9 Hz, 2H), 2.63 (s, 2H), 1.27 - 1.22 (m, 9H).
Intermediate A10-3:
Ethyl 5-bromo-2,2-dimethy1-4-oxopentanoate
To a solution of ethyl 4-chloro-2,2-dimethylpent-4-enoate A10-2 (11.0 g, 90 %
purity,
51.9 mmol) in water (50 mL) was added /V-bromosuccinimide (11.0 g, 61.8 mmol)
under nitrogen atmosphere. After stirred at room temperature for 2 hours, the
reaction mixture was diluted with water (10 mL) and extracted with ethyl
acetate
(40 mL) twice. The combined organic layers were washed with brine (20 mL),
dried
over Na2SO4(s) and filtered. The filtrate was concentrated to give a residue,
which
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was purified by silica gel column chromatography (petroleum ether : ethyl
acetate =
: 1) to give the desired compound (11.0 g, 90 % purity from 1H NMR, 76 %
yield)
as colourless oil. 1H NMR (300 MHz, CDC13) 6 4.07 (q, J= 7.2 Hz, 2H), 3.85 (s,
2H),
2.89 (s, 2H), 1.22 - 1.45 (m, 9H).
5 Intermediate A10-4:
Benzyl 4-(4-(3-ethoxy-2,2-dimethy1-3-oxopropyl)oxazol-2-
yl)cydohexanecarboxylate
To the solution of benzyl 4-carbamoylcyclohexanecarboxylate A6-1 (7.00 g, 90 %
purity, 24.1 mmol) in toluene (20 mL) and 1,4-dioxane (20 mL) was added ethyl
5-
bromo-2,2-dimethy1-4-oxopentanoate A10-3 (10.0 g, 90 % purity, 35.8 mmol)
under
10 nitrogen atmosphere. After stirred at 120 C overnight, the reaction
mixture was
cooled down to room temperature, diluted with water (20 mL) and extracted with
ethyl acetate (20 mL) twice. The combined organic layers were washed with
brine
(20 mL), dried over Na2SO4(s), filtered and concentrated to give a residue,
which was
purified by C18 column (acetonitrile : water = 67 % to 72 %) to give the title
compound (2.40 g, 90 % purity from 1H NMR, 23 % yield) as colourless oil. LC-
MS
(EST): RT = 1.65 min, mass calcd. for C24H3iN05 413.2, m/z found 414.0 [M411+.
1H
NMR (300 MHz, CDC13) 67.42 - 7.31 (m, 5H), 7.27 - 7.25 (m, 1H), 5.12 (s, 2H),
4.12
(q, J= 7.2 Hz, 2H), 2.79 - 2.66 (m, 2H), 2.48 - 1.63 (m, 10H), 1.30 - 1.21 (m,
9H).
Acid 10:
4-(4-(3-Ethoxy-2,2-dimethy1-3-oxopropyl)oxazol-2-ypcydohexanecarboxylic acid
To a solution of benzyl 4-(4-(3-ethoxy-2,2-dimethy1-3-oxopropyl)oxazol-2-
yl)cyclohexanecarboxylate A10-4 (1.40 g, 90 % purity, 3.05 mmol) in ethyl
acetate
(10 mL) was added 10 % palladium on charcoal wt. (500 mg, 4.70 mmol) at room
temperature. After stirred at room temperature under hydrogen atmosphere of
.. balloon overnight, the reaction mixture was filtered and concentrated to
give the
title compound (900 mg, 90 % purity from 1H NMR, 82 % yield) as colourless
oil. 1H
NMR (300 MHz, CDC13) 6 7.25 (s, 1H), 4.12 (q, J= 7.2 Hz, 2H), 2.76 (s, 2H),
2.65 -
1.95 (m, 6H), 1.89- 1.40 (m, 4H), 1.28- 1.15 (m, 9H).
Acid 11: Mixture of 4-(5-(ethoxycarbonyl)oxazol-2-0cydohexanecarboxylic acid
and
4-(5-(ethoxycarbonyl)oxazol-2-0cydohex-3-enecarboxylic acid (All)
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0 OBn ¨0, /0- _1 0
KHMDS(1.34eq), 0 OBn ______________
OBn
PhNTf2(1.2eq) (3.0eq) __
______________________ > 0,
THF, -60 C, 4h Pd(dP1302C12(0.05eq), >rg
KOAc(3.0eq),
0 OTf
1,4-dioxane
A1-2 A11-1 A11-2
80 C, overnight
Bn0
,O o
0 OBn
0 0\\
A11-2 (1.3 eq)
Pd(dPIDO2C12 (0.1 eq) 07
K2CO3 (2.0 eq),
A11-3 1 ,4-d ioxane/water
A11-4
100 C, 6 his
0 0
OH OH
0\\ 0\\ p
Pd/C, H2 balloon
Me0H, 25 C, 1.5 hrs (D\
All
Intermediate Al 1- 1:
Benzyl 4-0(trifluoromethyl)sulfony0oxy)cydohex-3-enecarboxylate
To a solution of benzyl 4-oxocyclohexanecarboxylate A1-2 (15.0 g, 98 % purity,
63.3
mmol) and 1, 1,1-trifluoro-N-phenyl-N
((trifluoromethyl)sulfonyl)methanesulfonamide (27.2 g, 76.1 mmol) in
tetrahydrofuran (350 mL) was added 1 M potassium bis(trimethylsilyl)amide in
tetrahydrofuran (85 mL, 85.0 mmol) under nitrogen atmosphere at - 60 C. After
stirred at - 60 C for 4 hours, the mixture was diluted with water (200 ml)
and
extracted with ethyl acetate (200 mL) twice. The combined organic layers were
washed with brine (150 mL), dried over Na2SO4(s) and filtered. The filtrate
was
concentrated under reduced pressure to give a residue, which was purified by
silica
gel column chromatography (petroleum ether: ethyl acetate = 10 :1 to 5 :1) to
give
the desired compound (12.5 g, 95 % purity from 111 NMR, 51 % yield) as yellow
oil.
111 NMR (400 MHz, CDC13) 6 7.39 - 7.33 (m, 511), 7.77 - 7.75 (m, 111), 5.14
(s, 211),
2.69 - 2.62 (m, 111), 2.49 - 2.46 (m, 211), 2.43 - 2.39 (m, 211), 2.19 - 2.13
(m, 111), 2.00 -
1.89 (m, 111).
Intermediate A11-2:
Benzyl 444,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cydohex-3-enecarboxylate
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To a solution of benzyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-
enecarboxylate
All- 1 (8.00 g, 95 % purity, 20.9 mmol), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-
bi(1,3,2-
dioxaborolane) (15.9 g, 62.6 mmol) and potassium acetate (6.14 g, 62.6 mmol)
in 1,4-
dioxane (150 mL) was added 1, 1'-bis(diphenylphosphino)ferrocene-
palladium(II)dichloride (0.76 g, 1.04 mmol) at room temperature under nitrogen
atmosphere. After stirred at 80 C under nitrogen atmosphere overnight, the
mixture was diluted with water (70 mL) and brine (70 mL). The organic layer
was
separated and the aqueous phase was extracted with ethyl acetate (150 mL)
twice.
The combined organic layers were washed with brine (100 mL), dried over
Na2SO4(s)
and filtered. The filtrate was concentrated under reduced pressure to give a
residue,
which was purified by silica gel column chromatography (petroleum ether :
ethyl
acetate = 10 :1 to 5 :1), then further purified by C18 column (acetonitrile :
water =
85 % to 90 %) to give the desired compound (4.60 g, 95 % purity, 61 % yield)
as
yellow oil. LC-MS (ESI): RT = 0.26 min, mass calcd. for C201127B04 342.2, m/z
found
343.3 [M+111 . 111 NMR (400 MHz, CDC13) 6 7.39 - 7.32 (m, 511), 6.54 (s, 111),
5.13 (s,
211), 2.63 - 2.55 (m, 111), 2.38 - 2.35 (m, 211), 2.30 - 2.25 (m, 111), 2.17 -
2.01 (m, 211),
1.68 - 1.58 (m, 111), 1.26 (s, 1211).
Intermediate A11-4:
Ethyl 244- qbenzyloxy)carbonypcyclohex- 1-en- 1-yl)oxazole-5-carboxylate
To a solution of ethyl 2-chlorooxazole-5-carboxylate A11-3 (3.00 g, 98 %
purity, 16.7
mmol) in 1,4-dioxane (100 mL) was added benzyl 4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-yl)cyclohex-3-enecarboxylate A11-2 (7.85 g, 95 % purity, 21.8
mmol),
1, l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (1.30 g, 98 %
purity,
1.74 mmol) and potassium carbonate (4.80 g, 98 % purity, 34.0 mmol) in water
(20
mL) at room temperature. After stirred at 100 C for 6 hours under nitrogen
atmosphere, the reaction mixture was allowed to cool down to room temperature
and
diluted with water (100 mL) slowly, extracted with ethyl acetate (100 mL) for
three
times. The combined organic layers were washed with brine (100 mL), dried over
Na2SO4(s) and filtered. The filtrate was concentrated under reduced pressure
to give
a residue, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 3 : 1 to 1: 1) to give the title compound (5.50 g, 95 % purity
from 111
NMR, 88 % yield) as white solids. LC-MS (ESI): RT = 1.899 min, mass calcd. for
C201121N05 355.1, m/z found 356.1 [M+111 . 111 NMR (400 MHz, DMSO-d6) 6 7.97
(s,
111), 7.39 - 7.31 (m, 511), 6.89 - 6.88 (m, 111), 5.15 (s, 111), 5.14 (s,
111), 4.32 (q, J= 7.2
Hz, 211), 2.79 - 2.72 (m, 111), 2.58 - 2.53 (m, 211), 2.49 - 2.37 (m, 211),
2.13 - 2.06 (m,
111), 1.77 - 1.67 (m, 111), 1.30 (t, J= 7.2 Hz, 311).
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Acid 11:
Mixture of 4-(5-(ethoxycarbonypoxazol-2-yl)cydohexanecarboxylic acid and 445-
(ethoxycarbony0oxazol-2-y0cydohex-3-enecarboxylic acid
To a solution of ethyl 2-(4-((benzyloxy)carbonyl)cyclohex-1-en-1-y0oxazole-5-
carboxylate A11-4 (4.60 g, 95 % purity, 12.3 mmol) in methanol (150 mL) was
added
% palladium on charcoal wt. (1.00 g) under nitrogen atmosphere at room
temperature. After replacing the inert nitrogen atmosphere with hydrogen gas,
the
mixture was stirred at 25 C under hydrogen atmosphere of balloon for 1.5
hours.
The catalyst was filtered off and the filtrate was concentrated under reduced
10 pressure to give the title product (3.60 g, 90 % purity, 99 % yield) as
yellow oil. LC
MS (ESI): RT = 0.224 min and 0.293 min, mass calcd. for C131117N05 and
C131115N05
267.1 and 265.1, m/z found 268.1 [M+Hi+ and 266.0 [M+Hi+, respectively.
Acid 12: 4-(4-(1-Ethoxy-2-methy1-1-oxopropan-2-yl)oxazol-2-
y1)cyclohexanecarboxylic
acid (Al2)
OBn OBn
OH
0 0
0
0 0 0
LiHMDS (4.0 eq) \ I Pd/C, H2,
N
Mel (4.0 eq), dry THF Et0Ac, r.t., 2.5h
-70 C- r.t. overnight
A6-3 ,----0 Al2-1
Al2
/ ro
Intermediate Al2-1:
Benzyl 4-(4-(1-ethoxy-2-methy1-1-oxopropan-2-yl)oxazol-2-
yl)cydohexanecarboxylate
To a solution of benzyl 4-(4-(2-ethoxy-2-oxoethyl)oxazol-2-
yl)cyclohexanecarboxylate
A6-3 (1.90 g, 90 % purity, 4.60 mmol) in dry tetrahydrofuran (20 mL) was added
dropwise 1.0 M lithium hexamethyldisilazide in tetrahydrofuran (18.4 mL, 18.4
mmol) at -70 C. After stirred at -70 C for 1 hour, iodomethane (2.61 g, 18.4
mmol)
was added dropwise at -70 C and the resulting reaction mixture was allowed to
warm to room temperature and stirring continued overnight. Then it was
acidified
with saturated ammonium chloride aqueous solution to pH 7 - 8 and, extracted
with
ethyl acetate (30 mL) twice. The combined organic layers were washed with
water
(30 mL) twice, brine (30 mL) twice, dried over Na2SO4(), filtered and
concentrated
under reduced pressure to give the title compound (1.90 g, 80 % purity from
HNMR,
83 % yield) as a yellow oil. LC-MS (ESI): RT = 2.029 min, mass calcd. for
C23H29N05
399.2, m/z found 400.2 [M411+. 11-1 NMR (400 MHz, CDC13) 6 7.36 - 7.33 (m,
6H),
5.12 (s, 2H), 4.17 - 4.11 (m, 2H), 2.98 - 2.94 (m, 0.3H), 2.80 - 2.74 (m,
0.7H), 2.60 -
2.57 (m, 0.2H), 2.43 - 2.35 (m, 0.8H), 2.17 - 1.96 (m, 4H), 1.83 - 1.72 (m,
1H), 1.60 -
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1.54 (m, 311), 1.51 (s, 611), 1.24 - 1.19 (m, 311).
Acid 12:
4-(4-(1-Ethoxy-2-methy1-1-oxopropan-2-y0oxazol-2-ypcydohexanecarboxylic acid
To a solution of benzyl 4-(4-(1-ethoxy-2-methyl-1-oxopropan-2-yl)oxazol-2-
yl)cyclo
hexanecarboxylate Al2-1 (1.90 g, 80 % pruity, 3.81 mmol) in ethyl acettate (20
mL)
was added 10 % palladium on charcoal wt. (1 g) under nitrogen atmosphere.
After
stirred for 2.5 hours at room temperature under hydrogen balloon, the mixture
was
filtered and concentrated to get the title compound (1.50 g, crude) as white
solids.
LC-MS (ESI): RT = 1.22 min, mass calcd. for C161123N05 309.2, m/z found 308.0
[M-
1-11
Acid 13: 4-(1-(2-ethoxy-2-oxoethyl)-1Hpyrazol-4-y1)cydohexanecarboxylic acid
(A13)
HN¨N
OTf
HNB/(3-
0
\O¨A (1.1 eq) Br.J-L,o,----õ, (1 .3 eq)
Pd(dppf)Cl2 (0.06 eq), K2CO3 (2.0 eq),
Bn0 0 Cs2CO3 (2.0 eq) DMF, 45 C, overnight
1,4-dixane/water Bn0 0
A11-1 95 C, 2h A13-1
0-1 oJ
1\114 0
N N
Pd/C, H2 (balloon),
Me0H, r.t., overnight
0 0
OBn OH
A13-2 A13
Intermediate A13-1:
Benzyl 4-(1Hpyrazol-4-0cyclohex-3-enecarboxylate
To a suspension of benzyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-
enecarboxylate A11-1 (10.0 g, 27.5 mmol) and 4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-y1)-1H-pyrazole (5.90 g, 30.4 mmol) and cesium carbonate (17.9
g,
54.9 mmol) in a mixed solvent of 1,4-dioxane (100 mL) and water (33 mL) was
added
[1, r-bis(diphenylphosphino)ferroceneidichloropalladium(II) (1.20 g, 1.60
mmol) at
room temperature. After stirred at 95 C under nitrogen atmosphere for 5 hours
and
cooled down to room temperature, the mixture was concentrated to give a
residue,
which was purified by silica gel column chromatography (petroleum ether ethyl
acetate = 5 :1 to 1:1) and C18 column (acetonitrilee water = 05 % to 95 %) to
afford
the desired product (3.70 g, 48 % yield) as brown solids. LC-MS (ESI): RT =
1.78 min,
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mass calcd. for C171118N202 282.1, m/z found 283.1 [M411+. 111 NMR (400 MHz,
CDC13) 6 7.90 (s, 0.511), 7.62 (s, 0.511), 7.58 (s, 211), 7.37 - 7.36 (m,
511), 6.37 (s, 0.211),
6.01 (s, 0.811), 5.15 (s, 211), 2.68 - 2.66 (m, 111), 2.45- 2.40 (m, 411),
2.19 - 2.15 (m, 111),
1.88 - 1.84 (m, 111).
Intermediate A13-2:
Benzyl 4-(1-(2-ethoxy-2-oxoethyl)-1Hpyrazol-4-yl)cydohex-3-enecarboxylate
To a mixture of benzyl 4-(1H-pyrazol-4-yl)cyclohex-3-ene carboxylate A13-1
(1.40 g,
4.96 mmol) and potassium carbonate (1.40 g, 10.0 mmol) in N,/V-dimethylformide
(20 mL) was added ethyl 2-bromoacetate (1.08 g, 6.45 mmol) in NN
.. dimethylformide (15 mL) at 0 C. Then the mixture was stirred at 45 C
overnight.
After cooling down to room temperature, the mixture was poured in water (100
mL)
and extracted with ethyl acetate (30 mL) for four times. The combined organic
layers
were concentrated to get a residue, which was purified by silica gel column
chromatography (petroleum ether : ethyl acetate = 10 :1 to 3 :1) followed by
C18
column (acetonitrile : water = 5 % to 95 %) to get the desired product (1.10
g, 61 %
yield) as pale green oil. LC-MS (ESI): RT = 1.882 min, mass calcd. for
C211124N204
368.2, m/z found 369.1 [M+11i+.111 NMR (400 MHz, CDC13) 6 7.60 (s, 111), 7.39
(s,
111), 7.38 - 7.32 (m, 511), 5.99 - 5.98 (m, 111), 5.15 (s, 211), 4.86 (s,
211), 4.26 - 4.21 (m,
211), 2.69 - 2.62 (m, 111), 2.44- 2.35 (m, 411), 2.17 - 2.13 (m, 111), 1.90 -
1.79 (m, 111),
1.32 - 1.24 (m, 311).
Acid 13:
4-(1-(2-ethoxy-2-oxoethyl)-1Hpyrazol-4-371)cydohexanecarboxylic acid
To a solution of benzyl 4-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-0cyclohex-3-
enecarboxylate A13-2 (1.10 g, 2.99 mmol) in methanol (20 mL) was added 10 %
palladium on charcoal wt. (600 mg) under nitrogen atmosphere at room
temperature.
Then the mixture was stirred at room temperature under hydrogen atmosphere
overnight. Another batch (280 mg) combined to work-up. Then the mixture was
filtered and the filtrate was concentrated to get the desired product (1.2 g,
crude) as
black oi1.1H NMR (400 MHz, CDC13) 6 7.41 (s, 111), 7.25 (s, 111), 4.86 (s,
211), 4.25 -
4.22 (m, 211), 2.73 - 2.59 (m, 211), 2.16 - 2.00 (m, 211), 1.90 - 1.77 (m,
211), 1.72 - 1.60
(m, 411), 1.31 - 1.24 (m, 311).
Acid 14: 4-(1-(3-methoxy-3-oxopropy1)-1H-pyrazol-4-yl)cydohexane-1-carboxylic
acid
(A14)
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\ 0 0
II
\0
HN-N
0
N-N N-N
eq)
Pd/C
K2CO3 (3.0 eq) H2 balloon,, Et0H
DMF, 60 C, overnight L. J r.t., overnight
Bn0 0
A13-1 0 OBn 0 OH
A14-1 A14
Intermediate A14-1:
Benzyl 4-(143-methoxy-3-oxopropy1)-1H-pyrazol-4-0cyclohex-3-enecarboxylate
To a solution of benzyl 4-(1H-pyrazol-4-yl)cyclohex-3-enecarboxylate A13-1
(1.40 g,
95 % purity, 4.71 mmol) in /V,/V-dimethylformamide (15 mL) was added potassium
carbonate (1.95 g, 14.1 mmol) and methyl acrylate (486 mg, 5.65 mmol) at room
temperature. After stirred at 60 C under nitrogen atmosphere overnight, it
was
cooled down and poured into water (50 mL), extracted with ethyl acetate (30
mL)
twice. The combined organic layers were washed with brine (30 mL), dried over
Na2SO4(s) and filtered. The filtrate was concentrated to give a residue, which
was
purified by silica gel column chromatography (petroleum ether ethyl acetate =
3 1)
to give the title compound (1.40 g, 65 % yield) as white oil. 1H NMR (400 MHz,
CDC13) 6 7.54 (s, 111), 7.39 - 7.30 (m, 611), 6.23 - 6.22 (m, 0.211), 5.95 (br
s, 0.811), 5.15
(s, 211), 4.39 - 4.36 (m, 211), 3.68 (s, 311), 2.91 - 2.87 (m, 211), 2.68 -
2.61 (m, 111), 2.43
- 2.30 (m, 411), 2.18 - 2.12 (m, 111), 1.89 - 1.79 (m, 111).
Acid 14:
4-(1-(3-methoxy-3-oxopropy1)-1H-pyrazol-4-ypcyclohexane-1-carboxylic acid
To a solution of benzyl 4-(1-(3-methoxy-3-oxopropy1)-1H-pyrazol-4-yl)cyclohex-
3-
enecarboxylate A14-1 (1.60 g, 80 % purity, 3.47 mmol) in ethanol (40 mL) was
added
10 % palladium on charcoal wt. (500 mg) at room temperature. After stirred at
room
temperature under hydrogen atmosphere of balloon overnight, the reaction
mixture
was filtered and the filtrate was concentrated under reduced pressure to give
the
title compound (1.40 g, 65 % purity from 1H NMR, 93 % yield) as white oil. 1H
NMR
(400 MHz, CDC13) 67.61 (d, J= 2.0 Hz, 0.111), 7.52 (d, J= 1.2 Hz, 0.211), 7.45
(d, J=
2.0 Hz, 0.311), 7.36 (s, 0.711), 7.22 (s, 0.711), 5.65 (br s, 111), 4.45 (t,
J= 6.4 Hz, 0.511),
4.37 (t, J= 6.4 Hz, 1.511), 3.68 (d, J= 2.0 Hz, 311), 2.93 - 2.87 (m, 211),
2.64 (br s, 111),
2.47 - 2.30 (m, 0.411), 2.12 - 2.03 (m, 2.611), 1.86 - 1.79 (m, 1.311), 1.71 -
1.52 (m,
2.711), 1.36 - 1.26 (m, 211).
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Acid 15: 4-(1-(4-Methoxy-2-methy1-4-oxobutan-2-y1)-1H-pyrazol-4-
yl)cydohexanecarboxylic acid (A15)
OBn Bn0
A15-1
N I K2CO3eq), DMF
90 C, 48 h ¨Ni
A13-1 A15-2
0
Pd/C HO
N H2 balloon, Me0H
15 C, 16 h
0
Al 5
Intermediate A15-2:
.. Benzyl 4-(1-(4-methoxy-2-methy1-4-oxobutan-2-y1)-1H-pyrazol-4-y0cydohex-3-
enecarboxylate
To a solution of benzyl 4-(111-pyrazol-4-yl)cyclohex-3-enecarboxylate A13-1
(3.00 g,
80 % purity, 8.50 mmol) and methyl 3-methyl-2-butenoate A15-1 (1.95 g, 17.9
mmol)
in N,N-dimethylformamide (30 mL) was added potassium carbonate (3.53 g, 25.5
mmol) at room temperature. After srirred at 90 C for 48 hours, the reaction
mixture
was cooled down to room temperature and diluted with water (200 mL). It was
extracted with ethyl acetate (100 mL) for three times. The combined organic
layers
were washed with brine (100 mL), dried over Na2SO4(s) and filtered. The
filtrate was
concentrated to give a residue, which was purified by C18 column (acetonitrile
water = 60 % to 90 %) to give the title compound (2.40 g, 97.8 % purity, 70 %
yield)
as yellow oil. 111 NMR (400 MHz, CDC13) 6 7.57 (s, 11I), 7.46 (s, 111), 7.40 -
7.30 (m,
51I), 5.97 - 5.95 (m, 11I), 5.15 (s, 21I), 3.58 (s, 311), 2.90 (s, 211), 2.69 -
2.61 (m, 11I),
2.44 - 2.30 (m, 411), 2.18 - 2.12 (m, 11I), 1.89 - 1.79 (m, 11I), 1.70 (s,
611).
Acid 15:
4-(1-(4-Methoxy-2-methy1-4-oxobutan-2-y1)-1H-pyrazol-4-yl)cydohexanecarboxylic
acid
To a mixture of benzyl 4-(1-(4-methoxy-2-methy1-4-oxobutan-2 -y1)- 1H-pyrazol-
4-
0cyclohex-3-enecarboxylate A15-2 (2.40 g, 97.8 % purity, 5.92 mmol) in
methanol
(50 mL) was added 10 % palladium on activated carbon wt. (500 mg) under
nitrogen
atmosphere. After stirred at 15 C under hydrogen atmosphere (balloon) for 16
hours,
the mixture was filtered and the filtrate was concentrated to give the title
compound
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(1.90 g, 90 % purity from 111 NMR, 94 % yield) as white solids. 111 NMR (400
MHz,
DMSO-d6) 6 12.07 (s, 111), 7.56 (s, 0.411), 7.54 (s, 0.611), 7.28 (s, 0.411),
7.26 (s, 0.611),
3.47 (s, 1.211), 3.46 (s, 1.811), 2.84 (s, 211), 2.60 - 2.53 (m, 0.611), 2.42 -
2.34 (m, 0.411),
2.22 - 2.15 (m, 0.411), 1.95 - 1.85 (m, 2.611), 1.78 - 1.69 (m, 1.611), 1.63 -
1.51 (m, 911),
1.42 - 1.23 (m, 1.411).
Acid 16: 4-(1-(4-methoxy-4-oxobutan-271)-1H-pyrazol-4-yl)cydohexane-1-
carboxylic
acid (A16)
NH (3.6 eq)
BnO
/)-CN _____________________________
K2CO3 (3.7 eq) , DMF Bn0
60 C, overnight
0
A13-1 A16-1
0
HO
Pd/C(10% w/w)
,N44-
H2 balloon, Me0H,
r.t., 16 h 0
Al 6
Intermediate A16-1:
Benzyl 4-(1(4-Methoxy-4-oxobutan-2-y1)- 1Hpyrazol-4-y0cydohex-3-enecarboxylate
To a solution of benzyl 4-(1H-pyrazol-4-yl)cyclohex-3-enecarboxylate A13-1
(6.40 g,
50 % purity, 11.3 mmol) in /V,/V-dimethylformide (30 mL) was added (0-methyl
but-
2-enoate (4.10 g, 40.9 mmol) and potassium carbonate (5.80 g, 42.0 mmol) at
room
temperature. After stirred at 60 .0 under nitrogen atmosphere overnight, the
reaction mixture was cooled down to room temperature and concentrated under
reduced pressure to give a residue, which was diluted with water (100 mL) and
extracted with ethyl acetate (80 mL) for three times. The combined organic
layers
were washed with water (80 mL) twice, brine (80 mL) twice, dried over
Na2SO4(s)
and filtered. The filtrate was concentrated under reduced pressure to give a
crude
product, which was purified by C18 column (acetonitrile water = 65 % to 70 %)
to
give the title compound (5.00 g, 70 % purity from 1H NMR, 81 % yield) as light
yellow oil. 1H NMR (400 MHz, CDC13) 6 7.55 (s, 111), 7.37 - 7.30 (m, 611),
5.95 (d, J=
1.6 Hz, 111), 5.15 (s, 211), 4.77 - 4.70 (m, 111), 3.64 (s, 311), 3.02 - 3.00
(m, 111), 2.76 -
2.72 (m, 111), 2.69 - 2.60 (m, 111), 2.44 - 2.33 (m, 411), 2.18 - 2.14 (m,
111), 1.89 - 1 .80
(m, 111), 1.58 - 1.53 (m, 311).
Acid 16:
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4-(1-(4-methoxy-4-oxobutan-2-y1)-1H-pyrazol-4-yl)cyclohexane-1-carboxylic acid
To a solution of benzyl 4-(1-(4-methoxy-4-oxobutan-2-y1)-1H-pyrazol-4-
yl)cyclohex-3-
enecarboxylate A16-1 (5.00 g, 70 % purity, 9.15 mmol) in methanol (100 mL) was
added 10 % palladium on charcoal wt. (500 mg). After stirred at room
temperature
for 16 hours under hydrogen atmosphere of balloon, the mixture was filtered
and the
filtrate was concentrated to give the title compound (4.30 g, 62 % purity from
111
NMR, 99 % yield) as colorless oil. 111 NMR (400 MHz, CDC13) 6 7.37 (s, 111),
7.22 (s,
111), 6.21 (t, J= 2.4 II, 111), 4.78 - 4.69 (m, 211), 3.64 (s, 311), 3.02 -
2.97 (m, 111), 2.76
- 2.72 (m, 111), 2.65 - 2.61 (m, 1.01I), 2.11 - 2.03 (m, 2.411), 1.85 - 1.81
(m, 1.611), 1.71
- 1.67 (m, 3.211), 1.55 - 1.53 (m, 311), 1.42 - 1.25 (m, 0.811).
Acid 17: 4-(1-(3-methoxy-3-oxopropy1)-1H-pyrazol-4-yl)cyclohexane-1-carboxylic
acid
(A17)
(2eq) N"-V _____ .0Bn
(=)Bn
HN 0
0
K2CO3(2eq), DMF, 50 C 0
A13-1 overnight A17-1
1\11) ___________________________ ( __
10% Pd/C, H2 1%
OH
Me0H, r.t., overnight
0
Al 7
Intermediate A17-1:
Benzyl 4-(1-(3-methoxy-3-oxopropy1)-1Hpyrazol-4-yl)cyclohex-3-enecarboxylate
To a solution of benzyl 4-(1H-pyrazol-4-yl)cyclohex-3-enecarboxylate A13-1
(2.2 g, 7.8
mmol) in /V,/V-dimethylformamide (400 mL) was added acrylic acid methyl ester
(1.34 g, 15.6 mmol) and potassium carbonate (2.15 g, 15.6 mmol) at room
temperature. After stirred at 50 C under nitrogen atmosphere overnight, the
mixture was cooled down to room temperature, poured into water (80 mL) and
extracted with ethyl acetate (50 mL) for three times. The combined organic
layers
were washed with water (50 mL) for three times, brine (50 mL), dried over
Na2SO4(s)
and filtered. The filtrate was concentrated under reduced pressure to give a
crude
product, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 4 : 1 to 2 :1) to give the title compound (1.8 g, 63 % yield)
as
colorless oil. LC-MS (ESI): RT = 2.467 min, mass calcd. for C211124N204 368.2,
m/z
found 369.1 [M+111 . 111 NMR (400 MHz, CDC13) 6 7.54 (s, 111), 7.44 - 7.36 (m,
611),
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5.96 - 5.94 (m, 1H), 5.15 (s, 2H), 4.37 (t, J= 6.8 Hz, 2H), 3.68 (s, 3H), 2.90
- 2.87 (m,
2H), 2.68 - 2.61 (m, 1H), 2.44- 2.41 (m, 2H), 2.36 - 2.32 (m, 2H), 2.18 - 2.11
(m, 1H),
1.89 -1.79 (m, 1H).
Acid 17:
4-(1-(3-Methoxy-3-oxopropy1)-1Hpyrazol-4-y1)cydohexane-1-carboxylic acid
To a solution of benzyl 44143-methoxy-3-oxopropy1)-1H-pyrazol-4-yl)cyclohex-3-
enecarboxylate A17-1 (1.80 g, 4.89 mmol) in methanol (20 mL) was added 10 %
palladium on charcoal wt (200 mg). The reaction was stirred at room
temperature
under hydrogen atmosphere overnight. The completed reaction was filtered and
the
filtrate was concentrated under reduced pressure to give the title compound
(1.0 g,
75 % yield) as colorless oil. 11-1 NMR (400 MHz, DMSO-d6) 6 12.04 (hr s, 1H),
7.47 (s,
1H), 7.26 (s, 1H), 4.27 (t, J= 6.8 Hz, 2H), 3.58 (s, 3H), 2.83 (t, J= 6.8 Hz,
2H), 2.55 -
2.51 (m, 1H), 2.50 - 2.49 (m, 1H), 1.94 - 1.86 (m, 3H), 1.73 - 1.70 (m, 2H),
1.60 - 1.48
(m, 3H).
Acid 18: (cis)-4-(1-(3-Methoxy-3-oxopropy1)-3-methy1-1Hpyrazol-4-
y1)cydohexanecarboxylic acid (A18)
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HN3_ ,c) _______________
rj 13\
01\ 0
A18-1 (1.7 eq)
0 OTf Pd(PPOCl2(0.13 eq) 0
/ NH 0
(2.7 eq)
1 __________ ..
Bn0 K2CO3(3.3 eq), dioxane/H20 Bn0 ¨N
K2CO3(2.7 eq), DMF
A11-1 (V/V 5/1), 95 C, overnight A18-2 50 C, overnight
O / ¨ 0 /¨
¨0 0
/ /
N N Pd/C, H2, Me0H
Bn0 ___________________________________________________ ..-
r.t., overnight
A18-3 Bn0
0 ¨ 0
0 / 0 /¨
/ / K2CO3(2.2 eq), BnBr(1.7 eq)
N N
1 1\1 1 1\I DMF, r.t.,
overnight
HO HO
A18-4
¨ 0
0
O / 0 /¨
\-0 0
/ / N
Chiral separation ,
N
i 1\1 1 1\I
B
Bn0 n0
A18-5
0 ¨ 0 ¨
O / 0 /
\-0 ,-0
/ /
N N
0 C(N + I zµN +
Bn0 , Bn0 Ile
)1\sµ A18-5A )1µ A18 5B
0 0
0 0
Bn0 Bn0
trans
--
-...... . ...,___ N¨\
A18-5C 0¨ 0¨_
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0 / 0
,¨d
N/
Pd/C, H2, Me0H
Bn0 / r.t., overnight
HO 410 sµ (1\1
)"µ A18-5A )"µ A18
0 0
Intermediate A18-2:
Benzyl 443-methy1-1H-pyrazol-4-0cydohex-3-enecarboxylate
To the solution of benzyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-
enecarboxylate
A11-1 (1.0 g, 90 % purity, 2.47 mmol) and 3-methyl-4-(4,4,5,5-tetramethy1-
1,3,2-
dioxaborolan-2-y1)-1H-pyrazole A18-1 (857 mg, 4.12 mmol) in 1,4-dioxane (20
mL)
and water (4 mL) were added potassium carbonate (1.12 g, 8.10 mmol) and [1,1'-
Bis(diphenylphosphino)ferrocenei dichloropalladium(H) (198 mg, 0.27 mmol) at
room
temperature under nitrogen atmosphere. After stirred at 95 C overnight, the
mixture was concentrated under reduced pressure to give a crude which was
diluted
with water (10 mL) and extracted with ethyl acetate (20 mL) for three times.
The
combined organic layers were washed with brine (20 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated and purified by silica gel column
chromatography (petroleum ether ethyl acetate = 4 1 to 1 1) to give the title
compound (670 mg, 73 % purity, 67 % yield) as colorless oil. LC-MS (ESI): RT =
2.350
min, mass calcd. for C181120N202 296.2, m/z found 297.1 [M+111 . 111 NMR (400
MHz,
CDC13) 6 7.44 (s, 111), 7.37 - 7.31 (m, 511), 5.78 (s, 111), 5.16 (s, 211),
2.71 - 2.64 (m,
111), 2.48 - 2.43 (m, 211), 2.42 - 2.37 (m, 211), 2.35 (s, 311), 2.20 - 2.10
(m, 111), 1.91 -
1.78 (m, 111).
Intermediate A18-3:
Mixture of benzyl 441-(3-methoxy-3-oxopropy1)-3-methy1-1H-pyrazol-4-ypcydohex-
3-enecarboxylate and benzyl 44143-methoxy-3-oxopropy1)-5-methy1-1H-pyrazol-4-
y1)cydohex-3-enecarboxylate
To the solution of benzyl 4-(3-methyl-1H-pyrazol-4-yl)cyclohex-3-
enecarboxylate
A18-2 (500 mg, 73 % purity, 1.23 mmol) in N,N-dimethylformamide (10 mL) were
added potassium carbonate (466 mg, 3.37 mmol) and methyl acrylate (291 mg,
3.38
mmol) at room temperature under nitrogen atmosphere. After stirred at 50 C
overnight, the mixture was diluted with water (15 mL) and extracted with ethyl
acetate (10 mL) for three times. The combined organic layers were washed with
.. brine (10 mL) for three times, dried over Na2SO4(s) and filtered. The
filtrate was
concentrated and purified by silica gel column chromatography (petroleum ether
ethyl acetate = 4 1 to 1 1) to give crude product and then further purified by
C18
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column (acetonitrile water = 5 % to 80 %) to give the title compound (300 mg,
95 %
purity, 61 % yield) as light yellow oil. LC-MS (ESI): RT = 2.509 min, mass
calcd. for
C22H26N204 382.2, m/z found 383.1 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 7.39 -
7.31
(m, 5H), 7.27 (s, 1H), 5.83 - 5.77 (m, 0.7H), 5.67 - 5.62 (m, 0.3H), 5.16 (s,
2H), 4.30 (t,
J= 6.4 Hz, 2H), 3.68 (s, 3H), 2.89 (t, J= 7.2 Hz, 0.5H), 2.86 (t, J= 6.4 Hz,
1.5H), 2.71
- 2.62 (m, 1H), 2.46 - 2.42 (m, 2H), 2.40 - 2.33 (m, 2H), 2.31 (s, 1H), 2.30
(s, 2H), 2.17
- 2.12 (m, 1H), 1.92 - 1.79 (m, 1H).
Intermediate A18-4:
Mixture of 4-(1-(3-methoxy-3-oxopropy1)-3-methyl-1H-pyrazol-4-
yl)cydohexanecarboxylic acid and 4-(143-methoxy-3-oxopropy1)-5-methyl-1H-
pyrazol-4-yl)cydohexanecarboxylic acid
To the solution of mixture of benzyl 4-(1-(3-methoxy-3-oxopropy1)-3-methyl-1H-
pyrazol-4-yl)cyclohex-3-enecarboxylate and benzyl 4-(1-(3-methoxy-3-oxopropy1)-
5-
methyl-1H-pyrazol-4-yl)cyclohex-3-enecarboxylate A18-3 (300 mg, 95 % purity,
0.745
mmol) in methanol (5 mL) was added 10 % palladium on charcoal wt. (30 mg). The
reaction was stirred at room temperature under hydrogen atmosphere of balloon
overnight. The completed reaction was filtered and the filtrate was
concentrated
under reduced pressure to give the title compound (220 mg, 90 % purity, 90 %
yield)
as colorless oil. 11-1 NMR (400 MHz, DMSO-d6) 6 12.15 (br s, 1H), 7.33 (s,
0.8H), 7.13
(s, 0.2H), 4.17 (t, J= 6.8 Hz, 2H), 3.58 (s,1.6H), 3.57 (s, 1.4H), 2.83 - 2.78
(m, 2H),
2.56 - 2.53 (m, 1H), 2.44 - 2.35 (m, 0.7H), 2.33 - 2.23 (m, 0.3H), 2.17 (s,
1H), 2.06 (s,
2H), 2.04 - 1.91(m, 2H), 1.67 - 1.51 (m, 3.4H), 1.47 - 1.22 (m, 2.6H).
Intermediate A18-5:
Mixture of benzyl 4-(1-(3-methoxy-3-oxopropy1)-3-methy1-1H-pyrazol-4-
yl)cydohexanecarboxylate (a mixture of 2 stereoisomers) and benzyl 4-(1-(3-
methoxy-3-oxopropy1)-5-methyl-1H-pyrazol-4-y1)cydohexanecarboxylate (a mixture
of 2 stereoisomers)
To the solution of mixture of 4-(1-(3-methoxy-3-oxopropy1)-3-methyl-1H-pyrazol-
4-
yl)cyclohexanecarboxylic acid and 4-(1-(3-methoxy-3-oxopropy1)-5-methy1-1H-
pyrazol-4-yl)cyclohexanecarboxylic acid A18-4 (220 mg, 90 % purity, 0.673
mmol) in
N,N-dimethylformamide (5 mL) were added potassium carbonate (207 mg, 1.49
mmol) and (bromomethyl)benzene (193 mg, 1.13 mmol) at room temperature under
nitrogen atmosphere. After stirred at room temperature overnight, the mixture
was
diluted with water (15 mL) and extracted with ethyl acetate (10 mL) for three
times.
The combined organic layers were washed with brine (10 mL) for three times,
dried
over Na2SO4(s) and filtered. The filtrate was concentrated and purified by
silica gel
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column chromatography (petroleum ether : ethyl acetate = 5 : 1 to 1: 1) to
give the
title compound (240 mg, 95 % purity from 111 NMR, 88 % yield) as light yellow
oil.
LC-MS (ESI): RT = 2.556 min, mass calcd. for C22H28N204 384.2, m/z found 385.1
[M+11] . 111 NMR (400 MHz, CDC13) 6 7.39 - 7.30 (m, 511), 7.21 (s, 0.311),
7.09 (s,
0.211), 7.05 (s, 0.511), 5.17 (s, 0.511), 5.16 (s, 111), 5.13 (s, 0.511), 4.30
- 4.25 (m, 211),
3.67 (s, 311), 2.91 - 2.83 (m, 211), 2.73 - 2.68 (m, 0.8H), 2.49 - 2.31 (m,
1.21I), 2.23 -
2.15 (m, 411), 2.12 - 1.87 (m, 111), 1.76 - 1.39 (m, 611).
Intermediates A18-5A, A18-5B and A18-5C: (cis)-benzyl 4-(1-(3-methoxy-3-
oxopropy1)-3-methyl-1Hpyrazol-4-y1)cydohexane carboxylate (a single
stereoisomer),
(trans)-benzyl 4-(1(3-methoxy-3-oxopropyI)-3-methyl- 1Hpyrazol-4-
yl)cydohexanecarboxylate (a single stereoisomer) and mixture of (cis)-benzyl 4-
(1-
(3-methoxy-3-oxopropy1)-5-methyl-1H-pyrazol-4-yl)cydohexanecarboxylate and
(trans)-benzyl 4-(1-(3-methoxy-3-oxopropy1)-5-methyl-1H-pyrazol-4-
yl)cydohexanecarboxylate (a mixture of 2 stereoisomers)
Mixture of benzyl 4-(1-(3-methoxy-3-oxopropy1)-3-methyl-1H-pyrazol-4-
yl)cyclohexanecarboxylate and benzyl 4-(1-(3-methoxy-3-oxopropy1)-5-methyl-111-
pyrazol-4-yl)cyclohexanecarboxylate A18-5 (7.90 g, 95 % purity, 19.5 mmol) was
separated by chiral Prep. SFC (separation condition: Column: Chiralpak IE 5 gm
20
* 250 nm; Mobile Phase: CO2 : Me0H = 60 : 40 at 45 g / min; Temp: 30 C;
Wavelength: 214 nm) to afford the title compounds A18-5A (4.35 g, 88 % purity,
51 %
yield) as light yellow oil, A18-5B (1.04 g, 87 % purity, 12 % yield) as light
yellow oil
and A18-5C (1.70 g, 84 % purity, 19 % yield) as light yellow oil.
A18-5A: LC-MS (ESI): RT = 2.544 min, mass calcd. for C221128N204 384.2, m/z
found
385.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm; Mobile
Phase: CO2 : Me0H = 60 : 40 at 3 g / min; Temp: 30 C; Wavelength: 230 nm,
Back
pressure: 100 bar, RT = 3.03 min). 1H NMR (400 MHz, CDC13) 6 7.40 - 7.36 (m,
511),
7.05 (s, 111), 5.16 (s, 211), 4.27 (t, J= 6.8 Hz, 211), 3.67 (s, 311), 2.84
(t, J= 6.8 Hz, 211),
2.72 - 2.68 (m, 111), 2.48 - 2.41 (m, 111), 2.19 - 2.15 (m, 511), 1.76 - 1.71
(m, 211), 1.68 -
1.60 (m, 211), 1.52 - 1.42 (m, 211).
A18-5B: LC-MS (ESI): RT = 2.689 min, mass calcd. for C221128N204 384.2, m/z
found
385.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm; Mobile
Phase: CO2 : Me0H = 60 : 40 at 3 g / min; Temp: 30 C; Wavelength: 230 nm,
Back
pressure: 100 bar, RT = 3.71 min). 1H NMR (400 MHz, CDC13) 6 7.39 - 7.30 (m,
511),
7.09 (s, 111), 5.13 (s, 211), 4.29 (t, J= 6.4 Hz, 211), 3.67 (s, 311), 2.85
(t, J= 6.4 Hz, 211),
2.41 - 2.32(m, 211), 2.19 (s, 311), 2.11 - 2.06 (m, 211), 1.98 - 1.94 (m,
211), 1.63 - 1.53 (m,
211), 1.33 - 1.23 (m, 211).
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A18-5C: LC-MS (ESI): RT = 2.588 min, mass calcd. for C221128N204384.2, m/z
found
385.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm; Mobile
Phase: CO2 : Me0H = 60 : 40 at 3 g / min; Temp: 30 C; Wavelength: 230 nm,
Back
pressure: 100 bar, RT = 4.45 min). 1H NMR (400 MHz, CDC13) 6 7.37 - 7.31 (m,
51I),
7.21 (s, 111), 5.17 (s, 1.61I), 5.13 (s, 0.411), 4.29 - 4.25 (m, 21I), 3.67
(s, 31I), 2.91 - 2.87
(m, 21I), 2.75 - 2.67 (m, 0.811), 2.43 - 2.31 (m, 1.211), 2.25 - 2.17 (m,
4.511), 2.15 - 2.08
(m, 0.511), 1.91 - 1.87 (m, 0.511), 1.72 - 1.52 (m, 511), 1.43 - 1.37 (m,
0.511).
Acid 18:
(cis)-4-(1-(3-Methoxy-3-oxopropyl)-3-methyl-1H-pyrazol-4-y1)cydohexanecarbox-
ylic
acid
To the solution of (cis)-benzyl 4-(1-(3-methoxy-3-oxopropy1)-3-methyl-1H-
pyrazol-4-
yl)cyclohexanecarboxylate A18-5A (4.35 g, 88 % purity, 9.96 mmol) in methanol
(20
mL) was added 10 % palladium on charcoal wt. (440 mg). After stirred at room
temperature under hydrogen atmosphere (balloon) overnight, the reaction
mixture
.. was filtered and the filtrate was concentrated under reduced pressure to
give the
title compound (3.22 g, 80 % purity, 88 % yield) as white solids. LC-MS (ESI):
RT =
1.718 min, mass calcd. for Ci51122N204 294.2, m/z found 295.1 [M+111 . 1H NMR
(400
MHz, DMSO-d6) 6 12.11 (s, 11I), 7.33 (s, 11I), 4.17 (t, J= 6.8 Hz, 21I), 3.58
(s, 31I),
2.80 (t, J= 6.8 Hz, 211), 2.59 - 2.57 (m, 11I), 2.43 - 2.37 (m, 11I), 2.06 (s,
31I), 2.02 -
1.98 (m, 211), 1.67 - 1.63 (m, 21I), 1.59 - 1.51 (m, 21), 1.40 - 1.34 (m,
21I).
Acid 19: 4-(1-(3-(tert-butoxycarbonyl)cydobuty1)-1H-pyrazol-4-yl)cydohexane-1-
carboxylic acid (A19)
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OH (Boc)20(2.0 eq) ___ o NaBH4(1.0 eq)
0=0-
0 DMAP(0.4 eq)
Me0H, 0 C-r.t.
t-BuOH, r.t., 12 h 0
1 h
A19-1 A19-2
______ O MsCI(1.5 eq)OH __ ,
TEA(2.0 eq) OMs
O DCM, r.t., 1 h 0
A19-3 A19-4
-HO
OBn OBn
0
A19-4
________________________________________ >(DO ____________________
NH Cs2CO3(3.0 eq), DMF, 120 C,
12 h
A13-1 A19-5
OH
0
H2, Pd/C, 50 Psi
o0 _______________________________________
50 C, overnight
Al 9
Intermediate A19-2:
tert-Butyl 3-oxocydobutanecarboxylate
To a solution of 3-oxocyclobutanecarboxylic acid A19-1 (20.0 g, 98 % purity,
0.172
mol) in 2-methylpropan-2-ol (200 mL) were added /V,/V-dimethylpyridin-4-amine
(8.48 g, 99 % purity, 68.7 mmol) and di- tert-butyl dicarbonate (75.5 g, 99.3
% purity,
0.344 mol) slowly at room temperature. After stirred at room temperature for
12
hours under nitrogen atmosphere, the reaction mixture was quenched with 1 M
hydrochloride aqueous solution (200 mL) slowly and extracted with ethyl
acetate
(200 mL) for three times. The combined organic layers were washed with brine
(200
mL), dried over Na2SO4(s), filtered and concentrated under reduced pressure to
give
a residue, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 50 : 1 to 30 :1) to afford the title compound (17.9 g, 95 %
purity from
111 NMR, 58 % yield) as colorless oil. 111 NMR (400 MHz, CDC13) 6 3.39 - 3.32
(m,
211), 3.27 - 3.20 (m, 211), 3.13 - 3.07 (m, 111), 1.47 (s, 911).
Intermediate A19-3:
tert-Butyl 3-hydroxycydobutanecarboxylate
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To a solution of tert-butyl 3-oxocyclobutanecarboxylate A19-2 (17.9 g, 95 %
purity,
0.100 mol) in methanol (180 mL) was added sodium tetrahydroborate (3.86 g,
98.5 %
purity, 0.101 mol) at 0 C. After stirred at room temperature for 1 hour under
nitrogen atmosphere, the reaction mixture was quenched with saturated aqueous
sodium bicarbonate solution (200 mL) slowly and extracted with ethyl acetate
(200
mL) for three times. The combined organic layers were washed with brine (200
mL),
dried over Na2SO4(s), filtered and concentrated under reduced pressure to give
the
title compound (17.9 g, 95 % purity from 111 NMR, 99 % yield) as colorless
oil. 111
NMR (400 MHz, CDC13) 64.15 (br s, 111), 2.59 - 2.46 (m, 311), 2.24- 2.17 (m,
111),
.. 2.12 - 2.04 (m, 211), 1.44 (s, 911).
Intermediate A19-4:
tert-Butyl 3-((methylsulfonyl)oxy)cydobutanecarboxylate
To a solution of tert-butyl 3-hydroxycyclobutanecarboxylate A19-3 (5.00 g, 95
%
purity, 27.6 mmol) in dichloromethane (50 mL) were added triethylamine (5.61
g,
99 % purity, 54.9 mmol) and methanesulfonyl chloride (4.79 g, 99 % purity,
41.4
mmol) at room temperature. After stirred at room temperature for 1 hour under
nitrogen atmosphere, the reaction mixture was quenched with saturated aqueous
sodium bicarbonate solution (50 mL) slowly and extracted with dichloromethane
(50
mL) for three times. The combined organic layers were washed with brine (50
mL),
dried over Na2SO4(s), filtered and concentrated under reduced pressure to
afford the
title compound (7.10 g, 85 % purity, 87 % yield) as yellow solids. 11-1 NMR
(300 MHz,
CDC13) 6 4.95 - 4.85 (m, 111), 3.00 (s, 311), 2.71 - 2.61 (m, 311), 2.55 -
2.46 (m, 211),
1.45 (s, 911).
Intermediate A19-5:
Benzyl 4-(1-(3-(tert-butoxycarbonyl)cydobuty1)-1H-pyrazol-4-y1)cydohex-3-
enecarboxylate
To a solution of benzyl 4-(1H-pyrazol-4-yl)cyclohex-3-enecarboxylate A13-1
(3.00 g,
90 % purity, 9.56 mmol) in /V,/V-dimethylformamide (30 mL) were added tert-
butyl
3-((methylsulfonyl)oxy)cyclobutanecarboxylate A19-4 (4.22 g, 85 % purity, 14.3
mmol) and cesium carbonate (9.44 g, 99 % purity, 28.7 mmol) at room
temperature.
After stirred at 120 C for 12 hours under nitrogen atmosphere, the reaction
mixture
was quenched with water (50 mL) slowly and extracted with ethyl acetate (50
mL)
for three times. The combined organic layers were washed with brine (50 mL),
dried
over Na2SO4(s), filtered and concentrated under reduced pressure to give a
residue,
which was purified by silica gel column chromatography (petroleum ether ethyl
acetate = 20 1 to 10 1) to afford the title compound (980 mg, 95 % purity, 22
%
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yield) as yellow oil. LC-MS (ESI): RT = 2.100 min, mass calcd. for C261132N204
436.2,
m/z found 437.2 [M+H] .
Acid 19:
4-(1- (3-(tert-butoxycarbonyl)cyclobutyl) - 1H pyrazol-4-yl)cyclohexane- 1-
carboxylic
acid
To a solution of benzyl 4-(1-(3-(tert-butoxycarbonyl)cyclobuty1)-1H-pyrazol-4-
yl)cyclohex-3-enecarboxylate A19-5 (980 mg, 95 % purity, 2.13 mmol) in
methanol
(20 mL) was added 10 % palladium on charcoal wt. (100 mg) under nitrogen
atmosphere at room temperature. After replacing the inner nitrogen atmosphere
with hydrogen gas, the mixture was stirred at 50 C under hydrogen atmosphere
(50
psi) overnight. After cooling down to room temperature and releasing the
inside
pressure into normal pressure, the catalyst was filtered off and the filtrate
was
concentrated under reduced pressure to give the title compound (490 mg, 95 %
purity, 63 % yield) as gray solids. 111 NMR (400 MHz, CDC13) 6 7.38 - 7.17 (m,
211),
6.43(br s, 111), 4.94 - 4.86 (m, 0.511), 4.66 - 4.57 (m, 0.511), 3.07 - 3.01
(m, 0.511), 2.84
- 2.76 (m, 1.511), 2.68 - 2.63 (m, 411), 2.53 - 2.50 (m, 0.811), 2.43 - 2.37
(m, 0.211), 2.00
- 1.98 (m, 2.511), 1.79 - 1.74 (m, 1.511), 1.66 - 1.58 (m, 311), 1.48 (s,
411), 1.45 (s, 511),
1.32 - 1.21 (m, 111).
Acid 20: 4-(3-(Methoxycarbony1)-1-methyl-1H-pyrazol-5-371)cyclohexane
carboxylic
acid (A20)
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N-NH CH3I (1.1 eq),
oy,}---NO2 K2CO3 (2.0 eq) ) 02N r, 0 N-
\\ JI\J
,
0 DMF, 0 C, 1 hour NO2
A20-1 A20-2
H2 (30 psi),
N 0 N-
Pd/C, Me0H H2 jiNN
r.t., overnight N 0 NH
A20-3A A20-3B
0-Bn
NaNO2 (1.2 eq), KI(2.2 eq), A20-5 Pd(PPh3)4 (0.1 eq),
AcOH/water N N (2.3 eq) K2CO3 (2.0 eq)
0
A20-3A _______________ 0
0 C, 3 hours 0
di
A20-4 oxane/water, 90 C, overnight
m
Bn
Pd/C, H2
0 ___________________________ > 0
Me0H, 50 C, HO
overnight
A20-6 A20
Intermediate A20-2:
Mixture of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate and methyl 1-
methyl-
3-nitro-1H-pyrazole-5-carboxylate
To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate A20-1 (8.4 g, 97 %
purity,
47.6 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate
(13.139 g, 95.068 mmol), then iodomethane (7.451 g, 52.495 mmol) was added
dropwise at 0 C. The reaction mixture was stirred at 0 .0 for 1 hour. The
solvent
was concentrated under reduced pressure to give the title compound (8.0 g, 88
%
purity, 80 % yield) as yellow solids. LC-MS (ESI): RT = 1.11 min and 1.30 min.
Intermediates A20-3A and A20-3B:
Methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate and methyl 3-amino-1-methyl-
1H-pyrazole-5-carboxylate
To a solution of A20-2 (8.0 g, 88 % purity, 38.0 mmol) in ethanol (100 mL) was
added
10 % palladium on charcoal wt. (1.0 g) at room temperature. The reaction
mixture
was stirred at room temperature under hydrogen atmosphere (30 psi) overnight.
The
reaction mixture was filtered and the filtrate was concentrated to give a
residue,
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which was purified by silica gel column chromatography (petroleum ether :
ethyl
acetate = 2 : 1 to dichloromethane : methanol = 20 :1) to give the title
compound
A20-3A (970 mg, 95 % purity from 1HNMR, 16 % yield) and A20-3B (5.26 g, 98 %
purity from 1HNMR, 89 % yield) as yellow solids.
A20-3A: LC-MS (ESI): RT = 0.32 min, mass calcd. for C6119N302 155.1, m/z found
156.2[M+111 . 111 NMR (400 MHz, CDC13) 6.08 (s, 111), 3.89 (s, 311), 3.75 (s,
311), 3.68
(br s, 21I).
A20-3B: LC-MS (ESI): RT = 0.38 min, mass calcd. for C6119N302 155.1, m/z found
156.2[M+111 . 111 NMR (400 MHz, CDC13) 6.11 (s, 111), 3.98 (s, 311), 3.83 (s,
311), 3.65
(br s, 21I).
Intermediate A20-4:
Methyl 5-iodo-1-methy1-1H-pyrazole-3-carboxylate
To a solution of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate A20-3A (970
mg, 95 % purity, 5.94 mmol) and potassium iodide (2.2 g, 13.3 mmol) in acetic
acid
(10 mL) and water (3 mL) was added a sodium nitrite (534 mg, 97 % purity, 7.51
mmol) in water (7 mL). After addition, the reaction mixture was stirred at 0
C for 3
hours then the mixture was basified to pH 7 - 8 with saturated sodium
bicarbonate
aqueous solution (200 mL). The mixture was extracted by ethyl acetate (100 mL)
twice. The combined organic layers were washed by brine (100 mL) twice, dried
over
Na2SO4(s) and filtered. The filtrate was concentrated under reduced pressure
to give
a residue, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 5 : 1) to give the title compound A20-4 (700 mg, 95 % purity,
40 %
yield) as white solids. LC-MS (ESI): RT = 1.26 min, mass calcd. for C6117IN202
266.0,
m/z found 266.9[M+11] . 1H NMR (400 MHz, CDC13) 6.97 (s, 11I), 4.00 (s, 31I),
3.91 (s,
311).
Intermediate A20-6:
Methyl 5-(4-0Benzyloxy)carbonypcydohex-1-en-1-y1)-1-methyl-1H-pyrazole-3-
carboxylate
The mixture of methyl 5-iodo-1-methy1-1H-pyrazole-3-carboxylate A20-4 (550 mg,
95 % purity, 1.96 mmol), benzyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)cyclohex-3-enecarboxylate A20-5 (1.7 g, 91 % purity, 4.5 mmol),
tetrakis(triphenylphosphine) palladium(0) (232 mg, 0.201 mmol) and potassium
carbonate (560 mg, 4.05 mmol) in dioxane (10 mL) and water (0.5 mL) was
stirred at
90 C under nitrogen atmosphere overnight. After cooling down to room
temperature,
the solvent was removed under reduced pressure, and the residue was purified
by
silica gel column chromatography (petroleum ether : ethyl acetate = 3 :1) to
give the
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title compound A20-6 (390 mg, 96 % purity, 54 % yield) as yellow oil. LC-MS
(ESI):
RT = 1.63 min, mass calcd. for C201122N204 354.2, m/z found 355.2[M+111 . 111
NMR
(400 MHz, CDC13) 7.38 - 7.33 (m, 511), 6.64 (s, 111), 5.93 - 5.90 (m, 111),
5.16 (s, 211),
3.91 (s, 311), 3.87 (s, 311), 2.74 -2.70 (m, 111), 2.53 - 2.50 (m, 211), 2.35 -
2.32 (m, 211),
2.17 - 2.14 (m, 111), 1.92 - 1.90 (m, 111).
Acid 20:
4-(3-(Methoxycarbony1)-1-methyl-1H-pyrazol-571)cydohexanecarboxylic acid
To a solution of methyl 5-(4-((benzyloxy)carbonyl)cyclohex-1-en-l-y1)-1-methyl-
111-
pyrazole-3-carboxylate A20-6 (810 mg, 97 % purity, 2.22 mmol) in methanol (5
mL)
was added palladium on charcoal (80 mg, 10 % wt) at room temperature. The
reaction mixture was stirred at 50 C under hydrogen atmosphere (50 psi)
overnight.
The reaction mixture was cooled down to room temperature and filtered. The
filtrate
was concentrated to give the title compound A20 (550 mg, 90 % purity from
1FINMR,
84 % yield) as white solids. 111 NMR (300 MHz, CDC13) 6.61 (s, 0.811), 6.59
(s, 0.211),
3.91 - 3.89 (m, 611), 2.79 - 2.77 (m, 111), 2.66 - 2.42 (m, 211), 2.30 - 2.18
(m, 211), 2.05 -
2.03 (m, 111), 1.87 - 1.80 (m, 211), 1.74 - 1.66 (m, 214).
Acid 21: 4-(5-(methoxycarbony1)-1-methyl-1H-pyrazol-3-ypcydohexanecarboxylic
acid (A21)
CI
I-I I
0 OH H
N 0
.1\1 (1.5 eq)
,N 0 O
I OH
HO (3 5 eq)
CD! (1.2 eq)
Ts0H (0.3 eq)
DCM, it., 1 h
0 toluene, r.t., overnight
(:) 0 '
0 0 0
A1-1 A21-1 A21-2
0
0
_,..-----õcrkr0,,..--
J
(1.5 eq) o
0
CH3MgBr (4.0 eq)
NaH (1.0 eq) ..- 0
THF, 0 C, 1 h 0 c) toluene, r.t., overnight 0 OH
\ __ /
A21-3 A21-4
H (1.0 eq) CO CO
NH2 H2SO4
N-N 0
0
Et0H, r.t., overnight \ / IN-N
A21-5A A21-5B
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00 _(13
)r ID\
0 0
TFA/DCM 0-1 N2 /
A21-5A _____________
(v/v1/4) A21-7 (1.5 eq)
\
r.t., overnight NN 0
K2CO3 (2.1 eq)
Me0H, 0 C - r.t., 2.5 h
A21-6
07 07
oi KMn04 (2.5 eq)
0 1 N HCI (2.8 eq) 0 0 NaHS03 (5.0 eq)
\
N-NN MeCN, r.t., 3 h N"N acetone/H20(v/v=5/1)
0 C - r.t., 1.25 h
A21-8 A21-9
OV
HO 0
0 NJ" N
A21
Intermediate A2 1- 1:
NMethoxy-Nmethy1-4-oxocydohexanecarboxamide
To a solution of 4-oxocyclohexanecarboxylic acid A1-1 (20.0 g, 141 mmol) in
dichloromethane (400 mL) was added N, 0-dimethylhydroxylamine hydrochloride
(20.5 g, 211 mmol) and N,N-carbonyldiimidazole (27.3 g, 169 mmol) at room
temperature. After stirred at room temperature for 1 hour, the mixture was
diluted
with water (300 mL), extracted with dichloromethane (400 mL) twice. The
combined
organic layers were concentrated under reduced pressure to give the title
compound
(13.3 g, 51 % yield) as yellow oil. LC-MS (ESI): RT = 0.63 min, mass calcd.
for
C911i5NO3 185.1, m/z found mass 186.0 [M+111 .111 NMR (300 MHz, CD30D) 6 3.75
(s, 311), 3.14 (s, 311), 2.54 - 2.43 (m, 311), 2.30 - 2.22 (m, 211), 2.05 -
1.99 (m, 211), 1.80
- 1.65 (m, 211)
Intermediate A2 1-2:
NMethoxy-Nmethyl- 1,4-dioxaspiro [4. 5]decane-8-carboxamide
To a solution of Nmethoxy-Nmethyl-4-oxocyclohexanecarboxamide A21- 1 (13.3 g,
71.8 mmol) and ethane-1,2-diol (15.5 g, 250 mmol) in toluene (150 mL) was
added 4-
methylbenzenesulfonic acid (3.69 g, 21.4 mmol). After stirred at room
temperature
overnight, the mixture was concentrated to give a residue, which was dissolved
in
dichloromethane (100 mL). The resulting solution was washed with water (100
mL)
and then concentrated under reduced pressure to give the title compound (9.00
g, 55 %
yield) as yellow oil. 111 NMR (300 MHz, DMSO-d6) 6 3.92 - 3.86 (m, 411), 3.66 -
3.63
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(m, 311), 3.13 - 3.12 (m, 311), 2.68 - 2.62 (m, 111), 1.86 - 1.74 (m, 611),
1.58 - 1.47 (m,
211)
Intermediate A21-3:
1-(1,4-Dioxaspiro[4.5]decan-8-yl)ethanone
To a solution of N-methoxy-N-methy1-1,4-dioxaspiro[4.5idecane-8-carboxamide
A21-
2 (9.00 g, 39.2 mmol) in anhydrous tetrahydrofuran (60 mL) at 0 C was added
dropwise 2 M methylmagnesium bromide in tetrahydrofuran (79 mL, 158 mmol).
After stirred at 0 C for 1 hour, the mixture was quenched with saturated
aqueous
ammonium chloride (79 mL), then extracted with ethyl acetate (100 mL) for
three
times. The separated combined organic layer was washed with brine (100 mL),
dried
over Na2SO4(s) and concentrated under reduced pressure to give a residue,
which
was purified by silica gel column chromatography (petroleum ether : ethyl
acetate =
10 : 1) to give the title compound (4.00 g, 55 % yield) as yellow oil. LC-MS
(ESI): RT
= 0.88 min, mass calcd. for C10111603 184.1, m/z found mass 185.1 [M411+. 111
NMR
(300 MHz, DMSO-d6) 6 3.83 - 3.76 (m, 411), 2.40 - 2.29 (m, 111), 2.09 - 2.02
(m, 311),
1.78 - 1.72 (m, 211), 1.70 - 1.58 (m, 211), 1.46 - 1.40 (m, 411).
Intermediate A21-4:
Ethyl 2-hydroxy-4-oxo-4-(1,4-dioxaspiro[4.5]decan-8-yObut-2-enoate
To a solution of 1-(1,4-dioxaspiro[4.5idecan-8-yl)ethanone A21-3 (3.30 g, 17.9
mmol)
in toluene (40 mL) was added 60 % wt. sodium hydride in mineral oil (716 mg,
17.9
mmol) at room temperature. After stirring at room temperature for 1 hour,
diethyl
oxalate (3.93 g, 26.9 mmol) was added. After stirred at room temperature
overnight,
the mixture was acidified to pH 3 - 4 with 10 % wt. citric acid aqueous
solution and
extracted with ethyl acetate (20 mL) twice. The combined organic layers were
washed with water (20 mL), brine (10 mL), dried over anhydrous Na2SO4(),
filtered
and concentrated to give a residue, which was purified by silica gel column
chromatography (petroleum ether : ethyl acetate = 15 :1) to give the title
compound
(3.30 g, 65 % yield) as yellow oil. LC-MS (ESI): RT = 1.45 min, mass calcd.
for
C14112006 284.1, m/z found mass 285.2 [M411+. 11-1 NMR (300 MHz, DMSO-d6) 6
7.24
- 7.13 (m, 111), 6.39 (s, 111), 4.28 - 4.19 (m, 211), 3.84 - 3.80 (m, 411),
2.4 - 2.47 (m, 111),
1.81 - 1.49 (m, 811), 1.27 - 1.16 (m, 311).
Intermediates A21-5A and A21-5B:
Ethyl 1-methyl-3-(1,4-dioxaspiro[4.5]decan-8-y1)-1Hpyrazole-5-carboxylate and
ethyl 1-methyl-5-(1,4-dioxaspiro[4.5]decan-8-y1)-1Hpyrazole-3-carboxylate
To a solution of triethylamine (2.35 g, 23.2 mmol) in ethanol (300 mL) was
added
methylhydrazine sulfate (1.67g, 11.6 mmol) at room temperature. After stirring
at
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room temperature for 1 hour, ethyl 2-hydroxy-4-oxo-4-(1,4-dioxaspiro[4.51decan-
8-
ylkut-2-enoate A21-4 (3.30 g, 11.6 mmol) was added. After stirred at room
temperature overnight, the mixture was concentrated to give a residue, which
was
dissolved in ethyl acetate (150 mL). The resulting solution was washed with
water
(100 mL), brine (100 mL), dried over Na2SO4(), filtered and concentrated under
reduced pressure to give a residue, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 4 1 to 2 1) to give the title
compounds A21-5A (1.50 g, 44 % yield) and A21-5B (520 mg, 15 % yield) as
yellow
oil.
.. A21-5A: 111 NMR (300 MHz, CDC13) 6 6.67 (s, 1H), 4.32 (q, J= 5.4 Hz, 2H),
4.11 (s,
3H), 3.96 (s, 4H), 2.74 - 2.66 (m, 1H), 1.99 - 1.95 (m, 2H), 1.85 - 1.81 (m,
2H), 1.78 -
1.63 (m, 4H), 1.37 (t, J= 5.4 Hz, 3H).
A21-5B: 111 NMR (300 MHz, DMSO-d6) 6 6.49 (s, 1H), 4.23 (q, J= 5.4 Hz, 2H),
3.88
(s, 4H), 3.85 (s, 3H), 2.84 - 2.77 (m, 1H), 1.88 - 1.84 (m, 2H), 1.76 - 1.73
(m, 2H), 1.67
.. - 1.50 (m, 4H), 1.27 (t, J= 5.4 Hz, 3H).
Intermediate A21-6:
Ethyl 1-methyl-3-(4-oxocydohexyl)-1Hpyrazole-5-carboxylate
To a solution of ethyl 1-methyl-3-(1,4-dioxaspiro[4.51decan-8-y1)-1H-pyrazole-
5-
carboxylate A21-5A (830 mg, 2.82 mmol) in dichloromethane (20 mL) was added
trifluoroacetic acid (5 mL) at room temperature. After stirred at room
temperature
overnight, the reaction mixture was concentrated to give a residue, which was
dissolved in ethyl acetate (40 mL). The resulting solution was washed with
saturated sodium bicarbonate aqueous solution (50 mL), brine (15 mL), dried
over
Na2SO4(s) and filtered. The filterate was concentrated under reduced pressure
to give
the title compound (700 mg, 99 % yield) as yellow oil. LC-MS (ESI): RT = 1.38
min,
mass calcd. for Ci3Hi8N203250.1, m/z found mass 251.2 [M+111 . 1H NMR (300
MHz,
DMSO-d6) 66.68 - 6.64 (m, 1H), 4.35 - 4.28 (m, 2H), 4.14- 4.06 (m, 3H), 3.18 -
3.06
(m, 1H), 2.48 - 2.41 (m, 2H), 2.27 - 2.26 (m, 2H), 2.02 - 1.86 (m, 2H), 1.68 -
1.53 (m,
2H), 1.38 - 1.32 (m, 3H).
Intermediate A21-8:
Methyl 344-(methoxymethylene)cydohexyl)-1-methyl-1Hpyrazole-5-carboxylate
To a solution of ethyl 1-methy1-3-(4-oxocyclohexyl)-1H-pyrazole-5-carboxylate
A21-6
(736 mg, 2.94 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate A21-7 (840
mg,
4.37 mmol) in dry methanol (15 mL) was added potassium carbonate (845 mg, 6.11
mmol) at 0 0C under nitrogen atmosphere. After stirred at 0 C for 30 minutes
and
then at room temperature for 2 hours, the reaction mixture was diluted with
water
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(20 mL) and extracted with ethyl acetate (30 mL) twice. The combined organic
layers were washed with water (30 mL), brine (30 mL) twice, dried over
Na2SO4(s)
and filtered. The filtrate wasconcentrated under reduced pressure to give a
residue,
which was purified by silica gel column chromatography (petroleum ether :
ethyl
acetate = 15 : 1) to give the title compound (380 mg, 49 % yield) as yellow
oil. LC-MS
(EST): RT = 1.78 min, mass calcd. for C141120N203 264.2, m/z found mass 265.2
[M+11] . 111 NMR (300 MHz, DMSO-d6) 6 6.64 (s, 1H), 5.84 (s, 111), 3.98 - 3.97
(m,
311), 3.77 - 3.76 (m, 311), 3.45 - 3.44 (m, 311), 2.70 - 2.60 (m, 111), 1.92 -
1.60 (m, 411),
1.32 - 1.05 (m, 411).
Intermediate A21-9:
Methyl 3(4-formylcydohexyl)-1-methyl-1H-pyrazole-5-carboxylate
To a solution of methyl 3-(4-(methoxymethylene)cyclohexyl)-1-methy1-1H-
pyrazole-
5-carboxylate A21-8 (380 mg, 1.44 mmol) in acetonitrile (18 mL) was added 1 M
hydrochloride aqueous solution (4 mL, 4.0 mmol) at 0 C. After stirred at room
temperature for 3 hours, the reaction mixture was basified with saturated
sodium
bicarbonate aqueous solution to pH 7 - 8 and extracted with ethyl acetate (20
mL)
twice. The combined organic layers were washed with brine (20 mL) twice, dried
over Na2SO4(), filtered and concentrated under reduced pressure to give the
crude
title compound (300 mg, 83 % yield) as brown oil. LC-MS (ESI): RT = 1.43 min,
mass
calcd. for C131118N203250.1, m/z found mass 251.2 [M+111 . 11-1 NMR (300 MHz,
DMSO-d6) 6 9.63 - 9.59 (m, 111), 6.71 - 6.65 (m, 111), 4.05 - 4.00 (m, 311),
3.84 - 3.80
(m, 311), 2.70 - 2.62 (m, 111) 2.34 - 2.26 (m, 111), 2.01- 1.97 (m, 211), 1.79
- 1.59 (m,
211), 1.49 - 1.41 (m, 211), 1.36 - 1.22 (m, 211).
Acid 21:
4-(5-(methoxycarbony0-1-methyl-1Hpyrazol-3-y1)cydohexanecarboxylic acid
To a solution of methyl 3-(4-formylcyclohexyl)-1-methy1-1H-pyrazole-5-
carboxylate
A21-9 (320 mg, 1.28 mmol) in acetone (15 mL) and water (3 mL) was added
potassium permanganate (504 mg, 3.19 mmol) at 0 C. After stirring at 0 0C for
1
hour, sodium bisulfite (660 mg, 6.34 mmol) was added. Then the mixture was
diluted with acetone (10 mL) and water (5 mL). The resulting suspension was
stirred at room temperature for 15 minutes and filtered through a pad of
celite. The
filtrate was concentrated under reduced pressure at room temperature to remove
acetone. The resulting aqueous solution was acidified with citric acid(s) to
pH 3 - 4
and extracted with ethyl acetate (20 mL) twice. The combined organic layers
were
washed with brine (20 mL), dried over Na2SO4(), filtered and concentrated
under
reduced pressure to give the title compound (250 mg, 73 % yield) as white
solids. 11-1
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NMR (300 MHz, DMSO-d6) 6 11.98 (s, 111), 6.67 - 6.64 (m, 111), 4.00 - 3.99 (m,
311),
3.79 - 3.78 (m, 311), 2.72 - 2.63 (m, 111), 2.27 - 2.11 (m, 0.511), 1.96 -
1.91 (m, 0.511),
1.89 - 1.78 (m, 211), 1.71 - 1.57 (m, 411), 1.43 - 1.32 (m, 211).
Acid 22: 4-(1-(3-(tert-butoxy)-2,2-dimethy1-3-oxopropy1)-1Hpyrazol-4-
yl)cydohexane-1-carboxylic acid (A22)
o o
o 0 DIBAL-H (2.5 eq)
NaH (2.0 eq), Mel (2.0 eq)
THF, - 78 C-r.t., overnight
A22-1 A22-2
400 0 9 0 0
(2.5 eq)
OH ________________________ OTs
DCM, pyridine
A22-3 0 C-r.t., overnight A22-4
0
N --
0
N \ JD
\OBn
HN
OBn Cs2CO3 (2.0 eq.), DMF 0
100 C, overnight
A13-1 A22-5
D (
Pd/C, H2 (50Psi 0 N \
"OH
Me0H, 50 C, 5 hrs oJ
A22
Intermediate A22-2:
1- tert-Butyl 3-methyl 2,2-dimethylmalonate
To a suspension of 60 % wt. sodium hydride in mineral oil (1.56 g, 39.0 mmol)
in
tetrahydrofuran (40 mL) was added tert-butyl methyl malonate A22-1 (3.50 g,
20.0
mmol) dropwise at 0 C. After stirring at this temperature for 30 minutes,
iodomethane (5.54 g, 39.0 mmol) was added dropwise and it was continued to
stir at
room temperature for another 5 hours. Then the mixture was quenched with water
(30 mL) and extracted with ethyl acetate (50 mL) twice. The combined organic
layers were washed with brine (50 mL), dried over Na2SO4(s) and filtered. The
filtrate was concentrated under reduced pressure to give the title compound
(3.80 g,
94 % yield) as brown oil. 11-1 NMR (300 MHz, CDC13) 6 3.72 (s, 311), 1.44 (s,
911), 1.40
61-1).
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Intermediate A22-3:
tert-Butyl 3-hydroxy-2,2-dimethylpropanoate
To a solution of 1- tert-butyl 3-methyl 2,2-dimethylmalonate A22-2 (5.00 g,
24.7
mmol) in tetrahydrofuran (30 mL) was added 1.5 M diisobutylaluminum hydride in
toluene (41.3 mL, 61.9 mmol) dropwise at - 78 C under nitrogen atmosphere.
After
stirred at this temperature under nitrogen atmosphere for 2 hours and then at
room
temperature overnight, the mixture was quenched with water (50 mL) and
extracted
with ethyl acetate (100 mL) for three times. The combined organic layers were
washed with water (200 mL) for three times and brine (100 mL), dried over
Na2SO4(s)
and filtered. The filtrate was concentrated under reduced pressure to give the
title
compound (2.00 g, 47 % yield) as white oil. 1H NMR (300 MHz, CDC13) 6 3.52 (d,
J=
5.4 Hz, 2H), 2.58 (br s, 1H), 1.47 (s, 9H), 1.16 (s, 611).
Intermediate A22-4:
tert-Butyl 2,2-dimethy1-3-(tosyloxy)propanoate
To a solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate A22-3 (2.00 g,
11.5
mmol) in pyridine (8 mL) and dichloromethane (20 mL) was added tosyl chloride
(5.49 g, 28.7 mmol) at 0 C. After stirred at room temperature under nitrogen
atmosphere overnight, the mixture was concentrated and dissolved in ethyl
acetate
(40 mL) and water (40 mL), then added 0.5 M hydrochloride aqueous solution (24
mL) and separated. The aqueous layer was extracted with ethyl acetate (40 mL)
twice. The combined organic layers were washed with 0.5 M hydrochloride
aqueous
solution (20 mL) and brine (20 mL), dried over Na2SO4(s) and filtered. The
filtrate
was concentrated and purified by silica gel column chromatography (petroleum
ether ethyl acetate = 10 1) to give the title compound (1.80 g, 48 % yield) as
white
solids. 1H NMR (300 MHz, CDC13) 6 7.79 (d, J= 8.1 Hz, 211), 7.35 (d, J= 8.1
Hz, 211),
3.98 (s, 211), 2.46 (s, 311), 1.40 (s, 911), 1.14 (s, 611).
Intermediate A22-5:
Benzyl 4-(1-(3-(tert-butoxy)-2,2-dimethy1-3-oxopropy1)-1Hpyrazol-4-ypcydohex-3-
enecarboxylate
To a suspension of benzyl 4-(1H-pyrazol-4-yl)cyclohex-3-enecarboxylate A13-1
(1.18 g,
95 % purity, 3.97 mmol) and cesium carbonate (2.60 g, 7.98 mmol) in /V,/V-
dimethylformamide (30 mL) was added tert-butyl 2,2-dimethy1-3-
(tosyloxy)propanoate A22-4 (1.10 g, 95 % purity, 3.18 mmol) at room
temperature.
After stirred at 100 C overnight, the reaction mixture was quenched with
water (60
mL) and extracted with ethyl acetate (60 mL) for three times. The combined
organic
layers were washed with water (60 mL), brine (60 mL), dried over Na2SO4(s) and
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filtered. The filtrate was concentrated under reduced pressure to give a
residue,
which was purified by silica gel column chromatography (petroleum ether :
ethyl
acetate = 10 : 1 to 3 :1) to give crude product, which was further purified by
C18
column (acetonitrile : water = 70 % to 100 %) to give the title compound (700
mg, 95 %
purity from 1H NMR, 38 % yield) as colorless oil. LC-MS (ESI): RT = 1.92 min,
mass
calcd. for C26H34N204 438.3, m/z found 439.1 [M411+. 1H NMR (400 MHz, CDC13) 6
7.50 (s, 1H), 7.39 - 7.30 (m, 6H), 5.94 (t, J= 4.0 Hz, 1H), 5.14 (s, 2H), 4.20
(s, 2H),
2.68 - 2.61 (m, 1H), 2.46 - 2.38 (m, 2H), 2.37 - 2.27 (m, 2H), 2.17 - 2.11 (m,
1H), 1.88 -
1.78 (m, 1H), 1.45 (s, 9H), 1.15 (s, 6H).
Acid 22:
4-(1-(3-(tert-Butoxy)-2,2-dimethy1-3-oxopropy1)- lif pyrazol-4-ypcydohexane- 1-
carboxylic acid
To a solution of benzyl 4-(1-(3-(tert-butoxy)-2,2-dimethy1-3-oxopropy1)-1H-
pyrazol-4-
yl)cyclohex-3-enecarboxylate A22-5 (700 mg, 95 % purity, 1.52 mmol) in
methanol
(30 mL) was added 10 % palladium on charcoal wt. (400 mg) at room temperature.
The reaction was stirred at 50 C under hydrogen atmosphere (50 Psi) for 5
hours.
The catalyst was filtered off and the filtrate was concentrated to give the
title
compound (570 mg, 90 % purity from 1H NMR, 97 % yield) as colorless oil. LC-MS
(ESI): RT = 1.46 and 1.59 min, mass calcd. for Ci91130N204 350.2, m/z found
351.1
[M+111 . 1H NMR (400 MHz, CDC13) 67.31 (d, J= 2.8 Hz, 1H), 7.17 (s, 1H), 4.19
(s,
2H), 2.66 - 2.56 (m, 1.5H), 2.48 - 2.42 (m, 0.3H), 2.34 - 2.28 (m, 0.2H), 2.12
- 1.98 (m,
2.5H), 1.84 - 1.74 (m, 1.5H), 1.69 - 1.53 (m, 3.2H), 1.44 - 1.43 (m, 9H), 1.35
- 1.25 (m,
0.8H), 1.13 - 1.12 (m, 6H).
Acid 23: 2-(3-Ethoxy-2,2-dimethy1-3-oxopropy1)-4,5,6,7-tetrahydro-2ifindazo1e-
5-
carboxylic acid (A23)
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0
0 OH
0
NH NaBH4 (2.0 eq) (1.0 eq)
Bn0
Me0H, 0 C, 1 h TPP (2.0eq) N
DIAD (2.0eq) N
0 OBn 0 OBn
THF, 0 C - r.t , 16 h 0-\
Al -2 A23-1 A23-2
0
HO-)
Pd/C, H2
Et0Ac
30 C, overnight N-
0-\
A23
Intermediate A23-1:
Benzyl 4-hydroxycydohexanecarboxylate
To a solution of benzyl 4-oxocyclohexanecarboxylate A1-2 (17.3 g, 93 % purity,
70.8
mmol) in methanol (150 mL) was added sodium borohydride (5.40 g, 143 mmol)
under nitrogen atmosphere at 0 C. After stirred at 0 C for 1.0 hour, the
mixture
was quenched with water (100 mL) and acidified with 2 M hydrochloride aqueous
solution to pH - 1, then extracted with ethyl acetate (200 mL) twice. The
combined
organic layers were washed with brine (100 mL), dried over Na2SO4(s) and
filtered.
The filtrate was concentrated under reduced pressure to give a residue, which
was
purified by silica gel column chromatography (petroleum ether ethyl acetate =
5 1
to 4:1) to give the desired compound (13.5 g, 90 % purity from 111 NMR, 76 %
yield)
as white solids. LC-MS (ESI): RT = 1.53 min, mass calcd. for C14111803 234.1,
m/z
found 235.0 [M411+. 111 NMR (400 MHz, CDC13) 6 7.39 - 7.30 (m, 511), 5.13 (s,
0.711),
5.11 (s, 1.311), 3.92 - 3.88 (m, 0.311), 3.65 - 3.57 (m, 0.711), 2.47 - 2.42
(m, 0.311), 2.35 -
2.27 (m, 0.711), 2.05 - 2.01 (m, 311), 1.74 - 1.61 (m, 211), 1.58 - 1.47 (m,
211), 1.34 -
1.24(m, 11I).
Intermediate A23-2:
Ethyl 1-(4-((benzyloxy)carbonyOcydohexyl)-1Hpyrazole-4-carboxylate
To a solution of benzyl 4-hydroxycyclohexanecarboxylate A23-1 (5.00 g, 90 %
purity,
19.8 mmol), ethyl 1H-pyrazole-4-carboxylate (2.78 g, 19.8 mmol) and
triphenylphosphine (10.4 g, 39.7 mmol) in tetrahydrofuran (70 mL) was added
dropwise diisopropyl diazene-1,2-dicarboxylate (8.03 g, 39.7 mmol) at 0 C
under
nitrogen atmosphere. After stirred at 0 C to room temperature under nitrogen
atmosphere for 16 hours, the mixture was quenched with water (80 mL) and
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extracted with ethyl acetate (100 mL) twice. The combined organic layers were
washed with brine (80 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under reduced pressure to give a residue, which was purified by
silica
gel column chromatography (petroleum ether: ethyl acetate = 10 : 1 to 5 :1)
and
further purified by C18 column (acetonitrile : water = 65 % to 72 %) to give
the title
compound (2.20 g, 90 % purity from 11-1 NMR, 28 % yield) as white solids. LC-
MS
(ESI): RT = 1.74 min, mass calcd. for C201124N204 356.2, m/z found 357.1
[M+111 . 11-1
NMR (400 MHz, CDC13) 6 7.91 (s, 0.211), 7.90 (s, 0.211), 7.89 (s, 0.811), 7.87
(s, 0.811),
7.40 - 7.32 (m, 511), 5.17 (s, 1.611), 5.14 (s, 0.411), 4.32 - 4.26 (m, 211),
4.22 - 4.16 (m,
111), 2.75 - 2.70 (m, 0.811), 2.46 - 2.39 (m, 0.211), 2.28 - 2.18 (m, 2.511),
2.09 - 1.84 (m,
311), 1.84 - 1.64 (m, 2.511), 1.37 - 1.32 (m, 311).
Acid 23:
2(3-Ethoxy-2,2-dimethy1-3-oxopropy1)-4,5,6,7-tetrahydro-2Hindazole-5-
carboxylic
acid
To the solution of ethyl 1-(4-((benzyloxy)carbonyl)cyclohexyl)-1H-pyrazole-4-
carboxylate A23-2 (2.15 g, 90 % purity, 5.43 mmol) in ethyl acetate (26 mL)
was
added 10 % palladium on charcoal wt. (400 mg). The mixture was stirred at 30
C
under hydrogen atmosphere (ballon) overnight. The catalyst was filtered off
and the
filtrate was concentrated to give the title compound (1.58 g, 90 % purity, 98
% yield)
as white solids. LC-MS (ESI): RT = 1.12 min, mass calcd. for Ci311i8N204
266.1, m/z
found 267.1 [M411+. 11-1 NMR (400 MHz, CDC13) 6 7.96 (s, 0.811), 7.93 (s,
0.211), 7.92
(s, 111), 4.29 (q, J= 7.2 Hz, 211), 4.24- 4.15 (m, 111), 2.78 - 2.66 (m, 111),
2.31 - 2.22
(m, 2.611), 2.12 - 1.99 (m, 3.411), 1.87 - 1.69 (m, 211), 1.34 (t, J= 7.2 Hz,
311).
Acid 24: 4(5-(Ethoxycarbony1)-1Hpyrazol-1-yl)cydohexanecarboxylic acid (A24)
0 N-
01=)Bn j_NH ______________________ 0 OBn
OH
r0 0 MO 0
A24-1 (1 5 eq) / N& Pd/C, H2
N
PPh3 (2.0 eq),DIAD (2.0 eq), Me0H, r.t., 16h
OH THF, 0 r.t., 16h
A23-1 A24-2 A24
Intermediate A24-2:
Ethyl 144-((benzyloxy)carbonyl)cydohexyl)-1Hpyrazole-5-carboxylate
To a solution of benzyl 4-hydroxycyclohexanecarboxylate A23-1 (5.7 g, 90 %
purity,
21.9 mmol), ethyl 1H-pyrazole-3-carboxylate A24-1 (4.70 g, 33.5 mmol) and
triphenylphosphine (11.7 g, 44.6 mmol) in tetrahydrofuran (100 mL) was added
diisopropyl azodicarboxylate (9.04 g, 44.7 mmol) dropwise at 0 C. After
stirred at
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room temperature for 16 hours, the mixture was concentrated and
dichloromethane
(100 mL) was added. It was washed with water (50 mL) twice, followed by brine
(50
mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated under
reduced
pressure to leave a yellow oil, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 50 1 to 30 1)and further
purified by C18 column (aetonitrile water = 20 % to 80 %) to give the title
compound (3.66 g, 96 % purity, 45 % yield) as colorless oil. LC-MS (ESI): RT =
1.62
and 1.63 min, mass calcd. for C20H24N204 356.2, m/z found 357.3 [M+111 . 11I
NMR
(400 MHz, CDC13) 6 7.49 (d, J= 2.0 Hz, 1H), 7.37 - 7.30 (m, 5H), 6.83 (d, J=
2.0 Hz,
.. 1H), 5.18 (s, 2H), 5.17 - 5.11 (m, 1H), 4.33 (q, J= 7.2 Hz, 2H), 2.78 -
2.69 (m, 1H) ,
2.45 - 2.32 (m, 2H), 2.17 - 2.06 (m, 2H), 1.98 - 1.88 (m, 2H), 1.80 - 1.68 (m,
2H), 1.38
(t, J= 7.2 Hz, 3H).
Acid 24:
4-(5-(Ethoxycarbony1)-1Hpyrazol-1-y1)cydohexanecarboxylic acid
.. To a solution of ethyl 1-(4-((benzyloxy)carbonyl)cyclohexyl)-1H-pyrazole-5-
carboxylate A24-2 (2.0 g, 96 % purity, 5.33 mmol) in methanol (50 mL) was
added
10 % palladium on charcoal wt. (284 mg, 0.267 mmol) under nitrogen atmosphere
at
room temperature. After stirred at room temperature under hydrogen atmosphere
for 16 hours, the mixture was filtered though a pad of celite. The filtrate
was
.. concentrated under reduced pressure to give the title compound (1.45 g, 95
% purity
from 11I NMR, 97 % yield) as white solids. 11I NMR (400 MHz, CDC13) 6 7.52 (d,
J=
1.6 Hz, 1H), 6.83 (d, J= 1.6 Hz, 1H), 5.24- 5.14 (m, 1H), 4.34 (q, J= 7.2 Hz,
2H),
2.79 - 2.72 (m, 1H), 2.44- 2.35 (m, 2H), 2.23 - 1.12 (m, 2H), 1.99 - 1.90 (m,
2H), 1.79 -
1.66 (m, 2H), 1.39 (t, J= 7.2 Hz, 3H).
.. Acid 25: 4-(5-(Ethoxycarbonyl)pyrimidin-2-yl)cyclohexanecarboxylic acid
(A25)
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CI _______________________ (10
N- 0-\
0 A25-1 (0.8 eq)
_____________________________________ > /
Bn0 \01 Pd(dP1302C12 (0.05 eq) Bn0
K2CO3 (2.0 eq)
A11-2 THF/H20= 4:1 A25-2
70 C overnight
0
Pd/C (50 ANNAN), OH
H2 balloon ,N
Et0Ac, r.t.,
1 overnight ON
0
A25
Intermediates A25-2:
Ethyl 244- ((benzyloxy)carbonyl)cydohex-1-en-1-yl)pyriraidine-5-carboxylate
To a solution of benzyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)cyclohex-3-
enecarboxylate A11-2 (2.00 g, 5.84 mmol) and ethyl 2-chloropyrimidine-5-
carboxylate A25-1 (0.90 g, 4.82 mmol) in tetrahydrofuran (20 mL) and water (5
mL)
was added potassium carbonate (1.60 g, 11.6 mmol) under nitrogen atmosphere.
The
resulting mixture was pourged with nitrogen for three times, and then [1, r-
bis(diphenylphosphino)ferroceneidichloropalladium(II) (200 mg, 0.29 mmol) was
added. Then it was pourged with nitrogen again three times and stirred at 70
.0
overnight. After cooled down and quenched with water (20 mL), the mixture was
extracted with ethyl acetate (20 mL) for three times. The combined organic
layers
were washed with brine (20 mL), dried over Na2SO4(s) and filtered. The
filtrate was
concentrated under reduced pressure to give a residue, which was purified by
silica
gel column chromatography (petroleum ether ethyl acetate = 8 1) to give the
title
compound (230 mg, 13 % yield) as yellow solids. LC-MS (ESI): RT = 1.80 min,
mass
calcd. for C21H22N204 366.2, m/z found 367.1 [M411+. 11-1 NMR (400 MHz, CDC13)
6
9.18 (s, 2H), 7.47 (s, 1H), 7.38 - 7.33 (m, 5H), 5.17 (s, 2H), 4.42 (q, J= 7.2
Hz, 2H),
2.90 - 2.84 (m, 1H), 2.76 - 2.69 (m, 1H), 2.64 - 2.62 (m, 2H), 2.58 - 2.49 (m,
1H), 2.29 -
2.24 (m, 1H), 1.92 - 1.82 (m, 1H), 1.41 (t, J= 7.2 Hz, 3H).
Acid 25:
445- (Ethoxycarbonyl)pyrimidin-2-y0cydohexanecarboxylic acid
To a solution of ethyl 2-(4-((benzyloxy)carbonyl)cydohex-1-en-1-Opyrimidine-5-
carboxylate A25-2 (600 mg, 1.64 mmol) in ethyl acetate (25 mL) was added 10 %
palladium on charcoal wt. (300 mg). After stirred at room temperature under
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hydrogen atmosphere of balloon overnight, the reaction mixture was filtered.
The
filtrate was concentrated under reduced pressure to give the title compound
(400 mg,
87 % yield) as white solids. LC-MS (EST): RT = 0.494 min, mass calcd. for
C141118N204 278.1, m/z found 279.1 [M+111 .
Acid 26: 4-(4-(Ethoxycarbonyl)thiazol-2-y0cydohexanecarboxylic acid (A26)
0 0
0 0
0 0 (Boc)20(2.6 eq), Li0H.H20 0
0
DMAP(0.4 eq) (0.97 eq) CD1(1.3 eq), Et0Ac
_________________________ > ________ >
t-BuOH, r.t., overnight THF/Me0H NH3(aq. 25%, 1.0 eq)
0 0 0 C, 6 h. r.t., 1 h.
0 OH
0 OH 0 NH2
A26-1 A26-2 A26-3 A26-4
0
S NH2 0 i_CO2Et
Lawesson's reagent BrS NS N
(0.5 eq) (1.2 eq)0 TFA/DCM(v/v=1/2)
THF, 70 C, 2 h. t-BuOH, r.t., 1 h. r.t., 2 h.
0 0 50 C, 2 h.
0 C)< HO 0
A26-5 A26-.6 A26
Intermediate A26-2:
1- tert-Butyl 4-methyl cydohexane-1,4-dicarboxylate
To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid A26-1 (14.4 g,
75.8
mmol) in tert-butanol (200 mL) was added di- tert-butyl dicarbonate (43.9 g,
197
mmol) and 4-dimethylaminopyridine (3.78 g, 30.3 mmol). After stirred at room
temperature overnight, the reaction mixture was concentrated under reduced
pressure to give a residue, which was dissolved in ethyl acetate (200 mL). The
resulting solution was washed with 1 M hydrochloride aqueous solution (100
mL),
saturated sodium bicarbonate (100 mL), brine (100 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated and purified by silica gel column
chromatography (petroleum ether ethyl acetate = 100 1 to 20 1) to give the
title
compound (11.8 g, 58 % yield, 90 % purity) as colorless oil. 111 NMR (300 MHz,
DMSO-d6) 6 3.60 (s, 1.811), 3.59 (s, 1.211), 2.48 - 2.45 (m, 0.411), 2.40 -
2.09 (m, 1.611),
1.92 - 1.82 (m, 211), 1.76 - 1.53 (m, 411), 1.39 (s, 911), 1.34 - 1.24 (m,
211).
Intermediate A26-3:
4-(tert-Butoxycarbonyl)cydohexanecarboxylic acid
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To a solution of 1- tert-butyl 4-methyl cyclohexane-1,4-dicarboxylate A26-2
(11.8 g,
90 % purity, 43.8 mmol) in tetrahydrofuran (39 mL) and methanol (13 mL) was
added a solution of lithium hydroxide monohydrate (1.87 g, 95 % purity, 42.3
mmol)
in water (13 mL). After stirred at 0 C for 6 hours, the mixture was poured
into
water (150 mL) and washed with ethyl acetate (100 mL). The aqueous layer was
acidified to pH 2 with 1 M hydrochloride aqueous solution. The solid which
formed
was collected by filtration and dried under reduced pressure to give the title
compound (7.8 g, 77 % yield) as white solids. 111 NMR (300 MHz, DMSO-d6) 6
12.07
(br s, 111), 2.40 - 2.31 (m, 111), 2.17 - 2.08 (m, 111), 1.93 - 1.83 (m, 211),
1.75 - 1.51 (m,
411), 1.39 (s, 911), 1.33 - 1.26 (m, 211).
Intermediate A26-4:
tert-Butyl 4-carbamoylcydohexanecarboxylate
To a solution of 4-(tert-butoxycarbonyl)cyclohexanecarboxylic acid A26-3 (7.80
g,
34.2 mmol) in ethyl acetate (150 mL) was added NN-carbonyldiimidazole (7.20 g,
44.5 mmol) at room temperature. After stirring at room temperature for 0.5
hour,
% wt. ammonium hydroxide aqueous solution (48.0 g, 34.2 mmol) was added. The
stirring was continued at room temperature for another 0.5 hour. Then the
separated organic layer was adjusted to PH 2 - 3 with 0.2 M hydrochloride
aqueous
solution, washed with water (100 mL), brine (100 mL), dried over Na2SO4(s),
filtered
20 and concentrated to give the crude product, which was purified by silica
gel column
chromatography (petroleum ether ethyl acetate = 10 1 to 6 1, then 100 % ethyl
acetate) to give the title compound (6.4 g, 82 % yield) as white solids. 111
NMR (300
MHz, DMSO-d6) 67.13 (s, 111), 6.63 (s, 111), 2.38 - 2.35 (m, 0.511), 2.14 -
1.94 (m,
1.511), 1.85 - 1.71 (m, 311), 1.55 - 1.41 (m, 311), 1.37 - 1.34 (m, 911), 1.26
- 1.18 (m, 211).
25 Intermediate A26-5:
tert-Butyl 4-carbamothioylcydohexanecarboxylate
To a solution of tert-butyl 4-carbamoylcyclohexanecarboxylate A26-4 (6.40 g,
28.2
mmol) in tetrahydrofuran (100 mL) was added 2,4-bis-(4-methoxy-phenyl)-
[1,3,2,4idithiadiphosphetane 2,4-disulfide (5.70 g, 14.1 mmol). The reaction
mixture
was stirred at 70 C for 2 hours. Then it was allowed to cool down to room
temperature and concentrated under reduced pressure to give a residue, which
was
diluted with ethyl acetate (50 mL). The solution was washed with saturated
sodium
dicarbonate aqueous solution to PH 7 - 8, then washed with water (50 mL),
brine (50
mL), dried over Na2SO4(s), filtered and concentrated to give the crude
product, which
.. was purified by silica gel column chromatography (petroleum ether ethyl
acetate =
10 1 to 2 1) to give the title compound (4.30 g, 62 % yield) as white solids.
1H NMR
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(300 MHz, DMSO-d6) 6 9.26 (s, 111), 9.00 (s, 111), 2.42 - 2.35 (m, 111), 2.09 -
2.02 (m,
111), 1.87 - 1.83 (m, 211), 1.70 - 1.66 (m, 211), 1.55 - 1.42 (m, 211), 1.35 -
1.18 (m, 1111).
Intermediate A26-6:
Ethyl 2-(4-(tert-butoxycarbonyl)cydohexyl)thiazole-4-carboxylate
To a solution of tert-butyl 4-carbamothioylcyclohexanecarboxylate A26-5 (3.20
g,
13.2 mmol) in 2-methylpropan-2-ol (50 mL) was added ethyl 3-bromo-2-
oxopropanoate (3.2 g, 16.4 mmol). After stirring at room temperature for 1
hour, it
was warmed up to 50 C and stirred at 50 C for 2 hours. After cooling down to
room
temperature, the mixture was concentrated to give a residue, which was diluted
with ethyl acetate (25 mL). The solution was adjusted with saturated sodium
dicarbonate aqueous solution to PH 7 - 8. The separated organic layer was
washed
with water (10 mL), brine (10 mL), dried over Na2SO4(s), filtered and
concentrated to
give a residue, which was purified by silica gel column chromatography
(petroleum
ether ethyl acetate = 10 1 to 6 1) to give the title compound (2.6 g, 58 %
yield) as
yellow solids. 1H NMR (400 MHz, DMSO-d6) 6 8.41 (s, 0.511), 8.40 (s, 0.511),
4.29 (q, J
= 7.2 Hz, 211), 3.18 - 3.11 (m, 0.511), 3.04 - 2.97 (m, 0.511), 2.56 - 2.54
(m, 0.511), 2.29 -
2.22 (m, 0.511), 2.12 - 2.10 (m, 111), 1.98 - 1.88 (m, 311), 1.80 - 1.72 (m,
111), 1.67 -
1.61 (m, 111), 1.57 - 1.44 (m, 211), 1.40 (s, 911), 1.29 (t, J= 7.2 Hz, 311).
Acid 26:
4-(4-(Ethoxycarbonypthiazol-2-ypcydohexanecarboxylic acid
To a solution of ethyl 2-(4-(tert-butoxycarbonyOcyclohexyl)thiazole-4-
carboxylate
A26-6 (2.60 g, 7.67 mmol) in dichloromethane (20 mL) was added trifluoroacetic
acid
(10 mL). The reaction mixture was stirred at room temperature for 2 hours.
Then
the solvent was removed to give a residue, which was purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 10 1 to 2 1, then 100 % ethyl
acetate) to give the title compound (2.1 g, 96 % yield) as yellow solids. 1H
NMR (300
MHz, DMSO-d6) 6 8.39 - 8.36 (m, 111), 4.30 - 4.21 (m, 211), 3.15 - 3.08 (m,
0.611), 3.02
- 2.94 (m, 0.411), 2.57 - 2.52 (m, 0.611), 2.28 - 2.21 (m, 0.411), 2.11 - 2.06
(m, 111), 1.99
- 1.86 (m, 311), 1.78 - 1.56 (m, 2.511), 1.52 - 1.41 (m, 1.511), 1.29 - 1.23
(m, 311).
Acid 27: 4-(3-(Methoxycarbonyl)isoxazol-5-yl)cydohexanecarboxylic acid (A27)
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0 OH OH
YDMS0(4.5 eq) -- C)y
AcC1(1.0 eq)
BH3.SMe2(2.9 eq) NaH(2.5 eq),, 0 (C0C1)2 (3.0 eq) 0
______________________ > _______________________________ >
THF, 0 THF, r.t., TEA(5.0 eq)
24 hrs 12 hrs DCM, -78 C,
0 OH OH OH 3 hrs
A4-1 A27-1 A27-2 A27-3
N2 \c)
.Hk pi, (1.5 eq) 0-N 0¨
0 k-)
0 NO2 (2.0 eq)
0
K2CO3(3.0 eq), HO DABC0(0.12 eq), HO
Me0H
r.t overnight Me0H, 80 C, overnight
.,
A27-4 A27-5
H5106(2.0 eq)
Cr03(0.3 eq) HO 0
/
CH3CN,
0 C, 2 h, r.t., 4 hrs
A27
A27-1:
Cydohexane-1, 4-diyldimethanol
To a solution of cyclohexane-1,4-dicarboxylic acid A4-1 (50.0 g, 0.276 mol) in
-- tetrahydrofuran (500 mL) was added 10 M borane-methyl sulfide complex (80
mL,
0.800 mol) at 0 C. After stirred at room temperature for 24 hours, the
reaction
mixture was quenched with methanol (100 mL) slowly and water (200 mL), then
extracted with ethyl acetate (200 mL) for three times. The combined organic
layers
were washed with brine (200 mL), dried over Na2SO4(), filtered and
concentrated
-- under reduced pressure to give a residue, which was purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 3 1) to give the title
compound
(42.0 g, 90 % purity from 111 NMR, 90 % yield) as white solids. 111 NMR (400
MHz,
DMSO-d6) 64.28 (br s, 211), 3.26 - 3.14 (m, 411), 1.71 - 1.69 (m, 311), 1.35 -
1.19 (m,
411), 0.84 - 0.77 (m, 311).
-- Intermediate A27-2:
(4-(Hydroxymethyl)cydohexypmethyl acetate
To a solution of cyclohexane-1,4-diyldimethanol A27-1 (80.0 g, 90 % purity,
0.499 mol)
in tetrahydrofuran (500 mL) was added 60 % wt. sodium hydride in mineral oil
(30.6
g, 1.25 mol) and acetyl chloride (41.3 g, 95 % purity, 0.499 mol) at 0 C.
After stirred
-- at room temperature for 12 hours. The reaction mixture was concentrated to
dryness
under reduced pressure to give a residue, which was purified by silica gel
column
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chromatography (petroleum ether : ethyl acetate = 3 :1) to give the title
compound
(21.0 g, 95 % purity from 11-1 NMR, 21 % yield) as yellow oil. 11-1 NMR (400
MHz,
DMSO-d6) 64.36 (m, 1H), 3.82 (d, J= 6.4 Hz, 1.6H), 3.30 - 3.27 (m, 0.4H), 3.21
- 3.18
(m, 1.6H), 1.99 (s, 3H), 1.75 - 1.70 (m, 3H), 1.53 - 1.23 (m, 4H), 0.94 - 0.87
(m, 3H).
Intermediate A27-3:
(4-Formylcydohexyl)methyl acetate
To a solution of dimethyl sulfoxide (40.0 g, 99 % purity, 0.507 mol) in
dichloromethane (200 mL) was added a solution of oxalyl chloride (43.8 g, 98 %
purity, 0.338 mol) in dichloromethane (50 mL) at - 78 C. After stirred at -
78 C for 1
hour, a solution of (4-(hydroxymethyl)cyclohexyl)methyl A27-2 (22.1 g, 95 %
purity,
0.113 mol) was added at - 78 C. After stirring at - 78 C for 3 hours,
triethylamine
(57.6 g, 99 % purity, 0.564 mol) was added dropwise at -78 C to quench the
reaction.
The reaction mixture was allowed to warm to room temperature and extracted
with
dichloromethane (200 mL) for three times. The combined organic layers were
dried
over anhydrous Na2SO4(s), filtered and concentrated to give the title compound
(16.0
g, 95 % purity from 11-1 NMR, 73 % yield) as yellow oil. 11-1 NMR (400 MHz,
DMSO-d6)
69.57 (s, 0.5H), 5.76 (s, 0.5H), 3.85 - 3.79 (m, 2H), 2.25 - 2.19 (m, 0.5H),
2.01 (s, 3H),
1.94- 1.92 (m, 1H), 1.79 - 1.70 (m, 2.5H), 1.58 - 1.43 (m, 2H), 1.22 - 1.11
(m, 1.5H),
1.05 - 0.90 (m, 2.5H).
Intermediate A27-4:
(4-Ethynylcydohexyl)methanol
To a solution of (4-formylcyclohexyl)methyl acetate A27-3 (13.1 g, 95 %
purity, 67.7
mmol) in methanol (100 mL) were added dimethyl (1-diazo-2-
oxopropyl)phosphonate
(20.5 g, 95 % purity, 101 mmol) and potassium carbonate (28.1 g, 203 mmol) at
room
temperature. After stirred at room temperature overnight under nitrogen
atmosphere, the mixture was allowed to cool down to room temperature and
filtered.
The filtrate was concentrated under reduced pressure to give a residue, which
was
purified by silica gel column chromatography (petroleum ether : ethyl acetate
= 5 :1)
to afford the title compound (4.00 g, 95 % purity from 11-1 NMR, 41 % yield)
as white
solids. 'H NMR (400 MHz, DMSO-d6) 6 3.45 (d, J= 6.4 Hz, 2H), 2.22 - 2.16 (m,
1H),
2.06 - 2.02 (m, 3H), 1.84 - 1.80 (m, 2H), 1.53 - 1.38 (m, 5H).
Intermediate A27-5:
Methyl 544-(hydroxymethyl)cydohexyl)isoxazole-3-carboxylate
To a solution of (4-ethynylcyclohexyl)methanol A27-4 (1.16 g, 95 % purity,
7.97 mmol)
in methanol (10 mL) was added methyl 2-nitroacetate (2.11 g, 90 % purity, 15.9
mmol) and triethylenediamine (110 mg, 98 % purity, 0.961 mmol). After stirred
at 80
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C overnight under nitrogen atmosphere, the mixture was allowed to cool down to
room temperature and filtered. The filtrate was concentrated under reduced
pressure to give a residue, which was purified by silica gel column
chromatography
(petroleum ether ethyl acetate = 3 1) to give the title compound (1.30 g, 95 %
purity from 11-1 NMR, 65 % yield) as white solids. LC-MS (ESI): RT = 1.484
min,
mass calcd. for Ci2Hi7N04 239.1, m/z found 240.1 [M411+. 11-1 NMR (400 MHz,
DMSO-d6) 6 6.67 (s, 1H), 3.88 (s, 3H), 3.24 (d, J= 6.0 Hz, 2H), 2.85 - 2.78
(m, 1H),
2.06 - 2.01 (m, 2H), 1.84 - 1.80 (m, 2H), 1.46 - 1.36 (m, 3H), 1.08 - 0.98 (m,
2H).
Acid 27:
4-(3-(Methoxycarbonyl)isoxazol-5-yl)cydohexanecarboxylic acid
To a solution of periodic acid (1.73 g, 99 % purity, 7.52 mmol) in
acetonitrile (20 mL)
was added chromium(VI) oxide (100 mg, 99 % purity, 0.990 mmol) at room
temperature over 2 hours under nitrogen atmosphere. After that, methyl 5-(4-
(hydroxymethyl)cyclohexyl)isoxazole-3-carboxylate A27-5 (928 mg, 95 % purity,
3.69
mmol) was added at 0 C and stirring continued at 0 C for 2 hours under
nitrogen
atmosphere. Then the reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (10 mL) for three times. The combined organic
layers
were dried over anhydrous Na2SO4(), filtered and concentrated to give the
title
compound (800 mg, 90 % purity, 77 % yield) as white solids. LC-MS (ESI): RT =
1.005
min, mass calcd. for Ci2Hi5N05 253.1, m/z found 254.1 [M+111 . 11-1 NMR (400
MHz,
DMSO-d6) 6 12.13 (br s, 1H), 6.69 (s, 1H), 3.88 (s, 3H), 2.91 - 2.84 (m, 1H),
2.28 - 2.21
(m, 1H), 2.07 - 1.97 (m, 4H), 1.51 - 1.40 (m, 4H).
Acid 28: 4-(4-(Ethoxycarbonynthiazol-2-y0cydohexanecarboxylic acid (A28)
OH
0
0 1 25 eq
NH2OH.HCI (1.5 eq) ) Bn0
NCS (1 eq)
Na0Ac (2 eq), H20
pyridine (0.1 eq
Et0H, 90 C 1h TEA (1 eq) N-0 0
0 OBn 0 OBn DCM, 18 C, 2h
A1-5 A28-1 A28-2
0
Pd/C, H2 HOflk
Et0H, 25 C, 15mins \
N---0 0
A28
Intermediate A28-1:
Benzyl 4-Ohydroxyimino)methypcydohexanecarboxylate
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To a solution of benzyl 4-formylcyclohexanecarboxylate A1-5 (17.6 g, 71.5
mmol) in
ethanol (348 mL) was added sodium acetate (11.7 g, 143 mmol) and a solution of
hydroxylamine hydrochloride (7.45 g, 107 mmol) in water (26 mL). After stirred
at
90 C for 1 hour, the mixture was cooled down to room temperature and filtered
off
and then the filtrate was concentrated to give a residue, which was diluted
with
ethyl acetate (300 mL). The organic phase was washed with water (60 mL) for
three
times, dried over Na2SO4(s) and filtered. The filtrate was concentrated under
reduced
pressure to give the title compound (17.5 g, 96 % yield) as yellow oil. LC-MS
(ESI):
RT = 2.069 min, mass calcd. for C151119N03261.1, m/z found 262.1 [M+111 . 111
NMR
(300 MHz, DMSO-do) 6 10.97 - 10.71 (m, 0.311), 10.42 - 10.39 (m, 0.711), 7.34 -
7.27
(m, 511), 7.21 - 7.18 (m, 111), 5.09 - 5.05 (m, 211), 2.34 - 2.23 (m, 111),
2.16 - 2.02 (m,
111), 1.93 - 1.87 (m, 211), 1.79 - 1.74 (m, 211), 1.61 - 1.53 (m, 111), 1.49 -
1.21 (m, 311).
Intermediate A28-2:
Ethyl 3-(4-qbenzyloxy)carbonypcyclohexypisoxazole-5-carboxylate
To a solution of 1-chloropyrrolidine-2,5-dione (8.95 g, 67.0 mmol) and
pyridine (530
mg, 6.70 mmol) in dichloromethane (150 mL) was added benzyl 4-
((hydroxyimino)methyl)cyclohexanecarboxylate A28-1 (17.5 g, 67.0 mmol) at
about 5
C. After stirring at room temperature for 10 minutes, ethyl propiolate (8.22
g, 83.0
mmol) and a solution of triethylamine (6.77 g, 67.0 mmol) in dichloromethane
(30
mL) were added into the mixture. The mixture was stirred at 18 C under
nitrogen
atmosphere for 2 hours. The mixture was washed with water (100 mL) for three
times, dried over Na2SO4(s) and filtered. The filtrate was concentrated under
reduced
pressure to give a residue, which was purified by silica gel column
chromatography
(petroleum ether ethyl acetate = 3 1) to give the title compound (11.0 g, 46 %
yield)
as yellow solids. LC-MS (ESI): RT = 2.552 min, mass calcd. for C201123N05
357.2, m/z
found 358.1 [M+111 . 11-1 NMR (300 MHz, DMSO-do) 6 7.38 - 7.28 (m, 511), 7.23 -
7.13
(m, 111), 5.08 (s, 211), 4.35 - 4.19 (m, 211), 3.10 - 2.64 (m, 111), 2.42 -
2.32 (m, 111),
2.03 - 1.95 (m, 211), 1.91 - 1.81 (m, 111), 1.77 - 1.59 (m, 211), 1.53 - 1.44
(m, 311), 1.32 -
1.23 (m, 311).
Acid 28:
4-(5-(Ethoxycarbonyl)isoxazol-3-yl)cydohexanecarboxylic acid
To a solution of ethyl 3-(4-((benzyloxy)carbonyl)cyclohexyl)isoxazole-5-
carboxylate
A28-2 (7.00 g, 19.0 mmol) in ethanol (200 mL) was added 10 % palladium on
charcoal wt. (500 mg) under nitrogen atmosphere at room temperature. After
replacing the inner nitrogen atmosphere with hydrogen gas, the mixture was
stirred
at 25 C under hydrogen atmosphere for 15 minutes. The catalyst was filtered
off
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and the filtrate was concentrated under reduced pressure to give a residue,
which
was purified by silica gel column chromatography (petroleum ether ethylacetate
=
3 1 to 1 1) to give the title compound (2.30 g, 44 % yield) as white solids.
LC-MS
(EST): RT = 0.720 min, mass calcd. for Ci3Hi7N05267.1, m/z found 268.1 [M+111
. 11-1
NMR (300 MHz, DMSO-d6) 6 12.06 (s, 1H), 7.24 (s, 1H), 4.31 (q, J= 7.2 Hz, 2H),
2.77
- 2.67 (m, 1H), 2.25 - 2.16 (m, 1H), 1.96 - 1.92 (m, 4H), 1.53 - 1.34(m, 4H),
1.30 - 1.25
(m, 3H).
Acid 29: 5-methylisoxazole-4-carbonyl chloride (A29)
Acid 30: 4-(4-(Methoxycarbonyl)phenypcydohexanecarboxylic acid (A30)
Br
(0.9 eq) 0
0õ0 0
0
Pd(PPh3)4 0.1 eq'
K2CO3 2.5 eq 0 OBn
Pd/C, H2
Me0H, overnight
OH
dioxane/H20=5/1 0
0 OBn 0
90 C, 12 h
A11-2 A30-1 A30
Intermediate A30-1:
4-Benzyl 4'-methyl 2,3,4,5-tetrahydro- [1, 1'-biphenyll-4,4'-dicarboxylate
To a solution of methyl 4-bromobenzoate (760 mg, 3.55 mmol), potassium
carbonate
(1.37 g, 9.93 mmol) and tetrakis(triphenylphosphine)palladium (462 mg, 0.40
mmol)
in dioxane (75 mL) and water (15 mL) was added benzyl 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate A11-2 (1.49 g, 3.94 mmol) at
room
temperature. After stirred at 90 C for 12 hours under nitrogen atmosphere,
the
reaction mixture was cooled down to room temperature, filtered and
concentrated
under reduced pressure to give a residue, which was purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 20 1) to give the title
compound
(1.15 g, 83% yield) as a white solids. 11-1 NMR (300 MHz, DMSO-d6) 67.95 -
7.86 (m,
2H), 7.59 - 7.49 (m, 2H), 7.40 - 7.33 (m, 5H), 6.34 (s, 1H), 5.14 (s, 2H),
3.85 - 3.83 (m,
3H), 2.75 - 2.66 (m, 1H), 2.48 - 2.38 (m, 4H), 2.14- 2.08 (m, 1H), 1.82 - 1.63
(m, 1H).
Acid 30:
4-(4-(Methoxycarbony1)pheny1)cydohexanecarboxylic acid
To a solution of 4-benzyl 4'-methyl 2,3,4,5-tetrahydro-[1, 1'-bipheny11-4,4'-
dicarboxylate A30-1 (1.10 g, 3.97 mmol) in methanol (50 mL) was added 10 %
palladium on charcoal wt. (110 mg) at room temperature. After stirred at room
temperature overnight under hydrogen atmosphere, the reaction mixture was
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filtered and concentrated under reduced pressure to give the title compound
(800 mg,
97 % yield) as a white solids. LC-MS (ESI): RT = 0.27 min, mass calcd. for
C15141804
262.1, m/z found 261.2 [M-111-. 111 NMR (300 MHz, DMSO-d6) 6 7.90 - 7.87 (m,
211),
7.39 - 7.32 (m, 211), 3.83 (s, 311), 2.63 (s, 1.611), 2.30 - 2.22 (m, 0.411),
2.12 - 1.98 (m,
211), 1.85 - 1.44 (m, 611).
Acid 31: 4-(1-(3-(tert-butoxy)-2,2-dimethy1-3-oxopropy1)-1H-pyrazol-4-
yl)cydohexane-1-carboxylic acid (A31)
) OH
0
NH2OH.HCI (1.5 eq) (1.0 eq) A26-3
'0)'Y N 'OH __________________________________________________
CN Na2CO3 (0.77 eq) EDCI (2.0 eq), HOBT (1.0eq),
Et0H/H20, r. t., 2 h. NH2
1,4-dioxane, 80 C, overnight
A31-1 A31-2
CO2Et
N=( NCO2Et
, N
,
0IINICO2Et N
N, OH pyridine TFA/DCM
120 C, overnight r.t., overnight
CO2t-Bu CO2t-Bu
CO2H
A31-3 A31-4 A31
Intermediate A31-2:
Ethyl 2-amino-2-(hydroxyimino)acetate
Water (150 mL) was added dropwise to a stirred mixture of ethyl
carbonocyanidate
A31-1 (25.5 g, 250 mmol), hydroxylamine hydrochloride (26.1 g, 375 mmol) and
sodium carbonate (20.5 g, 193 mmol) in ethanol (250 mL). After the mixture was
stirred at room temperature for 2 hours, the solvent was removed and the
aqueous
layer was extracted with dichloromethane (900 mL) for three times. The
combined
organic layers were dried over Na2SO4(), filtered and concentrated to afford
the title
compound (21.0 g, 88 % yield) as white solids. 11-1 NMR (300 MHz, CDC13) 6
9.52 (br
s, 111), 5.15 (s, 211), 4.35 - 4.27 (m, 211), 1.36 - 1.31 (m, 311).
Intermediate A31-3:
tert-Butyl 4-02-ethoxy-1-(hydroxyimino)-2-
oxoethyl)carbamoyl)cydohexanecarboxylate
To a solution of 4-(tert-butoxycarbonyl)cyclohexanecarboxylic acid A26-3 (1.60
g, 90 %
purity, 6.31 mmol) in 1,4-dioxane (30 mL) were added 1H-benzo[di
[1,2,3itriazol-1-ol
(947 mg, 90 % purity, 6.31 mmol) and NI-((ethylimino)methylene)-N2,N2-
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dimethylethane-1,2-diamine hydrochloride (2.50 g, 90 % purity, 12.7 mmol) at
room
temperature. After stirring at room temperature for 1 hour, ethyl 2-amino-2-
(hydroxyimino)acetate A31-2 (926 mg, 90 % purity, 6.31 mmol) was added. After
stirred at 80 C overnight, it was cooled down to room temperature and
concentrated
to give a residue, which was diluted with water (50 mL), extracted with ethyl
acetate (100 mL) for five times. The combined organic layers were washed with
water (50 mL), brine (50 mL), dried over Na2SO4(s), filtered and concentrated
under
reduced pressure to give a residue, which was purified by silica gel column
chromatography (100 % dichloromethane, then dichloromethane ethyl acetate = 6
1) to give the title compound (1.90 g, 95 % purity from 111 NMR, 84 % yield)
as
yellow solids. LC-MS (ESI): RT = 1.58 min, mass calcd. for Ci61126N206 342.2,
m/z
found 343.3 [M411+. 111 NMR (300 MHz, DMSO-d6) 6 6.89 (s, 211), 4.27 - 4.15
(m,
211), 2.40 - 2.31 (m, 111), 2.15 - 2.10 (m, 111), 1.93 - 1.81 (m, 411), 1.38 -
1.29 (m, 1211),
1.25- 1.17 (m, 411)
Intermediate A31-4:
Ethyl 544-(tert-butoxycarbonypcydohexyl)-1,2,4-oxadiazole-3-carboxylate
A solution of (tert-butyl 4-((2-ethoxy-1-(hydroxyimino)-2-
oxoethyl)carbamoyl)cyclohexanecarboxylate A31-3 (1.90 g, 95 % purity, 5.27
mmol)
in pyridine (20 mL) was stirred at 120 C overnight. Then it was cooled down
to
room temperature, the solvent was removed to give a residue, which was
purified by
silica gel column chromatography (petroleum ether ethyl acetate = 10 1 to 4 1)
to
give the title compound (1.50 g, 95 % purity from 11-1 NMR, 83 % yield) as
yellow oil.
LC-MS (ESI): RT = 1.73 min, mass calcd. for Ci61124N205 324.2, m/z found 325.3
[M+11] . 111 NMR (300 MHz, DMSO-d6) 64.51 - 4.44 (m, 211), 3.24- 3.13 (m,
111),
2.38 - 2.30 (m, 111), 2.23 - 2.18 (m, 211), 2.07 - 2.01 (m, 211), 1.72 - 1.45
(m, 1311), 1.43
- 1.37 (m, 311)
Acid 31:
4-(3-(Ethoxycarbony1)-1, 2, 4-oxadiazol-5-yl)cydohexanecarboxylic acid
To a solution of ethyl 5-(4-(tert-butoxycarbonyOcyclohexyl)-1,2,4 -oxadiazole-
3-
carboxylate A31-4 (1.50 g, 95 % purity, 4.39 mmol) in dichloromethane (10 mL)
was
added trifluoroacetic acid (5 mL) at room temperature. After stirred at room
temperature overnight, the mixture was concentrated to give a residue, which
was
purified by silica gel column chromatography (dichloromethane ethyl acetate =
1 1)
to give the title compound (1.20 g, 90 % purity from 11-1 NMR, 92 % yield) as
yellow
solids. 11-1 NMR (300 MHz, DMSO-d6) 6 12.09 (s, 111), 4.39 - 4.30 (m, 211),
3.10 - 3.00
(m, 111), 2.28 - 2.18 (m, 111), 2.09 - 2.05 (m, 211), 1.96 - 1.93 (m, 211),
1.59 - 1.39 (m,
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411), 1.30 - 1.23 (m, 311).
Acid 32: 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (A32)
Acid 33: (cis)-1-(tert-butoxycarbony0-2-methylpiperidine-4-carboxylic acid
(A33)
OOH 0 0 0 0
1) H2 (3 MPa), Pt02(0.07 eq)
Me0H, H2SO4 (cat.) HOAc, 40 C, 3 days
2) (Boc)20 (1.2 eq)
cis
r\j 85 C, 6 h K2CO3(1.5 eq)
Boc
A33-1 A33-2 H20, 30 C, overnight
A33-3
00H
Li0H.H20 (5.3eq)
cis
THF/H20, 30 C, 4h
Boo
A33
Intermediate A33-2:
methyl 2-methylisonicotinate
To a 500 mL flask was added 2-methyl-isonicotinic acid A33-1 (10 g, 72.9
mmol),
methanol (200 mL) and concentrated sulfuric acid (10 mL). After stirred at 85
C for
6 hours, the reaction mixture was cooled down to room temperature. The solvent
was evaporated under reduced pressure to give a residue, which was diluted
with
dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution
(100 mL) twice, dried over Na2SO4(s) and filtered. The filtrate was
concentrated
under reduced pressure to give the title compound (10 g, 90 % yield) as
colorless
liquid. LC-MS (ESI): RT = 1.37 min, mass calcd. for C8119NO2 151.1, m/z found
151.9
[M411+. 111 NMR (300 MHz, CDC13) 6 8.63 - 8.61 (m, 111), 7.66 (s, 111), 7.60 -
7.57 (m,
111), 3.85 (s, 311), 2.53 (s, 311).
Intermediate A33-3:
(del- tert-butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate
To a solution of methyl 2-methylisonicotinate A33-2 (6 g, 39.7 mmol) in acetic
acid
(60 mL) were added and platinum (IV) oxide (600 mg, 2.6 mmol). The mixture was
stirred at 40 C under 3 MPa hydrogen atnosphere for 3 days. The mixture was
filtered and the filtrate was concentrated under reduced pressure to give the
crude
intermediate (11 g, 70.0 mmol). To the mixture of the crude intermediate in
water
(100 mL) was added di- tert-butyl dicarbonate (18.3 g, 84.0 mmol) and
potassium
carbonate (14.5 g, 105.0 mmol). The reaction mixture was stirred at room
temperature overnight. Then the reaction mixture was extracted with ethyl
acetate
(70 mL) twice. The combined organic layers were dried over Na2SO4(s) and
filtered.
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The filtrate was concentrated under reduced pressure to leave a residue, which
was
purified by silica gel column chromatography (petroleum ether ethyl acetate =
10
1 to 9:1) to give the title compound ( 9.2 g, 90 % yield) as colorless oil. LC-
MS (ESI):
RT = 1.839 min, mass calcd. For Ci3H23N04 257.2, m/z found 258.1 [M411+. 11-1
NMR
(400 MHz, CDC13) 6 4.20 - 4.15 (m, 1H), 3.90 - 3.81 (m, 1H), 3.71 (s, 3H),
3.13 - 3.05
(m, 1H), 2.62 - 2.56 (m, 1H), 2.00 - 1.87 (m, 3H), 1.79 - 1.72 (m, 1H), 1.47
(s, 9H),
1.08 (d, J= 6.8 Hz, 3H).
Acid 33:
(cis)-1-(tert-butoxycarbony1)-2-methylpiperidine-4-carboxylic acid
To a solution of 1- tert-butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate
A33-3
(2.5 g, 9.72 mmol) in tetrahydrofuran/water (13 mL/6.5 mL) was added a
solution of
Lithium hydroxide monohydrate (2.16 g, 51.4 mmol) in water (6 mL) at 0 C. The
reaction mixture was stirred at 30 C for 4 hours. Tetrahydrofuran was removed
under reduced pressure. Then the residue was diluted with water(30 mL) and
washed with ethyl acetate (20 mL). The aquous layer was acidified with 1 M
hydrochloride aqueous solution to pH 4 - 5 and extracted with ethyl acetate
(30 mL).
The organic layers were dried over Na2SO4(s) and filtered. The filtrate was
concentrated under reduced pressure to give the title compound (2.5 g, 90 %
purity,
95 % yield) as white solids. LC-MS (ESI): RT = 0.39 min, mass calcd. for
Ci2H2iN04
243.1, m/z found 242.0 [M-111-. 11-1 NMR (400 MHz, DMSO-d6) 6 12.31 (s, 1H),
4.06 -
3.99 (m, 1H), 3.67 - 3.61 (m, 1H), 3.06 - 2.98 (m, 1H), 2.53 - 2.47 (m, 1H),
1.88 - 1.76
(m, 3H), 1.62 - 1.53 (m, 1H), 1.39 (s, 9H), 1.05 (d, J= 6.8 Hz, 3H).
Acid 34: 1-(tert-butoxycarbonyOpyrrolidine-3-carboxylic acid (A34)
Acid 35: tert-Butyl 3-(3-ethoxy-3-oxopropanoyl)azetidine-1-carboxylate (A35)
Acid 36: 4-(5-(1-(methoxycarbonyl)cydopropyl)pyrimidin-2-y0cydohexane-1-
carboxylic acid (A36)
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0 0-/
Bo i
N CI
JCW
Br Br
\ _____________________ /(1.0 eq) N A3-3 (0.9 eq)
0
NaH (2.2 eq), DMF Pd(dppf)C12 (0.1 eq),
0 C r.t., 1 h K2CO3 (1.8 eq),
A36-1 A36-2 Dioxane:H20 (10:1)
100 C, 6 h
>0 >0
0 0
Pd/C, H2 N TFA/ DCM
EA, r.t., 16 h c)
N TEA (5 eq) N 0 OC r.t., 2 h
A36-3 A36-4
OH
0
0
N
A36
Intermediate A36-2:
Methyl 1(2-chloropyrimidin-5-yl)cydopropanecarboxylate
To a solution of methyl 2-(2-chloropyrimidin-5-yl)acetate A36-1 (700 mg, 3.75
mmol)
in N,N-dimethylformamide (21 mL) was added 60 % sodium hydride in mineral oil
(330 mg, 8.25 mmol) at 0 C. The resulting mixture was stirred at 0 C under
nitrogen atmosphere for 30 minutes, and then 1,2-dibromoethane (700 mg, 3.73
mmol) was added. After stirred at room temperature for 1 hour, the reaction
mixture
was quenched with ice water (30 mL) at 0 C and extracted with ethyl acetate
(30
mL) twice. The combined organic layers were washed with water (50 mL) twice
and
brine (50 mL) twice, dried over Na2SO4(s) and filtered. The filtrate was
concentrated
and purified by silica gel column chromatography (petroleum ether: ethyl
acetate =
20: 1 to 9 : 1) to give the title compound (456 mg, 57 % yield) as white
solids. LC-MS
(EST): RT = 1.36 min, mass calcd. for C9H9C1N202 212.0, m/z found 213.0 [M+1-
11 . 11-1
NMR (400 MHz, CDC13) 6 8.59 (s, 2H), 3.67 (s, 3H), 1.75 (dd, J= 7.2 Hz, 4.4
Hz, 2H),
1.23 (dd, J= 7.2 Hz, 4.4 Hz, 2H).
Intermediate A36-3:
tert-butyl 445-(1-(methoxycarbonypcydopropyl)pyrimidin-2-ypcydohex-3-
enecarboxylate
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To a solution of tert-butyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)cyclohex-3-
enecarboxylate A3-3 (600 mg, 1.95 mmol) in 1,4-dioxane (38 ml) and water (3.8
mL)
was added methyl 1-(2-chloropyrimidin-5-yl)cyclopropanecarboxylate A36-2 (454
mg,
2.14 mmol), potassium carbonate (538 mg, 3.89 mmol) and [1,1'-
Bis(diphenylphosphino)ferroceneldichloropalladium(H) (142 mg, 0.194 mmol) at
room temperature. After stirred at 100 C for 6 hours under nitrogen
atmosphere,
the reaction mixture was cooled down to room temperature, diluted with water
(100
mL) slowly and then extracted with ethyl acetate (50 mL) twice. The combined
organic layers were washed with brine (50 mL), dried over Na2SO4(s) and
filtered.
The filtrate was concentrated and purified by silica gel column chromatography
(petroleum ether ethyl acetate = 10 1 to 4 1) to give the title compound (600
mg,
86 % yield) as white solids. LC-MS (ESI): RT = 1.80 min, mass calcd. for
Ci9H26N204
358.2, m/z found 359.2 [M411+. 1H NMR (400 MHz, CDC13) 6 8.62 (s, 2H), 7.29 -
7.27
(m, 1H), 3.65 (s, 3H), 2.87 -2.81 (m, 1H), 2.57 - 2.47 (m, 4H), 2.21 - 2.15
(m, 1H), 1.83
- 1.73 (m, 1H), 1.70 (dd, J= 7.2 Hz, 4.0 Hz, 2H), 1.47 (s, 9H), 1.20 (dd, J=
7.2 Hz, 4.0
Hz, 2H).
Intermediate A36-4:
tert-butyl 445-(1-(methoxycarbonypcydopropyl)pyrimidin-2-
yl)cydohexanecarboxylate
To a mixture of tert-butyl 4-(5-(1-(methoxycarbonyl)cyclopropyl)pyrimidin-2-
y1)
cyclohex-3-enecarboxylate A36-3 (600 mg, 1.67 mmol) and triethylamine (846 mg,
8.38 mmol) in ethyl acetate (20 mL) was added 10 % palladium on charcoal wt.
(200
mg) under nitrogen atmosphere. After stirred at room temperature under
hydrogen
atmosphere (balloon pressure) for 16 hours, the mixture was filtered. The
filtrate
was concentrated to give the title compound (500 mg, 83 % yield) as brownish
oil.
LC-MS (EST): RT = 1.76 min, mass calcd. for C20H28N204 360.2, m/z found 361.2
[M+111 . 1H NMR (400 MHz, CDC13) 6 8.61 (s, 2H), 3.65 (s, 3H), 3.00 -2.93 (m,
0.8H),
2.90 - 2.83 (m, 0.2H), 2.55 - 2.50 (m, 0.8H), 2.30 - 2.22 (m, 0.2H), 2.14 -
1.96 (m,
4.4H), 1.92 - 1.85 (m, 1.6H), 1.71 - 1.67 (m, 2.6H), 1.63 - 1.53 (m, 1.6H),
1.45 (s, 9H),
1.20 (dd, J= 7.2 Hz, 4.0 Hz, 2H).
Acid 36:
4-(5- (1-(methoxycarbonyl)cydopropyl)pyninidin-2-yl)cydohexane- 1-carboxylic
acid
To a solution of tert-butyl 4-(5-(1-(methoxycarbonyl)cyclopropyl)pyrimidin-2-
y1)
cyclohexanecarboxylate A36-4 (500 mg, 1.39 mmol) in dichloromethane (10 mL)
was
added trifluoroacetic acid (5 mL) at 0 C. After stirred at room temperature
for 2
hours, the mixture was concentrated under reduced pressure to give the tilte
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compound (400 mg, 95 % yield) as brownish oil. LC-MS (EST): RT = 1.12 min,
1.27
min, mass calcd. for C161120N204 304.1, m/z found 305.1 [M+111 .
Acid 37: 4(4-(ethoxycarbony1)-5-methylpyriraidin-2-y1)cyclohexane-1-carboxylic
acid
(A37)
0
0
0 j 7_6
o (
0
(Y-(:) A3-3 (1.2 eq) Pd/C (10 /0 WM), H2
N,N1 0
Pd(dP1302Cl2 (0.1 eq) Et0Ac, r.t., 12
CI 0 N-
K2CO3 (2.0 eq)
A37-1 THF/H20(5:1), 70 C, 12 h A37-2
0
0
DCM / TFA 0
0
1/3-
r.t., overnight HO \1
N-
A37-3 A37
Intermediate A37-2:
ethyl 2-(44tert-butoxycarbonyl)cyclohex-1-en-1-y1)-5-methylpyrimidine-4-
carboxylate
To a solution of ethyl 2-chloro-5-methylpyrimidine-4-carboxylate (3 g, 97 %
purity,
14.5 mmol) A37-1 and tert-butyl 4-(4,4,5,5-tetramethy1-1,3,2- dioxaborolan-2-
yl)cyclohex-3-enecarboxylate A3-3 (5.947 g, 93 % purity, 17.9 mmol) in
tetrahydrofuran (100 mL) was added a solution of potassium carbonate (4.151 g,
30.1 mmol) in water (20 mL), then [1,1'-bis(diphenylphosphino)ferrocenei
dichloropalladium(H) (1.094 g, 1.50 mmol) was added under nitrogen atmosphere.
After stirred at 70 .0 for 12 hours, the reaction mixture was cooled down to
room
temperature and poured into water (60 mL). The aqueous layer was extracted
with
ethyl acetate (60 mL) twice. The combined organic layers were dried over
Na2SO4(s)
and filtered. The filtrate was concentrated and purified by silica gel column
chromatography (petroleum ether ethyl acetate = 10 1) to give the title
compound
(4.9 g, 95.7 % purity, 93 % yield) as colorless oil. LC-MS (ESI): RT = 2.009
min, mass
calcd. for C191126N204 346.2, m/z found 347.1 [M+111 . 11-1 NMR (400 MHz, DMSO-
d6)
6 8.80 (s, 111), 7.19 - 7.18 (m, 111), 4.38 (q, J= 7.2 Hz, 211), 2.70 - 2.66
(m, 111), 2.56 -
2.52 (m, 111), 2.46 - 2.37 (m, 311), 2.35 (s, 311), 2.07 - 2.03 (m, 111), 1.70
- 1.61 (m, 111),
1.42 (s, 911), 1.33 (t, J= 7.2 Hz, 311).
Intermediate A37-3:
Ethyl 244-(tert-butoxycarbonypcyclohexyl)-5-methylpyrimidine-4-carboxylate
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To a solution of ethyl 2-(4-(tert-butoxycarbonyl)cyclohex-1-en-1-y1)-5-
methylpyrimidine-4-carboxylate A37-2 (2 g, 95.7 % purity, 5.53 mmol) in ethyl
acetate (20 mL) was added 10 % palladium on charcoal wt. (600 mg) under
nitrogen
atmosphere. After stirred at room temperature under hydrogen atmosphere for 12
hours, the mixture was filtered. The filtrate was concentrated to give the
title
compound (2 g, 90 % purity from 11-1 NMR, 94 % yield) as colorless oil. 11-1
NMR (400
MHz, DMSO-d6) 6 8.80 (s, 1H), 4.39 - 4.34 (m, 2H), 2.95 - 2.87 (m, 0.7H), 2.82
- 2.75
(m, 0.3H), 2.34 (s, 3H), 1.98 - 1.85 (m, 4H), 1.77 - 1.73 (m, 2H), 1.63 - 1.56
(m, 3H),
1.41 (s, 9H), 1.32 (t, J= 7.2 Hz, 3H).
Acid 37:
4-(4-Ethoxycarbony1)-5-methylpyrimidin-2-y1)cydohexanecarboxylic acid
To a solution of ethyl 2-(4-(tert-butoxycarbonyl)cyclohexyl)-5-
methylpyrimidine-4-
carboxylate A37-3 (2 g, 90 % purity, 5.17 mmol) in dichloromethane (5 mL) was
added trifluoroacetic acid (5 mL) at 0 C. After stirred at room temperature
overnight, the reaction mixture was concentrated and purified by C18 column
(acetonitrile water = 20 % to 80 %) to give the title compound (1.2 g, 97.7 %
purity,
78 % yield) as colorless oil. LC-MS (ESI): RT = 1.111 min, mass calcd. for
Ci5H20N204,
292.1 m/z found 291.1 [M-Ht.
Acid 38: 4-(4-(2-Methoxy-2-oxoethyl)-5-methyloxazol-2-371)cydohexanecarboxylic
acid
(A38)
HCI NH2 0
HO OH
H
0 0 0 0 0 N
0
OBn A38-2 (1.0 eq.)
CI
¨ , 0
sat Na2CO3 aqueous /acetone pyridinetoluene
Bn0 0 Bn0 0
A38-1 A38-3 A38-4
0 0
OBn OH
POCI3 (3.0 eq.) 0 Pd/C, H2 (balloon) 0
_________ H C N EA/H20 = 20/1 3 \
DMF, 90 C N
it., overnight
mins
0 0
0 0 A38
\A38-5
Intermediate A38-3:
2-(4-((Benzyloxy)carbonyl)cyclohexanecarboxamido)-4-methoxy-4-oxobutanoic acid
To a solution of 2-amino-4-methoxy-4-oxobutanoic acid hydrochloride A38-2 (600
mg,
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98 % purity, 3.20 mmol) in acetone (25 mL) and saturated sodium bicarbonate
aqueous solution (25 mL) was added dropwise a solution of benzyl 4-
(chlorocarbonyl)cyclohexanecarboxylate A38-1 (1 g, 95 % purity, 3.38 mmol) in
tetrahydrofuran (5 mL) at room temperature over 30 minutes. After stirred at
room
temperature for 2 hours, the mixture was concentrated under reduced pressure
at
room temperature to give a residue, which was diluted with water (100 mL) and
acidified with 1 M hydrochloride aqueous solution to pH = 3 - 4. The resulting
mixture was extracted with ethyl acetate (100 mL) twice. The combined organic
layers were washed with water (50 mL) twice and brine (50 mL), dried over
Na2SO4(s)
and filtered. The filtrate was concentrated and purified by C18 colunm
(acetonitril
water = 50 % to 70 %) to afford the title compound (500 mg, 90 % purity from
11-1
NMR, 36 % yield) as yellow oil. LC-MS (ESI): RT = 1.48 min, mass calcd. for
C201125N07 391.2, m/z found 391.9 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 6 12.73
(br s, 111), 8.08 - 8.04 (m, 111), 7.40 - 7.30 (m, 5H), 5.11(s, 1.211), 5.08
(m, 0.811), 4.56
- 4.50 (m, 111), 3.58 (s, 1.211), 3.57 (s, 1.811), 2.79 - 2.73 (m, 111), 2.65 -
2.59 (m, 111),
2.36 - 2.24 (m, 111), 2.16 - 2.07 (m, 0.511), 1.95 - 1.90 (m, 211), 1.77 -
1.72 (m, 111),
1.64 - 1.53 (m, 3.511), 1.41 - 1.24 (m, 211).
Intermediate A38-4:
Benzyl 4-((1-methoxy-1,4-dioxopentan-3-yOcarbamoyl)cydohexanecarboxylate
.. To a solution of 2-(4-((benzyloxy)carbonyl)cyclohexanecarboxamido)-4-
methoxy-4-
oxobutanoic acid A38-3 (2.4 g, 95 % purity, 5.8 mmol) in toluene (20 mL) was
added
pyridine (11 mL) and acetic anhydride (9 mL) at room temperature. After
stirred at
90 C for 2 hours, the mixture was cooled to room temperature and concentrated
under reduced pressure to give a residue, which was dissolved in water (20 mL)
and
.. extracted with ethyl acetate (20 mL) twice. The combined organic layers
were
washed with water (10 mL) twice and brine (10 mL), dried over Na2SO4(s) and
filtered. The filtrate was concentrated and purified by C18 colunm
(acetonitril
water = 50 % to 70 %) to afford the title compound (1.0 g, 95 % purity from 11-
1 NMR,
42 % yield) as yellow oh. LC-MS (ESI): RT = 1.52 min, mass calcd. for
C211127N06
389.2, m/z found 390.0 [M+Hi . 11-1 NMR (400 MHz, DMSO-d6) 6 7.40 - 7.30 (m,
611),
5.11 (s, 1.211), 5.08 (s, 0.811), 4.50 - 4.45 (m, 111), 3.58 (s, 111), 3.57
(s, 211), 2.79 - 2.74
(m, 111), 2.68 - 2.62 (m, 111), 2.34 - 2.27 (m, 111), 2.06 (s, 111), 2.05 (s,
211), 1.96 - 1.91
(m, 211), 1.78 - 1.75 (m, 111), 1.62 - 1.53 (m, 411), 1.43 - 1.32 (m, 211).
Intermediate A38-5:
Benzyl 44442-methoxy-2-oxoethyl)-5-methyloxazol-2-y1)cydohexanecarboxylate
To a solution of benzyl 44(1-methoxy-1,4-dioxopentan-3-
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yl)carbamoyl)cyclohexanecarboxylate A38-4 (860 mg, 95 % purity, 2.10 mmol) in
/V,/V-dimethylformamide (8 mL) was added phosphoryl trichloride (985 mg, 6.3
mmol)
at 0 C. After stirred at 90 .0 for 30 minutes, the mixture was cooled down to
room
temperature, dissolved in water (50 mL) and extracted with ethyl acetate (100
mL)
twice. The combined organic layers were washed with water (50 mL) twice and
brine
(50 mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated and
purified
by C18 colunm (acetonitril water = 50 % to 70 %) to afford the title compound
(530
mg, 95 % purity from 111 NMR, 65 % yield) as yellow oil. LC-MS (ESI): RT =
1.72 min,
mass calcd. for C211125N05 371.2, miz found 372.1 [M+111 . 111 NMR (400 MHz,
DMSO-d6) 6 7.39 - 7.29 (m, 511), 5.10 (s, 211), 3.60 (s, 311), 3.49 (s,
1.211), 3.48 (s,
0.811), 2.92 - 2.86 (m, 0.611), 2.72 - 2.61 (m, 111), 2.43 - 2.38 (m, 0.411),
2.21 (s, 311),
2.03 - 1.95 (m, 1.611), 1.84 - 1.75(m, 3.411), 1.70 - 1.62 (m, 1.411), 1.52 -
1.41 (m, 1.611).
Acid 38:
4-(4-(2-Methoxy-2-oxoethyl)-5-methyloxazol-2-y0cydohexanecarboxylic acid
To a solution of benzyl 4-(4-(2-methoxy-2-oxoethyl)-5-methyloxazol-2-
yl)cyclohexanecarboxylate A38-5 (400 mg, 95 % purity, 1.02 mmol) in ethyl
acetate
(20 mL) and water (1 mL) was added 10 % palladium on charcoal (40 mg, wt.%) at
room temperature. After stirred at room temperature under hydrogen atmosphere
(balloon) overnight, the mixture was filtered. The filtrate was concentrated
under
reduced pressure to afford the title compound (300 mg, 95 % purity from 111
NMR,
99 % yield) as colorless oil. 11-1 NMR (400 MHz, DMSO-d6) 6 12.09 (br s, 111),
3.60 (s,
311), 3.48 (s, 1.211), 3.47 (s, 0.811), 2.89 - 2.85 (m, 0.611), 2.70 - 2.62
(m, 0.411), 2.45 -
2.42 (m, 0.611), 2.25 - 2.14 (m, 3.411), 2.05 - 2.00 (m, 0.611), 1.96 - 1.94
(m, 0.811), 1.83
- 1.69 (m, 3.611), 1.65 - 1.59 (m, 1.311), 1.49 - 1.34 (m, 1.711).
Acid 39: 4-(5-(2-methoxy-2-oxoethyl)pyrimidin-2-yl)cydohexane-1-carboxylic
acid
(A39)
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0 __
0<
N CI 7-6
o A3-3 (0.94 eq)
0 Pd/C, H2
o
Pd(dppf)C12 (0.1 eq), 0 TEA(5 eq)
K2CO3 (1.9 eq) o)N EA, r.t.,
overnight
A36-1 dioxane/H20, 95 C, 6 h
A39-1
0< OH
0
0 TFA/DCM
)0NN oj-N
A39-2 A39
Intermediate A39-1:
tert-butyl 4-(5-(2-methoxy-2-oxoethyl)pyrimidin-2-yl)cydohex-3-enecarboxylate
The mixture of methyl 2-(2-chloropyrimidin-5-yl)acetate A36-1 (1.8 g, 9.65
mmol),
tert-butyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y0cyclohex-3-ene
carboxylate
A3-3 (2.79 g, 9.05 mmol), potassium carbonate (2.47 g, 17.9 mmol) and [1, 1' -
bis(diphenylphosphino)ferroceneidichloropalladium(H) (0.76 g, 1.04 mmol) in
dioxane (25 mL) and water (2.5 mL) was stirred at 95 C under nitrogen
atmosphere
for 6 hours. After cooled down to room temperature, the mixture was filtered,
concentrated under reduced pressure and purified by silica chromatography
(petroleum ether ethyl acetate =10 1) to give the title compound (1.88 g, 95 %
purity from 111 NMR, 59 % yield) as brown oil. LC-MS (ESI): RT = 1.70 min,
mass
calcd. for C181124N204 332.2, m/z found 333.2 [M+111 . 111 NMR (400 MHz, DMSO-
d6)
6 8.66 (s, 211), 7.20 (s, 111), 3.77 (s, 211), 3.65 (s, 311), 2.71 - 2.67 (m,
111), 2.54 - 2.53
(m, 111), 2.47 - 2.32 (m, 311), 2.07 - 2.04 (m, 111), 1.69 - 1.63 (m, 111),
1.42 (s, 911).
Intermediate A39-2:
tert-butyl 4-(5-(2-methoxy-2-oxoethyl)pyrimidin-2-yl)cydohexanecarboxylate
To a solution of tert-butyl 4-(5-(2-methoxy-2-oxoethyl)pyrimidin-2-yl)cyclohex-
3-
enecarboxylate A39-1 (1.42 g, 95 % purity, 4.06 mmol) in ethyl acetate (10 mL)
and
triethylamine (2.1 g, 20.8 mmol) at room temperature was added 10 % palladium
on
charcoal wt. (0.42 g). After stirred at room temperature hydrogen atmosphere
overnight, the mixture was filtered. The filtrate was concentrated under
reduced
pressure to give the title compound (1.4 g, 90 % purity from 111 NMR, 93 %
yield) as
brown oil. LC-MS (ESI): RT = 1.67 min, mass calcd. for C181126N204 334.2, m/z
found
335.2 [M+111 . 111 NMR (400 MHz, DMSO-d6) 6 8.64 (s, 211), 3.75 (s, 211), 3.65
(s, 311),
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2.93 - 2.86 (m, 0.811), 2.78 - 2.74 (m, 0.211), 2.56 - 2.53 (m, 0.711), 2.23 -
2.18 (m,
0.311), 2.01 - 1.93 (m, 0.411), 1.90 - 1.87 (m, 3.611), 1.79 - 1.75 (m, 211),
1.64 - 1.56 (m,
211), 1.40 (s, 911).
Acid 39:
4-(5-(2-methoxy-2-oxoethyl)pyrimidin-2-yl)cydohexanecarboxylic acid
To a solution of tert-butyl 4-(5-(2-methoxy-2-oxoethyl)pyrimidin-2-
yl)cyclohexane
carboxylate A39-2 (1.4 g, 90 % purity, 3.77 mmol) in dichloromethane (10 mL)
was
added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature
for 2
hours. The mixture was concentrated under reduced pressure to give the
compound
(1.2 g, 90 % purity from 111 NMR, 100 % yield) as brown oil. LC-MS (ESI): RT =
1.10
min, mass calcd. for C141118N204 278.1, miz found 279.2 [M+111 . 111 NMR (400
MHz,
CDC13) 6 8.63 (s, 211), 3.75 (s, 211), 3.65 (s, 311), 2.93 - 2.86 (m, 111),
2.31 - 2.15 (m,
111), 1.99 - 1.93 (m, 211), 1.89 - 1.83 (m, 111), 1.78 - 1.72 (m, 211), 1.63 -
1.56 (m, 211),
1.50 - 1.39 (m, 111).
Acid 40: 1-(5-(4-(ethoxycarbonyppiperidin-1-y1)pyrimidin-2-y1)piperidine-4-
carboxylic acid (A40)
r).LOH (Boc)20 (1.6 eq) r)LO<
DMAP (2.1 eq)
Nr
t-BuOH, r.t., overnight [r
BrN BrN
A40-1 A40-2
0 0
r0<
HN
A40-3 II TFA:DCM = 1 : 2
_____________________________ r
Cs2CO3 (3.0 eq) r.t., 3 h
Pd2(dba)3 (0.1 eq), xphos (0.2 eq)
1,4-dioxane, 100 C, overnight 0 A40-4
0
rOH
Nr
r
(:))
0 A40
Intermediate A40-2:
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tert-butyl 1-(5-bromopyrimidin-2-yppiperidine-4-carboxylate
To a solution of 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylic acid A40-1
(14.8 g,
90 % purity, 46.6 mmol) in tert-butanol (150 mL) was added di-tert-butyl
dicarbonate (16.0 g, 73.3 mmol) and 4-dimethylaminopyridine (12.0 g, 98.2
mmol) at
room temperature. After stirred at room temperature overnight, the reaction
mixture was concentrated and purified by silica gel column chromatography
( petroleum ether : ethyl acetate = 20 :1) to afford the title compound (13.0
g, 90 %
purity from 11-1 NMR, 73 % yield) as white solids. 11-1 NMR (400 MHz, CDC13) 6
8.27
(s, 211), 4.57 - 4.52 (m, 211), 3.08 - 3.01 (m, 211), 2.51 - 2.43 (m, 111),
1.95 - 1.91 (m,
.. 211), 1.70 - 1.60 (m, 211), 1.45 (s, 911).
Intermediate A40-3:
tert-butyl 1-044-(ethoxycarbonyppiperidin-1-Opyrimidin-2-Opiperidine-4-
carboxylate
To a solution of tert- butyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate
A40-2
(1.2 g, 90 % purity, 3.16 mmol), ethyl piperidine-4-carboxylate A40-3 (600 mg,
3.82
mmol) and cesium carbonate (3.10 g, 9.51 mmol) in 1,4-dioxane (60 mL) was
added
dicyclohexyl(2',4',6'-triisopropy111, 1'-biphenyli-2-y0 phosphine (300 mg,
0.629 mmol)
and tris(dibenzylideneacetone)dipalladium(0) (290 mg, 0.317 mmol) at room
temperature under nitrogen atmosphere. After stirred at 100 C under nitrogen
.. atmosphere overnight, the reaction mixture was cooled down to room
temperature,
concentrated and purified by silica gel column chromatography (petroleum ether
:
ethyl acetate = 12 : 1 to 3 :1) to give the title compound (980 mg, 90 %
purity from
11-1 NMR, 67 % yield) as yellow solids. LC-MS (EST): RT = 1.990 min, mass
calcd. for
C221134N404 418.3, m/z found 419.2 [M411+. 11-1 NMR (400 MHz, CDC13) 6 8.10
(s, 211),
4.54- 4.49 (m, 211), 4.16 (q, J= 7.2 Hz, 211), 3.35 - 3.30 (m, 211), 3.02 -
2.95 (m, 211),
2.73 - 2.67 (m, 211), 2.47 - 2.35 (m, 211), 2.05 - 2.01 (m, 211), 1.94 - 1.87
(m, 411), 1.71 -
1.62 (m, 211), 1.44 (s, 911), 1.27 (t, J= 7.2 Hz, 311).
Acid 40:
1-044-(ethoxycarbonyppiperidin-1-y1)pyrimidin-2-yDpiperidine-4-carboxylic acid
To a solution of tert- butyl 1-(5-(4-(ethoxycarbonyOpiperidin-1-y1)pyrimidin-2-
y1)
piperidine-4-carboxylate A40-4 (980 mg, 90 % purity, 2.11 mmol) in
dichloromethane
(6 mL) was added trifluoroacetic acid (3 mL) at 0 C. After stirred at room
temperature for 3 hours, the mixture was poured into water (15 mL) and
extracted
with ethyl acetate (15 mL) twice. The combined organic layers were washed with
brine (20 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under
reduced pressure to give the title compound (840 mg, 90 % purity from 11-1
NMR, 98 %
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yield) as yellow solids. LC-MS (ESI): RT = 1.269 min, mass calcd. for
C181126N404
362.2, m/z found 363.1 [M411+. 1H NMR (400 MHz, CDC13) 6 8.23 (s, 2H), 4.56 -
4.51
(m, 2H), 4.17 (q, J= 7.2 Hz, 2H), 3.41 - 3.36 (m, 211), 3.17 - 3.10 (m, 2H),
2.84 - 2.78
(m, 2H), 2.65 - 2.60 (m, 1H), 2.47 - 2.41 (m, 1H), 2.12 - 1.92 (m, 6H), 1.80 -
1.70 (m,
2H), 1.28 (t, J= 7.2 Hz, 3H).
Acid 41: 1-(5-(3-(tert-butoxy)-3-oxopropyl)pyridin-2-yl)piperidine-4-
carboxylic acid
(A41)
F HN
A41-2 rOj 0
A41-4
Br Cs2CO3 (2.0 eq.) Pd(OAc)2 (0.15 eq.)
DMF, 100 C, 6 h Br
P(o-To1)3 (0.51 eq.)
A41-1 A41-3 TEA (6.2 eq.)
DMF, 100 C, overnight
0 0
0
N= Pd/C, H2 N- LiOH (3.0 eq.)
/ Et0H, 30 C \ Me0H/H20 (4/1)
overnight r.t., 8 h
04 A41-5 A41-6
x0 0
0
H
0
A41
Intermediate A41-3:
Ethyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate
To the solution of ethyl piperidine-4-carboxylate A41-2 (5.9 g, 37.5 mmol) in
NN
dimethylformamide (80 mL) was added cesium carbonate (19.0 g, 58.3 mmol) and 5-
bromo-2-fluoropyridine A41-1 (5.0 g, 28.4 mmol) under nitrogen atmosphere at
room
temperature. After stirred at 100 C for 6 hours, the mixture was cooled down
to
room temperature and filtered. The filtrate was poured into water (100 mL) and
extracted with ethyl acetate (150 mL) for three times. The combined organic
layers
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were washed with water (200 mL) and brine (200 mL), dried over Na2SO4(s) and
filtered. The filtrate was concentrated and purified by silica gel column
chromatography (petroleum ether : ethyl acetate = 50 : 1 to 20 :1) to give the
title
compound (7.1 g, 95 % purity from 11-1 NMR, 76 % yield) as colorless oil. LC-
MS
(EST): RT = 1.66 min, mass calcd. for C131-117BrN202 312.0, m/z found 313.0
[M+H] .
11-1 NMR (400 MHz, CDC13) 6 8.17 (d, J= 2.4 Hz, 111), 7.51 (dd, J= 9.2 Hz, 2.8
Hz,
1H), 6.56 (d, J= 9.2 Hz, 1H), 4.15 (q, J= 7.2 Hz, 4H), 3.00 - 2.93 (m, 2H),
2.56 - 2.49
(m, 1H), 2.01 - 1.95 (m, 2H), 1.80 - 1.70 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H).
Intermediate A41-5:
(0-Ethyl 1-(5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)pyridin-2-yOpiperidine-4-
carboxylate
To the solution of ethyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate A41-3
(3 g,
9.1 mmol) and tert-butyl acrylate A41-4 (2.40 g, 18.7 mmol) in /V,/V-
dimethylformamide (90 mL) was added tri-o-tolylphosphine (1.40 g, 4.60 mmol),
triethylamine (5.70 g, 56.3 mmol) and diacetoxypalladium (0.30 g, 1.34 mmol)
at
room temperature under nitrogen atmosphere. After stirred at 100 C under
nitrogen atmosphere overnight, the mixture was cooled down to room
temperature,
poured into water (100 mL) and extracted with ethyl acetate (150 mL) for three
times. The combined organic layers were washed with water (250 mL) and brine
(250 mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated and
purified by silica gel column chromatography (petroleum ether : ethyl acetate
= 20 :
1 to 8 : 1) to give the title compound (3.6 g, 90 % purity from 11-1 NMR, 99 %
yield) as
light green solids. LC-MS (ESI): RT = 1.78 min, mass calcd. for C201-128N204
360.2,
m/z found 361.1 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 68.24 (d, J= 2.4 Hz, 1H),
7.63
(dd, J= 9.2 Hz, 2.4 Hz, 1H), 7.48 (d, J= 15.6 Hz, 111), 6.64 (d, J= 8.8 Hz,
1H), 6.17
(d, J= 16.0 Hz, 1H), 4.29 (dt, J= 13.6 Hz, 3.6 Hz, 2H), 4.15 (q, J = 7.2 Hz,
2H), 3.09 -
3.02 (m, 2H), 2.60 - 2.53 (m, 1H), 2.02 - 1.98 (m, 2H), 1.80 - 1.71 (m, 2H),
1.53 (s, 9H),
1.26 (t, J = 7.2 Hz, 3H).
Intermediate A41-6:
Ethyl 1-(5-(3-(tert-butoxy)-3-oxopropyppyridin-2-yOpiperidine-4-earboxylate
To the solution of ethyl 1-(5-(3-(tert-butoxy)-3-oxoprop-1-en-l-y1)pyridin-2-
y1)piperidine-4-carboxylate A41-5 (1.50 g, 90 % purity, 3.75 mmol) in ethanol
(40 mL)
was added 10 % palladium on charcoal (450 mg, wt.). After stirred at 30 C
under
hydrogen atmosphere overnight, the mixture was filtered and the filtrate was
concentrated to give the title compound (1.37 g, 90 % purity from 11-1 NMR, 91
%
yield) as brown oil. LC-MS (ESI): RT = 1.68 min, mass calcd. for C201-130N204
362.2,
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m/z found 363.1 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.03 (d, J= 2.4 Hz, 1H),
7.33
(dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.61 (d, J= 8.8 Hz, 1H), 4.19 - 4.12 (m, 4H),
2.95 - 2.89
(m, 2H), 2.77 (t, J= 8.0 Hz, 2H), 2.53 - 2.45 (m, 3H), 2.02 - 1.96 (m, 2H),
1.81 - 1.72
(m, 2H), 1.42 (s, 9H), 1.26 (t, J= 7.2 Hz, 3H).
.. Acid 41:
1-(5-(3-(tert-Butoxy)-3-oxopropyl)pyridin-2-yDpiperidine-4-carboxylic acid
To the solution of ethyl 1-(5-(3-(tert-butoxy)-3-oxopropyl)pyridin-2-
yl)piperidine-4-
carboxylate A41-6 (1.37 g, 90 % purity, 3.40 mmol) in methanol (32 mL) and
water (8
mL) was added lithium hydroxide monohydrate (430 mg, 10.2 mmol) under nitrogen
atmosphere at room temperature. After stirred at room temperature for 8 hours,
the
mixture was poured into ethyl acetate (80 mL). The mixture was acidified with
1 M
hydrochloride aqueous solution to pH = 5 - 6, then washed with water (40 mL)
twice
and brine (50 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated
under reduced pressure to give the title compound (1.1 g, 95 % purity from 11-
1 NMR,
92 % yield) as brown solids. LC-MS (ESI): RT = 0.94 i nhn, mass calcd. for
C181126N204
334.2, m/z found 335.0 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.04 (d, J= 2.0
Hz, 1H),
7.36 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.64 (d, J= 8.8 Hz, 1H), 4.17 - 4.12 (m,
2H), 3.00 -
2.94 (m, 2H), 2.78 (t, J= 8.0 Hz, 2H), 2.61 - 2.53 (m, 1H), 2.47 (t, J= 8.0
Hz, 2H),
2.05 - 2.02 (m, 2H), 1.85 - 1.75 (m, 2H), 1.42 (s, 9H).
Part II: Preparation of Ketoesters of general formula IV-1 and IV-2
Intermediate KT1: (exemplified with Method A)
methyl 244-(3-methoxy-3-oxopropanoypcyclohexyDoxazole-4-carboxylate
To a solution of 4-(4-(methoxycarbonyl)oxazol-2-yl)cyclohexanecarboxylic acid
Al
(1.30 g, 5.14 mmol) in acetonitrile (18 mL) was added N,N'-carbonyldiimidazole
(998
mg, 6.17 mmol) at room temperature. The solution was stirred at room
temperature
under nitrogen atmosphere for 2 hours (mixture A). To the suspension of
potassium
3-methoxy-3-oxopropanoate (1.67 g, 10.7 mmol) and magnesium chloride (1.21 g,
12.8 mmol) in acetonitrile (25 mL) was added triethylamine (1.65 g, 16.3
mmol).
After stirred at room temperature under nitrogen atmosphere for 1 hour, the
suspension was added mixture A and stirring continued at 80 C under nitrogen
atmosphere for 3 hours Then it was cooled down and concentrated under reduced
pressure to give a residue, which was taken up into water (100 mL) and ethyl
acetate (100 mL). The mixture was acidified with 0.5 M hydrochloride aqueous
solution to give a clear solutionand then the organic phase was separated. The
aqueous layer was extracted with ethyl acetate (50 mL) twice. The combined
organic
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layers were washed with brine (50 mL), dried over Na2SO4(s) and filtered. The
filtrate was concentrated under reduced pressure to give the title compound
(1.55 g,
98.1 % yield) as colorless oil. LC-MS (ESI): RT = 1.399 min, mass calcd. for
C151119N06 309.1, m/z found 310.1 [M+111 . 111 NMR (400 MHz, CDC13) 6 8.16 (s,
111),
3.91 (s, 1.211), 3.90 (s, 1.811), 3.75 (s, 1.211), 3.73 (s, 1.811), 3.53 (s,
1.0811), 3.51 (s,
0.7211), 3.10 - 3.05 (m, 0.411), 2.87 - 2.77 (m, 0.611), 2.69 - 2.63 (m,
0.411), 2.56 - 2.50
(m, 0.611), 2.28 - 2.23 (m, 111), 2. - 2.03 (m, 211), 1.89 - 1.83 (m, 111),
1.79 - 1.61 (m,
311), 1.54 - 1.44 (m, 111).
Spectral analyses of Ketoesters
Intermediate KT2:
methyl 2(443-ethoxy-3-oxopropanoypcydohexyDoxazole-4-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from Al as colorless oil. LC-MS (ESI): RT = 1.454 min, mass calcd.
for
C161121N06 323.1, m/z found 324.1 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.16
(s, 111),
4.23 - 4.16 (m, 211), 3.91 (s, 1.511), 3.90 (s, 1.511), 3.51 - 3.45 (m, 211),
3.09 - 3.05 (m,
0.411), 2.86 - 2.78 (m, 0.611), 2.69 - 2.63 (m, 0.411), 2.58 - 2.50 (m,
0.611), 2.23 - 2.02
(m, 311), 1.88 - 1.77 (m, 211), 1.68 - 1.54 (m, 211), 1.47 - 1.39 (m, 111),
1.30 - 1.26 (m,
311).
Intermediate KT3:
methyl 24343-methoxy-3-oxopropanoylThicydo[1.1.1]pentan-l-yDoxazole-4-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A2 as gray solids. LC-MS (ESI): RT = 1.815 min, mass calcd.
for
Ci411i5N06 293.1, m/z found 293.9 [M+Hi . 11-1 NMR (300 MHz, CDC13) 6 11.75
(s,
0.411), 8.17 (s, 111), 5.02 (s, 0.411), 3.91 (s, 311), 3.74 (s, 311), 3.52 (s,
1.211), 2.52 (s,
3.811), 2.44 (m, 2.211).
Intermediate KT4:
Ethyl 244-(3-ethoxy-3-oxopropanoypcydohex-1-en-l-yDoxazole-4-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A3 as gray solids.
LC-MS (ESI): RT = 1.53 min, mass calcd. for Ci7112iN06 335.1, m/z found 336.3
[M+11] . 1H NMR (400 MHz, CDC13) 6 8.13 (s, 111), 6.86 (s, 111), 4.39 (q, J=
7.2 Hz,
211), 4.21 (q, J= 7.2 Hz, 211), 3.61 (s, 0.511), 3.56 (s, 1.511), 2.87 - 2.77
(m, 211), 2.55 -
2.42 (m, 311), 2.20 - 2.16 (m, 111), 1.76 - 1.68 (m, 111), 1.38 (t, J = 7.2
Hz, 311), 1.29 (t,
J= 7.2 Hz, 311).
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Intermediate KT5:
Methyl 2-(4-(3-ethoxy-3-oxopropanoy0cyclohexy0-5-methyloxazole-4-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A4 as white solids.
LC-MS (ESI): RT = 1.57 min, mass calcd. for Ci7H23N06 337.2, m/z found 338.3
[M41]+. 1H NMR (400 MHz, CDC13) 6 12.21 (s, 0.1H), 5.02 (s, 0.1H), 4.22 (s,
2H),
3.92 (d, J= 1.6 Hz, 3H), 3.53 (s, 1.8H), 3.02 (s, 0.4H), 2.78 - 2.56 (m,
4.6H), 2.26 -
2.09 (m, 4H), 1.79 - 1.49 (m, 4H), 1.34 - 1.28 (m, 311).
Intermediate KT6:
Methyl 2-04-0-ethoxy-3-oxopropanoyOcydohexypmethypoxazole-4-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A5 as yellow oil which was directly used without further
purification. LC-MS (EST): RT = 1.65 min, mass calcd. for Ci7H23N06 337.2, m/z
found 338.1 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 8.73 (s, 1H), 4.09 - 4.04 (m,
2H), 3.79 (s, 3H), 3.64 - 3.63 (m, 2H), 2.73 - 2.69 (m, 2H), 2.65 - 2.60 (m,
0.6H), 2.44 -
2.37 (m, 0.4H), 1.99 - 1.68 (m, 4H), 1.59 - 1.48 (m, 2.7H), 1.26 - 1.22 (m,
1.3H), 1.19 -
1.16 (m, 3H), 1.09- 1.02 (m, 1H).
Intermediate KT7:
methyl 3-(4-(4-(2-ethoxy-2-oxoethypoxazol-2-y1)cydohexyl)-3-oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A6 as yellow oil. 1H NMR (400 MHz, CDC13) 6 7.54 (s, 1H),
4.22 -
4.16 (m, 2H), 3.74- 3.73 (m, 3H), 3.60 - 3.56 (m, 211), 3.53 - 3.48 (m, 2H),
3.03 - 3.00
(m, 0.3H), 2.78 - 2.71 (m, 0.7H), 2.62 - 2.61 (m, 0.311), 2.56 - 2.47 (m,
0.7H), 2.24 -
2.12 (m, 2H), 2.11 - 2.01 (m, 1.5H), 1.84- 1.76 (m, 1.5H), 1.65 - 1.43 (m,
3H), 1.30 -
1.24 (m, 3H).
Intermediate KT8:
Methyl 3-(4-(442-ethoxy-2-oxoethyl)-5-methyloxazol-2-y1)cydohexyl)-3-
oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A7 as yellow oil. LC-MS (ESI): RT = 1.55 min, mass calcd. for
C181125N06 351.2, m/z found 352.0 [M+111 . 1H NMR (400 MHz, CDC13) 6 4.16 (q,
J=
6.8 Hz, 2H), 3.75 - 3.73 (m, 3H), 3.53 (s, 1.5H), 3.51 (s, 0.5H), 3.45 (s,
2H), 2.96 - 2.93
(m, 0.2H), 2.71 - 2.65 (m, 1H), 2.54 - 2.48 (m, 0.8H), 2.24 (s, 2H), 2.19 (s,
1H), 2.07 -
2.04 (m, 2H), 1.86 - 1.74 (m, 2H), 1.62 - 1.44 (m, 411), 1.26 (t, J= 7.2 Hz,
3H).
Intermediate KT9:
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Ethyl 344-(442-methoxy-2-oxoethyDoxazol-2-y1)cydohexy0-3-oxopropanoate (a
mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A6 as yellow oil.
LC-MS (ESI): RT = 1.49 min, mass calcd. for C181125N06 351.2, miz found 352.2
[M+111 . 1H NMR (400 MHz, CDC13) 6 12.2 (s, 0.1H), 7.54 (s, 111), 4.99 (s,
0.111), 4.23
- 4.16 (m, 411), 3.61 - 3.58 (m, 1.811), 3.51 - 3.48 (m, 211), 3.04- 2.99 (m,
0.311), 2.78 -
2.71 (m, 0.711), 2.65 - 2.60 (m, 0.311), 2.57 - 2.48 (m, 0.711), 2.24 - 1.98
(m, 411), 1.84 -
1.74 (m, 111), 1.65 - 1.47 (m, 311), 1.30 - 1.26 (m, 611).
Intermediate KT10:
ethyl 3-(444-(3-methoxy-3-oxopropyl)oxazol-2-yl)cydohexy0-3-oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A9 as yellow oil. 1H NMR (300 MHz, DMSO-d6) 6 7.65 (s, 111),
4.06
(q, J= 7.2 Hz, 211), 3.63 (s, 211), 3.56 (s, 311), 2.71 - 2.67 (m, 111), 2.65 -
2.63 (m, 211),
2.58 - 2.56 (m, 211), 2.05 - 2.01 (m, 211), 1.95 - 1.90 (m, 211), 1.70 - 1.55
(m, 111), 1.48 -
1.24 (m, 411) , 1.15 (t, J=7.2 Hz, 311).
Intermediate KT11:
Ethyl 342-4-(3-methoxy-3-oxopropanoyl)cydohexypoxazol-4-y1)-2,2-
dimethylpropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A10 as yellow oil. 1H NMR (300 MHz, CDC13) 6 7.24 (s, 111),
4.11 (q,
J= 6.9 Hz, 211), 3.73 - 3.72 (m, 311), 3.52 - 3.50 (m, 211), 2.73 (s, 211),
2.71 - 2.64 (m,
111), 2.58 - 2.43 (m, 111), 2.24- 2.19 (m, 111), 2.11 - 1.99 (m, 211), 1.84-
1.38 (m, 511),
1.26 - 1.20 (m, 911).
.. Intermediate KT12:
Ethyl 244-(3-ethoxy-3-oxopropanoypcydohexyl)oxazole-5-carboxylate (a mixture
of 2
stereoisomers)
Intermediate KT12-1:
Mixture of ethyl 244-(3-ethoxy-3-oxopropanoyl)cydohexyl)oxazole-5-carboxylate
and
ethyl 2-443-ethoxy-3-oxopropanoyl)cydohex-1-en-1-yDoxazole-5-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized as yellow oil. LC-MS (ESI): RT = 1.635 min, mass calcd. for
Ci7H23N06
and Ci7112iN06 337.2 and 335.1, miz found 338.1 [M+Hi+ and 336.1 [M411+,
respectively.
Intermediate KT12:
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Ethyl 244-(3-ethoxy-3-oxopropanoy0cyclohexyDoxazole-5-carboxylate (a mixture
of 2
stereoisomers)
To a mixture of ethyl 2-(4-(3-ethoxy-3-oxopropanoyl)cyclohex-1-en-1-yl)oxazole-
5-
carboxylate and ethyl 2-(4-(3-ethoxy-3-oxopropanoyl)cyclohexyl)oxazole-5-
carboxylate KT12-1 (3.48 g, 90 % purity, about 9.34 mmol)) in methanol (100
mL)
was added 10 % palladium on charcoal wt. (1.00 g) under nitrogen atmosphere at
room temperature. After replacing the inert nitrogen atmosphere with hydrogen
gas,
the mixture was stirred at 25 C under hydrogen atmosphere of balloon for 1.5
hours.
The catalyst was filtered off and the filtrate was concentrated under reduced
pressure to give the title compound (3.05 g, 90 % purity from 11-1 NMR, 87 %
yield)
as yellow oil. LC-MS (ESI): RT = 1.498 min, mass calcd. for Ci7H23N06 337.2,
m/z
found 338.1 [M411+. 11-1 NMR (400 MHz, DMSO-d6) 6 7.89 (s, 0.5H), 7.88 (s,
0.5H),
4.31 (q, J= 7.2 Hz, 2H), 4.12 - 4.05 (m, 2H), 3.68 (s, 1H), 3.65 (s, 1H), 3.17
- 3.14 (m,
0.6H), 2.94 - 2.85 (m, 0.4H), 2.72 - 2.63 (m, 0.5H), 2.13 - 2.09 (m, 0.5H),
1.99 - 1.97
(m, 2H), 1.85 - 1.74 (m, 2H), 1.64 - 1.57 (m, 2H), 1.47 - 1.36 (m, 2H), 1.29
(t, J= 7.2
Hz, 3H), 1.21 - 1.16 (m, 3H).
Intermediate KT13:
Ethyl 344-4-(1-ethoxy-2-methyl-1-oxopropan-2-yDoxazol-2-ypcyclohexyl)-3-
oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from Al2 as colorless oil. LC-MS (ESI): RT = 2.138 min, mass
calcd. for
C201129N06 379.2, m/z found 380.1 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 7.37
(s, 1H),
4.23 - 4.12 (m, 4H), 3.50 - 3.48 (m, 2H), 3.04- 3.00 (m, 0.2H), 2.81 - 2.72
(m, 0.8H),
2.62 - 2.51 (m, 1H), 2.20 - 2.00 (m, 3.5H), 1.86 - 1.55 (m, 4.5H), 1.51 (s,
6H), 1.30 -
1.21 (m, 6H).
Intermediate KT14:
Ethyl 344-(142-ethoxy-2-oxoethyl)-1Hpyrazol-4-yl)cyclohexyl)-3-oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A13 as pink oil. LC-MS (ESI): RT = 1.918 min, mass calcd. for
C181-126N205 350.2, m/z found 351.1 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 12.24
(s,
0.1H), 12.17 (s, 0.1H), 7.41 (s, 1H), 7.25 (s, 1H), 4.87 (s, 0.6H), 4.85 (s,
1.4H), 4.25 -
4.18 (m, 4H), 3.51 (s, 0.5H), 3.49 (s, 1.3H), 2.75 - 2.65 (m, 1H), 2.53 - 2.46
(m, 0.3H),
2.11 - 1.67 (m, 6.7H), 1.57 - 1.35 (m, 2H), 1.30 - 1.26 (m, 6H).
Intermediate KT15:
methyl 344-(1-(3-methoxy-3-oxopropy1)-1H-pyrazol-4-y1)cyclohexyl)-3-
oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
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synthesized from A14 which was directly used without further purification. LC-
MS
(ESI): RT = 1.46 min, mass calcd. for C171124N205 336.2, m/z found 337.0
[M411+.
Intermediates KT16:
Methyl 344-(4-(3-ethoxy-3-oxopropanoyl)cydohexyl)-1H-pyrazol-1-y1)-3-
methylbutanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A15 as yellow oil. LC-MS (ESI): RT = 1.867 min, mass calcd.
for
C201130N205 378.2, m/z found 379.2 [M+111 . 1HNMR (400 MHz, CDC13) 6 7.37 (s,
0.411), 7.35 (s, 0.611), 7.29 (s, 0.411), 7.28 (s, 0.611), 4.23 - 4.15 (m,
211), 3.57 (s, 1.211),
3.56 (s, 1.811), 3.51 (s, 0.811), 3.50 (s, 1.211), 2.88 (s, 0.811), 2.87 (s,
1.211), 2.72 - 2.64
(m, 1.411), 2.53 - 2.43 (m, 0.611), 2.12 - 1.92 (m, 311), 1.83 - 1.73 (m,
311), 1.71 - 1.67
(m, 611), 1.53 - 1.30 (m, 1.511), 1.27 - 1.24 (m, 3.511).
Intermediate liT17:
Methyl 344-(4-(3-ethoxy-3-oxopropanoyl)cydohexyl)-1H-pyrazol-1-ylkutanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A16 as brown oil which was directly used without further
purification. 1H NMR (400 MHz, CDC13) 6 7.36 - 7.33 (m, 111), 7.21 - 7.20 (m,
111),
4.77 - 4.68 (m, 111), 4.19 (q, J= 7.2 Hz, 211), 3.64 (s, 311), 3.51 - 3.49 (m,
211), 3.06 -
2.95 (m, 1.411), 2.78 - 2.68 (m, 2.5 H), 2.09 - 1.91 (m, 211), 1.82 - 1.66 (m,
411), 1.58 -
1.53 (m, 411), 1.49 - 1.33 (m, 111), 1.30 - 1.26 (m, 311).
Intermediate KT18:
Ethyl 344-(1-(3-methoxy-3-oxopropy1)-1H-pyrazol-4-ypcydohexyl)-3-oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A17 as colorless oil. LC-MS (ESI): RT = 2.134 min, mass
calcd. for
Ci81126N205 350.2, m/z found 351.2 [M+111 .
Intermediate KT19:
Ethyl 344-(1-(3-methoxy-3-oxopropy1)-3-methyl-1Hpyrazol-4-y1)cydohexyl)-3-
oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A18 as light yellow oil. LC-MS (ESI): RT = 2.592 min, mass
calcd.
for Ci91128N205 364.2, m/z found 365.1 [M+111 . 1H NMR (400 MHz, CDC13) 6
12.34 (s,
0.111), 7.12 (s, 111), 5.07 (s, 0.111), 4.28 (t, J= 6.8 Hz, 211), 4.23 - 4.18
(m, 211), 3.68 (s,
311), 3.52 (s, 1.811), 2.84 (t, J= 6.8 Hz, 211), 2.77 - 2.71 (m, 0.711), 2.55 -
2.46 (m, 111),
2.40 - 2.30 (m, 0.311), 2.19 (s, 111), 2.18 (s, 211), 2.09 - 1.97 (m, 2.511),
1.77 - 1.64 (m,
3.511), 1.56 - 1.44 (m, 211), 1.29 (t, J= 7.2 Hz, 311).
Intermediate KT20:
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tert-Butyl 34444-(3-ethoxy-3-oxopropanoy0cydohexyl)-1H-pyrazol-1-
y1)cydobutanecarboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A19 as colorless oil. 111 NMR (400 MHz, CDC13) 6 7.40 - 7.29
(m,
211), 5.00 - 4.90 (m, 0.511), 4.70 - 4.62 (m, 0.511), 4.21 - 4.16 (m, 211),
3.61 (s, 0.311),
3.51 - 3.49 (m, 1.511), 3.36 (s, 0.211), 3.08 - 3.01 (m, 0.411), 2.87 - 2.78
(m, 1.611), 2.72 -
2.64 (m, 411), 2.17 (s, 111), 2.09 - 1.93 (m, 211), 1.84- 1.76 (m, 1.511),
1.73 - 1.67 (m,
2.511), 1.49 (s, 411), 1.46 (s, 511), 1.33 - 1.25 (m, 511).
Intermediate KT21:
Methyl 544-(3-ethoxy-3-oxopropanoypcyclohexyl)-1-methyl-1H-pyrazole-3-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A20 as colorless oil. LC-MS (ESI): RT = 1.38 and 1.43 min,
mass
calcd. for Ci71124N205 336.2, m/z found 337.2[M+111 .
Intermediate KT22:
Methyl 344-(3-ethoxy-3-oxopropanoypcyclohexyl)-1-methyl-1Hpyrazole-5-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A21 as yellow oil. LC-MS (ESI): RT = 1.52 min, mass calcd.
for
Ci71124N205 336.2, m/z found mass 337.3 [M+111 . 1H NMR (300 MHz, DMSO-d6) 6
6.68 - 6.66 (m, 111), 4.12 - 4.04 (m, 211), 4.02 - 3.99 (m, 311), 3.80 - 3.79
(m, 311), 3.66 -
3.61 (m, 211), 2.80 - 2.64 (m, 111), 2.01 - 1.98 (m, 111), 1.95 - 1.91 (m,
211), 1.82 - 1.61
(m, 41), 1.42 - 1.33 (m, 211), 1.18 - 1.12 (m, 311).
Intermediate KT23:
tert-Butyl 34444-(3-ethoxy-3-oxopropanoy0cydohexyl)-1H-pyrazol-1-y1)-2,2-
dimethylpropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A22 as colorless oil. LC-MS (ESI): RT = 1.80 min, mass calcd.
for
C231136N205 420.3, m/z found 421.1 [M+111 . 1H NMR (400 MHz, CDC13) 6 12.22 -
12.16 (m, 0.111), 7.32 - 7.27 (m, 111), 7.22 - 7.15 (m, 111), 4.98 - 4.97 (m,
0.111), 4.29 -
4.10 (m, 41), 3.60 (s, 0.111), 3.50 (s, 0.411), 3.47 (s, 111), 3.36 (s, 0.31),
2.88 - 2.44 (m,
1.51), 2.14- 1.59 (m, 8.511), 1.45 - 1.44 (m, 91), 1.30 - 1.23 (m, 31), 1.14-
1.13 (m,
611).
Intermediate KT24:
Ethyl 144-(3-ethoxy-3-oxopropanoypcydohexyl)-1H-pyrazole-4-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
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synthesized from A23 as white solids.
LC-MS (ESI): RT = 1.55 min, mass calcd. for Ci7H24N205 336.2, miz found 337.1
[M41]+. 1H NMR (400 MHz, CDC13) 6 12.35 (s, 0.1H), 7.93 (s, 0.8H), 7.92 (s,
0.2H),
7.91 (s, 0.2H), 7.90 (s, 0.8H), 6.36 (s, 0.1H), 4.29 (q, J= 7.2 Hz, 2H), 4.24 -
4.20 (m,
3H), 3.53 (s, 1.5H), 3.52 (s, 0.3H), 2.82 - 2.77 (m, 0.7H), 2.63 - 2.55 (m,
0.3H), 2.30 -
2.03 (m, 5H), 1.84 - 1.73 (m, 2H), 1.63 - 1.56 (m, 111), 1.36 - 1.29 (m, 6H).
Intermediate KT25:
Ethyl 144-(3-ethoxy-3-oxopropanoypcydohexyl)-1H-pyrazole-5-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A24 as colorless oil. LC-MS (EST): RT = 1.88 min, mass calcd.
for
Ci7H24N205 336.2, miz found 337.4 [M+111 . 1H NMR (300 MHz, CDC13) 6 12.41 (s,
0.1H), 7.54- 7.45 (m, 1H), 6.87 - 6.80 (m, 1H), 5.27 - 5.09 (m, 1.1H), 4.38 -
4.29 (m,
2H), 4.24 - 4.17 (m, 2H), 3.61 - 3.48 (m, 1.8H), 2.81 - 2.72 (m, 0.7H), 2.64 -
2.53 (m,
0.3H), 2.37 - 2.18 (m, 1.8H), 2.14- 1.99 (m, 2.4H), 1.94- 1.86 (m, 1.8H), 1.84-
1.71
(m, 2H), 1.38 (t, J= 7.2 Hz, 3H), 1.29 (t, J= 7.2 Hz, 3H).
Intermediate KT26:
Ethyl 244-(3-ethoxy-3-oxopropanoypcydohexyl)pyriraidine-5-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A25 as yellow solids.
LC-MS (ESI): RT = 1.671 min and 1.987 min, mass calcd. for C181124N205 348.2,
miz
found 349.1 [M+H] .
Intermediate KT27:
(trans)-Ethyl 244-(3-ethoxy-3-oxopropanoy0cydohexyl)thiazole-4-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A26 as yellow oil.
1H NMR (400 MHz, DMSO-d6) 6 12.15 (s, 0.1H), 8.40 (s, 1H), 5.10 (m, 0.1H),
4.29 (q,
J= 7.2 Hz, 2H), 4.12 (q, J= 7.2 Hz, 2H), 3.68 (s, 1.8H), 3.01 (tt, J= 12.0,
3.6 Hz, 1H),
2.57 (tt, J= 12.0, 3.6 Hz, 1H), 2.16 - 2.13 (m, 2H), 2.02 - 1.99 (m, 2H), 1.58
- 1.48 (m,
2H), 1.45 - 1.35 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H).
Intermediate KT28:
Methyl 544-(3-ethoxy-3-oxopropanoypcyclohexyl)isoxazole-3-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A27 as yellow oil.
LC-MS (ESI): RT = 1.721 min, mass calcd. for Ci6H2iN06 323.1, miz found 324.1
[M+111 . 1H NMR (400 MHz, DMSO-d6) 6 6.70 (s, 0.7H), 6.68 (s, 0.3H), 4.12 -
4.07 (m,
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2H), 3.88 (s, 3H), 3.68 (s, 2H), 2.90 - 2.84 (m, 1H), 2.57 - 2.51 (m, 1H),
2.10 - 2.07 (m,
2H), 2.00 - 1.96 (m, 2H), 1.51- 1.36 (m, 4H), 1.19 (t, J= 7.0 Hz, 3H).
Intermediate KT29:
Ethyl 3-(4-(3-ethoxy-3-oxopropanoy0cyclohexyl)isoxazole-5-carboxylate
.. By utilizing the analogous procedure of Method A, the title compound was
synthesized from A28 as yellow oil.
LC-MS (ESI): RT = 2.114 min, mass calcd. for Ci7H23N06 337.2, m/z found 338.1
[M+1-11 . 1H NMR (300 MHz, DMSO-d6) 6 7.25 (s, 1H), 4.32 (q, J= 7.2 Hz, 2H),
4.06
(q, J= 7.2 Hz, 2H), 3.65 (s, 2H), 2.77 - 2.66 (m, 1H), 2.55 - 2.48 (m, 1H),
2.03 - 1.89
(m, 4H), 1.53 - 1.31 (m, 4H), 1.28 (t, J= 7.2 Hz, 3H), 1.16 (t, J= 7.2 Hz,
3H).
Intermediate KT30:
tert-Butyl 44443-ethoxy-3-oxopropanoyl)piperidin-1-yl)benzoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A8 as yellow solids.
1H NMR (400 MHz, CDC13) 6 12.18 (hr s, 0.1H), 7.86 (d, J= 8.8 Hz, 2H), 6.84
(d, J=
8.8 Hz, 2H), 5.00 (s, 0.1H), 4.23 - 4.18 (m, 2H), 3.92 - 3.84 (m, 2H), 3.52
(s, 1.8H),
2.93 - 2.82 (m, 2H), 2.72 - 2.64 (m, 1H), 2.00 - 1.93 (m, 2H), 1.81 - 1.71 (m,
2H), 1.57
(s, 9H), 1.31 - 1.24 (m, 3H).
Intermediate KT31:
Methyl 4-4-(3-ethoxy-3-oxopropanoy0cyclohexylkenzoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A30 as colorless oil. 1H NMR (300 MHz, DMSO-d6) 6 7.91 - 7.88
(m,
2H), 7.41 - 7.32 (m, 2H), 4.15 - 4.07 (m, 2H), 3.84 (s, 3H), 3.70 (s, 2H),
2.86 - 2.58 (m,
2H), 2.13 - 1.98 (m, 2H), 1.89 - 1.37 (m, 6H), 1.25 - 1.18 (m, 3H).
Intermediate KT32:
(trans)-Ethyl 544-(3-ethoxy-3-oxopropanoyl)cydohexyl)-1,2,4-oxadiazole-3-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A31 as yellow solids.
1H NMR (400 MHz, DMSO-d6) 6 4.40 (q, J= 7.2 Hz, 2H), 4.10 (q, J= 7.2 Hz, 2H),
3.68 (s, 2H), 3.11 (tt, J= 11.6, 4.0 Hz, 1H), 2.56 (tt, J= 12.0, 3.6 Hz, 1H),
2.19 - 2.15
(m, 2H), 2.02 - 1.98 (m, 2H), 1.57 (qd, J= 12.4, 3.6 Hz, 2H), 1.40 (qd, J=
12.0, 3.2 Hz,
2H), 1.32 (t, J= 7.2 Hz, 3H), 1.19 (t, J= 7.2 Hz, 311).
Intermediate KT33:
tert-butyl 443-methoxy-3-oxopropanoyl)piperidine-1-earboxylate
By utilizing the analogous procedure of Method A, the title compound was
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synthesized from A32.
LC-MS (ESI): RT = 2.484 min, mass calcd. for Ci4H23N05 285.2, m/z found 230.0
[M+H-t-Bui . 11-1 NMR (300 MHz, CDC13) 6 4.96 (s, 0.2H), 4.10-4.06 (m, 2H),
3.71 (s,
3H), 3.49 (s, 1.8H), 3.77 (t, J= 16 Hz, 2H), 2.60 (tt, J= 11.3, 3.83 Hz, 1H),
1.84-1.80
(m, 2H), 1.58-1.46 (m, 2H), 1.44 (s, 9H).
Intermediate KT34:
442-Ethoxycarbonyl-acety1)-piperidine-1-carboxylic acid tert-butyl ester
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A32.
11-1 NMR (300 MHz, CDC13) 6 12.17 (s, 0.2 H), 4.99 (s, 0.2H), 4.26 - 4.03 (m,
4H), 3.50
(s, 1.6H), 2.87 - 2.72 (m, 2H), 2.68 - 2.58 (m, 1H), 1.94 - 1.76 (m, 2H), 1.63
- 1.49 (m,
2H), 1.46 (s, 9H), 1.28 (t, J= 10.5 Hz, 3H).
Intermediate KT35:
tert-butyl 4-(3-ethoxy-3-oxopropanoyI)-2-methylpiperidine-1-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A33 as colorless oil. LC-MS (ESI): RT = 2.043 min, mass
calcd. for
Ci6H27N05 313.2, m/z found 314.1 [M+111 . 1FINMR (400 MHz, CDC13) 6 12.24 (s,
0.1H), 12.17 (s, 0.1H), 5.02 (s, 0.1H), 4.97 (s, 0.1H), 4.20 (q, J= 7.2 Hz,
2H), 4.10 -
4.05 (m, 1H), 3.87 - 3.81 (m, 1H), 3.52 (s, 1H), 3.49 (s, 0.6H) 3.08 - 3.00
(m, 0.8H),
2.86 - 2.70 (m, 1.2H), 2.05 - 1.98 (m, 0.7H), 1.89 - 1.85 (m, 2H), 1.72 - 1.67
(m, 1.3H),
1.46 (s, 9H), 1.30 - 1.26 (m, 3H), 1.14- 1.11 (m, 3H).
Intermediate KT36:
tert-Butyl 3-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A34.
LC-MS (ESI): RT = 1.939 min, mass calcd. for Ci4H23N05 285.2, m/z found 230.1
[M-
Boc+111 . 11-1 NMR (400 MHz, CDC13) 6 12.12 (hr s, 0.2H), 6.17 (hr s, 0.2H),
4.17 (q, J
= 7.2 Hz, 2H), 3.64 - 3.58 (m, 1.4H), 3.49 (s, 1.6H), 3.39 - 3.27 (m, 3.6H),
2.09 - 2.05
(m, 2H), 1.42 (s, 9H), 1.25 (t, J= 7.2 Hz, 3H).
Intermediate KT37:
tert-Butyl 3-(3-ethoxy-3-oxopropanoy0azetidine-1-carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A35 as red oil. 11-1 NMR (300 MHz, CDC13) 6 12.17 (hr s,
0.2H), 5.06
(s, 0.2H), 4.18 (q, J= 7.2 Hz, 2H), 4.10 - 4.00 (m, 411), 3.64- 3.55 (m,
0.8H), 3.45 (s,
1.6H), 3.26 - 3.20 (m, 0.2H), 1.41 (s, 9H), 1.27 (t, J= 7.2 Hz, 3H).
Intermediate KT38:
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tert-Butyl 3-(3-methoxy-3-oxopropanoyl)azetidine-1-carboxylate
o o
o OH oo o o
rl- o
o -0
eq) / \
KT38-2 0 Me0H
BOG! (1.2eq) Boc
Boc/N
DMAP (1.5 eq) overnight Bõ/
KT38-1 DCM, overnight, r.t. KT38-3 KT38
Intermediate KT38-3:
tert-Butyl 3-(2,2-dimethy1-4,6-dioxo-1,3-dioxane-5- carbonyl)azetidine-l-
carboxylate
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid KT38-1
(4.00 g,
19.9 mmol), 2,2-dimethy1-1,3-dioxane-4,6-dione KT38-2 (3.15 g, 21.9 mmol) and
4-
dimethylaminopyridine (3.64 g, 29.8 mmol) in dichloromethane (80 mL) was added
N-(3-dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride (4.58 g, 23.9
mmol).
The reaction mixture was stirred at room temperature under nitrogen atmosphere
overnight. Then the mixture was diluted with dichloromethane (100 mL) and
washed with 5 % potassium bisulfate aqueous solution (200 mL) for three times.
The
combined organic layers were dried over Na2SO4(s) and filtered. The filtrate
was
concentrated to give the title compound (6.3 g, 97 % yield) as yellow oil. 111
NMR
(300 MHz, CDC13) 64.60 - 4.50 (m, 1H), 4.27 (t, J= 8.7 Hz, 2H), 4.16 - 4.11
(m, 3H),
1.75 (s, 6H), 1.45 (s, 9H).
Intermediate KT38:
tert-Butyl 3-(3-methoxy-3-oxopropanoyl)azetidine-1-carboxylate
The solution of tert-butyl 3-(2,2-dimethy1-4,6-dioxo-1,3-dioxane-5-
carbonyl)azetidine
-1-carboxylate KT38-3 (6.30 g, 19.3 mmol) in methanol (80 mL) was heated to 80
C.
After stirred at 80 C overnight, the mixture was allowed to cool down to room
temperature, concentrated under reduced pressure and purified by silica gel
column
chromatography (petroleum ether : ethyl acetate = 4 : 1 to 2 :1) to give the
title
compound (3.3 g, 67 % yield) as yellow oil. LC-MS (ESI): RT = 1.44 min, mass
calcd.
for Ci2Hi9N05 257.1, m/z found 258.2 [M+111 . 11-1 NMR (400 MHz, CDC13) 6
12.11 (s,
0.2H), 5.09 (s, 0.2H), 4.13 - 4.03 (m, 4H), 3.75 (s, 3H), 3.65 - 3.57 (m, 1H),
3.49 (s,
1.6H), 1.43 (s, 9H).
Intermediate KT39:
Methyl 142-(4-(3-methoxy-3-oxopropanoyl)cyclohexyl)pyrimidin-5-yl)cyclopropane-
1-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A36 as red oil. 11-1 NMR (300 MHz, CDC13) 6 12.17 (br s,
0.2H), 5.06
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(s, 0.2H), 4.18 (q, J= 7.2 Hz, 2H), 4.10 - 4.00 (m, 4H), 3.64- 3.55 (m, 0.8H),
3.45 (s,
1.6H), 3.26 - 3.20 (m, 0.2H), 1.41 (s, 9H), 1.27 (t, J= 7.2 Hz, 3H).
Intermediate KT40:
Ethyl 2-(4-(3-methoxy-3-oxopropanoyl)cyclohexyl)-5-methylpyrimidine-4-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A37 as brown oil. LC-MS (ESI): RT = 1.599 min, mass calcd.
for
C181124N205 348.2, miz found 349.1 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 8.80
(s,
1H), 4.37 (q, J= 7.2 Hz, 2H), 3.72 (s, 0.5H), 3.69 (s, 1.5H), 3.63 (s, 0.8H),
3.62 (s,
2.2H), 2.99 - 2.94 (m, 0.7H), 2.82 - 2.73 (m, 1H), 2.58 - 2.55 (m, 0.3H), 2.34
(s, 3H),
2.01 - 1.99 (m, 0.8H), 1.91 - 1.85 (m, 3H), 1.76 - 1.54 (m, 4.2H), 1.32 (t, J=
7.2H, 3H).
Intermediate KT41:
Methyl 3-(4-(4-(2-methoxy-2-oxoethyl)-5-methyloxazol-2-y0cyclohexyl)-3-
oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A38 as colorless oil. 11-1 NMR (400 MHz, DMSO-d6) 6 3.69 -
3.65 (m,
2H), 3.63 - 3.60 (m, 6H), 3.49 (s, 1.2H), 3.48 (s, 0.8H), 2.94 - 2.89 (m,
0.5H), 2.69 -
2.62 (m, 1H), 2.56 - 2.52 (m, 0.3H), 2.49 - 2.47 (m, 0.2H), 2.21 (s, 3H), 2.05
- 1.84 (m,
3H), 1.74 - 1.65 (m, 3H), 1.46 - 1.31 (m, 2H).
Intermediate KT42:
Methyl 3-(4-(5-(2-methoxy-2-oxoethyl)pyriraidin-2-y1)cydohexyl)-3-
oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A39 as colorless oil. 11-1 NMR (400 MHz, CDC13) 6 8.61 - 8.59
(m,
2H), 3.75 - 3.73 (m, 6H), 3.60 - 3.29 (m, 2H), 3.54 - 3.53 (m, 2H), 3.06 -
3.02 (m, 0.5H),
2.89 - 2.87 (m, 0.5H), 2.73 - 2.70 (m, 0.5H), 2.59 - 2.53 (m, 0.5H), 2.18 -
2.07 (m, 3H),
2.03 - 1.97 (m, 1H), 1.91 - 1.85 (m, 1H), 1.78 - 1.73 (m, 2H), 1.58 - 1.53 (m,
1H).
Intermediate KT43:
Ethyl 1-(2-(4-(3-methoxy-3-oxopropanoyl)piperidin-1-yl)pyrimidin-5-
yl)piperidine-4-
carboxylate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A40 as yellow solid. LC-MS (EST): RT = 1.671 min, mass calcd.
For
C21H30N405 418.2, miz found 419.2 [M+111 . 11-1 NMR (300 MHz, CDC13) 6 8.10
(s,
2H), 4.74 - 4.63 (m, 2H), 4.16 (q, J= 7.2 Hz, 2H), 3.75 (s, 3H), 3.54 (s, 2H),
3.35 -
3.31 (m, 2H), 2.98 - 2.87 (m, 2H), 2.75 -2.67 (m, 3H), 2.43 -2.34 (m, 1H),
2.05 -
2.01 (m, 2H), 1.95 - 1.82 (m, 4H), 1.69 - 1.55 (m, 2H), 1.27 (t, J= 7.2 Hz,
3H).
Intermediate KT44:
Methyl 3-(1-0-(3-(tert-butoxy)-3-oxopropyl)pyridin-2-
yppiperidin-4-y0-3-
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oxopropanoate
By utilizing the analogous procedure of Method A, the title compound was
synthesized from A41 as brown oil. LC-MS (ESI): RT = 1.56 min, mass calcd. for
C211-130N205 390.2, miz found 391.1 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 6
12.09 (s,
0.2H), 8.02 (d, J= 2.4 Hz, 1H), 7.34 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.61 (d, J=
8.8 Hz,
1H), 5.01 (s, 0.2H), 4.32 - 4.23 (m, 2H), 3.75 - 3.73 (m, 3H), 3.54 (s, 1.6H),
2.92 - 2.82
(m, 2H), 2.77 (t, J= 8.0 Hz, 2H), 2.73 - 2.65 (m, 1H), 2.47 (t, J= 7.2 Hz,
2H), 1.97 -
1.91 (m, 2H), 1.71 - 1.67 (m, 2H), 1.42 (s, 9H).
Part III: Preparation of Aryl Aldehydes of general formula V (P1)
Aldehyde 1, AL 1: 2-Chloro-4-fluoro-benzaldehyde
Aldehyde 2, AL2: 2-Chloro-3-fluoro-benzaldehyde
Aldehyde 3, AL3: 4-Fluoro-2-methylbenzaldehyde
Aldehyde 4, AL4: 2-Bromo-4-fluorobenzaldehyde
Aldehyde 5, AL5: 3-Fluoro-2-methyl-benzaldehyde
Aldehyde 6, AL6: 2-Bromo-3,4-difluorobenzaldehyde
Aldehyde 7, AL7: 4-Fluoro-2-methyl-benzaldehyde
Aldehyde 8, AL8: 2-Bromo-3-fluoro-benzaldehyde
Aldehyde 9, AL9: 2-Chloro-3,4-difluorobenzaldehyde
Aldehyde 10, AL 10: 3,4-Difluoro-2-methylbenzaldehyde
Aldehyde 11, AL11: 4-bromo-2-chlorobenzaldehyde
Aldehyde 6, AL6: 2-Bromo-3,4-difluorobenzaldehyde
,
HN0 (leg) F
HCI
F DIBAL-H(1.3 eq)
F AL6-2 (1.5M in Toluene),
Br HOBt (1.5 eq) Br THF, -78 C, lh Br
EDCI (1.5 eq) ,0
0 N
HO 0 DIEA (5 eq)
DMF, r.t.
AL6-1 AL6-3 AL6
overnight
Intermediate AL6-3:
2-Bromo-3,4-difluoro-Nmethoxy-Nmethyl-benzamide
To a solution of 2-bromo-3,4-difluoro-benzoic acid AL6-1 (2.50 g, 10.6 mmol)
in NN
dimethylformamide (25 MO was added 1-hydroxybenzotriazole (2.15 g, 15.9 mmol),
/V,N-diisopropylethylamine (6.84 g, 53.0 mmol) and N-ethyl-N`-(3-
.. dimethylaminopropyl)carbodiimide hydrochloride (3.05 g, 15.9 mmol) under
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nitrogen atmosphere at room temperature. The mixture was stirred for 10
minutes
and N, 0-dimethylhydroxylamine hydrochloride AL6-2 (1.04 g, 10.6 mmol) was
added. After stirred at room temperature overnight, the mixture was poured
into
water (80 Ml) and extrated with ethyl acetate (75 Ml) twice. The separated
organic
layers were washed with water (100 Ml) twice, brine (50 Ml) twice, dried over
Na2SO4(,), filtered, concentrated and purified by silica gel column
chromatography
(petroleum ether ethyl acetate = 10 1 to 5 1) to give the title compound (1.9
g, 66 %
yield) as yellow solids. 111 NMR (300 MHz, CDC13) 6 7.26 ¨ 7.17 (m, 111), 7.14
¨ 7.09
(m, 111), 3.93 ¨ 3.16 (m, 611).
Aldehyde 6:
2-Bromo-3,4-difluoro-benzaldehyde
To a solution of 2-bromo-3,4-difluoro-Nmethoxy-Nmethyl-benzamide AL6-3 (1.90
g,
6.81 mmol) in tetrahydrofuran (30 Ml) was added 1.5 M diisobutylaluminum
hydride in toluene (5.90 Ml, 8.85 mmol) at -78 C dropwise under nitrogen
atmosphere. After stirred at -78 C for 1 hour, the mixture was quenched with
water
(40 Ml), extracted with ethyl acetate (75 Ml) three times. The separated
organic
layers were washed with 2 M hydrochloride aqueous solution (30 Ml), water (40
Ml),
brine (20 Ml) twice, dried over Na2SO4(s) and filtered. The filtrate was
concentrated
under reduced pressure to give a residue, which was purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 10 1 to 5 1) to give the title
compound (1.0 g, 67% yield) as yellow solids. 1H NMR (300 MHz, DMSO-d6) 6
10.12
(s, 111), 7.81 ¨ 7.65 (m, 211).
Aldehyde 9, AL9: 2-Chloro-3,4-difluorobenzaldehyde
Intermediate AL9-1: 2-Chloro-3,4-difluorobenzoic acid
A solution of N1,N1,N2,N2-tetramethylethane-1,2-diamine (3.7 g, 69.6 mmol) in
tetrahydrofuran (45 Ml) was cooled to -70 C under nitrogen atmosphere before
dropwise addition of 1.3 M sec-butyllithium in hexane (60 Ml, 75.9 mmol)
followed
by a solution of 3,4-difluorobenzoic acid (5.0 g, 31.6 mmol) in
tetrahydrofuran (20 Ml)
over 10 minutes. The resulting mixture was stirred at -70 C for 1 hour and
then a
solution of 1,1,1,2,2,2-hexachloroethane (26 g, 110.8 mmol) in THF (45 Ml) was
added dropwise. Stirring continued at -70 C for 2 hours. The mixture was
warmed
to -10 C, quenched with water (125 MI), added diethyl ether (60 MI) and then
separated two phases. The aqueous layer was acidified to Ph 1 by using
concentrated hydrochloride aqueous solution and extracted with diethyl ether
(125
Ml) twice. The combined organic extracts were concentrated in vacuo to give
yellow
solids, which was recrystallized with ethyl acetate (30 Ml) to afford the
title
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compound (2.7 g, 45 % yield) as yellow solids. 111 NMR (400 MHz, DMSO-d6) 6
13.69
(hr s, 111), 7.75 - 7.71 (m, 111), 7.55 - 7.48 (m, 111).
Intermediate AL9-2 2-Chloro-3,4-difluoro-N-methoxy-N-methyl-benzamide
To a solution of 2-chloro-3,4-difluorobenzoic acid Intermediate AL9-1 (1.0 g,
5.2
mmol) in N, N-dimethylformamide (10 MO were added 1-hydroxybenzotriazole (1.1
g,
7.8 mmol), N,N-diisopropylethylamine (4.6 Ml, 26 mmol) and N(3-
Dimethylaminopropy0-N-ethylcarbodiimide hydrochloride (1.5 g, 7.8 mmol) under
nitrogen atmosphere at room temperature. The resulting mixture was stirred at
room temperature for 10 minutes. 0, N-dimethyl-hydroxylamine hydrochloride
(0.5
g, 5.2 mmol) was added and stirring continued at room temperature overnight.
After
quenched with water (20 MO, the mixture was extracted with ethyl acetate (20
Ml)
for three times. The combined organic layers were washed with water (20 MO,
brine
(20 MO, dried over Na2SO4(s), filtered and concentrated to leave a residue,
which was
purified by silica gel column chromatography (petroleum ether : ethyl acetate
= 4 : 1
to 2 :1) to give the title compound (1.06 g, 87 % yield) as yellow solids. 111
NMR (400
MHz, DMSO-d6) 6 7.60 - 7.53 (m, 111), 7.42 - 7.38 (m, 111), 3.80 - 3.45 (m,
311), 3.39
- 3.06 (m, 311).
Aldehyde 9: 2-Chloro-3,4-difluorobenzaldehyde
To a solution of 2-chloro-3,4-difluoro-N-methoxy-N-methyl-benzamide
Intermediate
AL9-2 (500 mg, 2.13 mmol) in tetrahydrofuran (8 MO was added 1 M
diisobutylaluminium hydride in toluene (2.8 Ml, 2.8 mmol) dropwise at -78 C
under
nitrogen atmosphere. After the addition, the mixture was stirred at -78 C for
1 hour.
It was then quenched with water (15 MO and extracted with ethyl acetate (25 MO
for three times. The combined organic layers were washed with 1 M hydrochloric
acid aqueous solution (10 MO, dried over Na2SO4(s), filtered and evaporated
under
reduced pressure to leave a yellow residue, which was purified by silica gel
column
chromatography (petroleum ether: ethyl acetate = 20 :1) to give the title
compound
(200 mg, 53 % yield) as yellow solids. 111 NMR (400 MHz, DMSO-d6) 6 10.23 (s,
111),
7.80 - 7.76 (m, 111), 7.69 - 7.62 (m, 111).
Aldehyde 10, AL 10: 3,4-Difluoro-2-methylbenzaldehyde
Intermediate AL10-1: 3,4-Difluoro-N-methoxy-N,2-dimethylbenzamide
To a solution of 3,4-difluoro-2-methylbenzoic acid (3.0 g, 17.4 mmol) in N, N-
dimethylformamide (30 MO were added 1-hydroxybenzotriazole (3.5 g, 26.2 mmol),
N,N-diisopropylethylamine (15.4 Ml, 87.0 mmol) and N1-((ethylimino)methylene)-
N3,
N3-dimethylpropane-1,3-diamine hydrochloride (5.0 g, 26.2 mmol) under nitrogen
atmosphere at room temperature. Having stirred at room temperature for 10
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minutes, the resulting mixture was added N,0-dimethylhydroxylamine
hydrochloride (1.7 g, 17.4 mmol) and stirring continued at room temperature
overnight. After quenched with water (50 MO, the mixture was extracted with
ethyl
acetate (50 Ml) for three times. The combined organic layers were washed with
water (50 MO, brine (50 MO, dried over Na2SO4(), and concentrated to leave a
residue, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 8 : 1 to 5 :1) to give the title compound (3.1 g, 84 % yield)
as yellow
oil. 111 NMR (300 MHz, CDC13) 6 7.07 ¨ 6.96 (m, 211), 3.47 (s, 311), 3.30 (s,
311), 2.26
(s, 311).
.. Aldehyde 10: 3,4-Difluoro-2-methylbenzaldehyde
To a solution of 3,4-difluoro-N-methoxy-N,2-dimethylbenzamide AL10-1 (3.1 g,
14.4
mmol) in tetrahydrofuran (40 MO was added 1.5 M diisobutylaluminium hydride in
toluene (12.5 Ml, 18.7 mmol) dropwise at -78 C under nitrogen atmosphere.
After
the addition, the mixture was stirred at -78 C for 1.5 hour. It was then
quenched
with water (15 MO and extracted with ethyl acetate (50 MO for three times. The
combined organic layers were washed with water (50 MO for three times, brine
(50
MO, dried over Na2SO4(s) and evaporated under reduced pressure to leave a
yellow
residue, which was purified by silica gel column chromatography (petroleum
ether:
ethyl acetate = 20: 1 to 10 :1) to give the title compound (1.87 g, 85 %
yield) as
colorless oil. 111 NMR (400 MHz, CDC13) 6 10.15 (s, 111), 7.61 ¨ 7.57 (m,
111), 7.18 ¨
7.12 (m, 111), 2.61 (s, 311).
Part IV: Preparation of Carboxamidines of general formula VI (P2)
Carboxamidine 1: Thiazole-2-carboxaraidine hydrochloride (Cal)
NH
S
H2N 1
NJ
HCI
.. Carboxamidine 2: 3,5-Difluoropicolinimidamide hydrochloride (Ca2)
NH
H2N N 1
HCI FF
To a stirred suspension of ammonium chloride (1.89 g, 35.7 mmol) in toluene
(100
MO was added 2M trimethylaluminum in toluene (21 Ml, 42.8 mmol) dropwise at 0
C under nitrogen atmosphere. The resulting mixture was then brought up to room
temperature and stirring continued for 30 minutes. A solution of 3,5-
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difluoropicolinonitrile (5.00 g, 35.7 mmol) in toluene (50 M1) was added and
the
reaction mixture was subsequently stirred at 80 C overnight. After cooled
down to
room temperature, the mixture was poured into slurry of silica gel in
dichloromethane (50 MO. After stirring for 10 minutes, the slurry was filtered
and
washed with methanol. The filtrate was concentrated in vacuum to give the
title
compound (1.90 g, 34% yield) as white solids.LC-MS (ESI): RT = 0.357 min, mass
calcd. For C6H6C1F2N3 193.0, m/z found 157.9 [M+H-HC11 .11-1 NMR (400 MHz,
DMSO-d6) 6 9.77 (br s, 2H), 9.60 (br s, 2H), 8.79 (d, J= 1.6 Hz, 1H), 8.41 -
8.35 (m,
1H).
Part V: Assembly of Dihydropyrimidines of general formula VII and VIII
Compound VII-1-x: (exemplified with Method B)
(trans)-Methyl 2-(4-(6-(2-chloro-3,4-difluorophenyl)-5-(methoxycarbonyl)-
2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)oxazole-4-carboxylate (a
single
stereoisomer)
Intermediates VII-1-P and VII-1-Q:
(cis)-Methyl 24-4-(6-(2-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers) and (trans)-methyl 2-(-4-(6-(2-chloro-3,4-difluorophenyl)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-ypcyclohexyl)oxazole-
4-
carboxylate (a mixture of 2 stereoisomers)
To a solution of methyl 2-(4-(3-ethoxy-3-oxopropanoyl)cyclohexyl)oxazole-4-
carboxylate KT1 (1.55 g, 5.02 mmol), 2-chloro-3,4-difluorobenzaldehyde AL9
(893 mg,
5.02 mmol) and thiazole-2-carboximidamide hydrochloride Cal (823 mg, 5.02
mmol)
in methanol (40 MO was added sodium acetate (412 mg, 5.02 mmol). The miuxture
was heated to 70 C for 16 hours. The reaction mixture was allowed to cool
down to
room temperature and concentrated under reduced pressure to give a residue,
which
was purified by silica gel column chromatography (petroleum ether ethyl
acetate =
5 1 to 2 1) and further purified by C18 column (acetonitrile water = 30 % to
75 %)
to give the title compound VII-1-P (320 mg, 12 % yield) as yellow solids and
VIE-1-Q
(700 mg, 26 % yield) as yellow solids. VII-1-P: LC-MS (EST): RT = 1.63 min,
mass
calcd. For C26H23C1F2N405S 576.1, m/z found 576.9 [M+111 . 11-1NMR (400 MHz,
DMSO-d6) 6 9.55 (d, J= 4.0 Hz, 1H), 8.87 - 8.86 (m, 0.8H), 8.71 (s, 0.2H),
7.98 - 7.92
(m, 2H), 7.48 - 7.41 (m, 1H), 7.18 - 7.14 (m, 1H), 6.02 (s, 0.3H), 5.89 (d, J=
3.6 Hz,
0.7H), 3.90 - 3.86 (m, 0.3H), 3.83 (s, 2.1H), 3.82 (s, 0.9H), 3.73 - 3.68 (m,
0.7H), 3.53
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(s, 2.1H), 3.52 (s, 0.9H), 3.31 (s, 0.3H), 3.28 (hr s, 0.7H), 2.42 -2.31 (m,
2H), 1.96 -
1.44 (m, 6H).
VII-1-Q: LC-MS (ESI): RT = 1.967 min, mass calcd. For C26H23C1F2N405S 576.1,
m/z
found 577.0 [M+1-11 . 1HNMR (400 MHz, DMSO-d6) 6 9.58 (d, J= 3.6 Hz, 0.6H),
9.07
(s, 0.4H), 8.78 (d, J= 4.0 Hz, 1H), 8.01 (s, 1.5H), 7.95 (d, J= 3.2 Hz, 0.5H),
7.50 -
7.41 (m, 1H), 7.23 - 7.15 (m, 1H), 6.03 (s, 0.4H), 5.93 (d, J= 4.0 Hz, 0.6H),
3.96 -
3.87 (m, 0.4H), 3.80 (s, 3H), 3.70 - 3.61 (m, 0.6H), 3.54 (s, 1.8H), 3.53 (s,
1.2H), 3.10
-3.01 (m, 0.4H), 2.93 - 2.86 (m, 0.6H), 2.26 - 2.14 (m, 2H), 2.10 - 2.01 (m,
0.4H),
1.95 - 1.50 (m, 5.6H).
A stereoisomeric mixture of (trans)-methyl 2-(4-(6-(2-chloro-3,4-
difluoropheny1)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)oxazole-4-
carboxylate VII-1-Q (700 mg, 1.15 mmol, 90 % purity) was purified by chiral
Prep.
SFC (Column: Chiralpak IC 5 pm 20 * 250 mm; Mobile Phase: CO2 : Me0H = 70 : 30
at 50 g/min; Col. Temp: 40 C; Wavelength: 254 nm; Back pressure: 100 bar) to
give
VII-1-X (280 mg, 41 % yield, 98.0 % purity, 100 % stereopure) as yellow solids
and
VII-1-Y (300 mg, 44 % yield, 98.2 % purity, 98.0 % stereopure) as yellow
solids.
VII-1-X: LC-MS (ESI): RT = 2.028 min, mass calcd. For C26H23C1F2N405S 576.1,
m/z
found 577.1 [M+Hi . Chiral analysis (Column: Chiralpak IC 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 70: 30 at 3 g/min; Col. Temp: 40 C; Wavelength:
254
nm, Back pressure: 100 bar, RT = 6.41 min). 1H NMR (400 MHz, CDC13) 6 8.18 (s,
1H), 8.17 (s, 0.5H), 7.83 (t, J= 2.8 Hz, 1H), 7.51 (d, J= 2.8 Hz, 0.4H), 7.46
(d, J= 3.2
Hz, 0.6H), 7.39 (d, J= 1.6 Hz, 0.5H), 7.10 - 7.01 (m, 2H), 6.19 (s, 0.6H),
6.06 (d, J=
2.4 Hz, 0.4 H), 4.09 - 4.02 (m, 0.6H), 3.92 (s, 3H), 3.86 - 3.78 (m, 0.4H),
3.63 (s,
1.2H), 3.60 (s, 1.8H), 3.01 - 2.93 (m, 1H), 2.36 - 2.11 (m, 2.5H), 2.05 - 2.01
(m, 1.5H),
1.92 - 1.78 (m, 3H), 1.72 - 1.62 (m, 1H).
LC-MS (ESI): RT = 2.026 min, mass calcd. For C26H23C1F2N405S 576.1, m/z
found 577.1 [M+Hi . Chiral analysis (Column: Chiralpak IC 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 70 : 30 at 3 g/min; Col. Temp: 40 C; Wavelength:
254
nm, Back pressure: 100 bar, RT = 7.98 min). 1H NMR (400 MHz, CDC13) 6 8.18 (s,
1H), 8.17 (s, 0.5), 7.83 (d, J= 2.8 Hz, 1H), 7.51 (d, J= 3.2 Hz, 0.5H), 7.46
(d, J= 3.2
Hz, 0.5H), 7.39 (d, J= 1.2 Hz, 0.5H), 7.10 - 6.99 (m, 2H), 6.19 (s, 0.6H),
6.06 (d, J=
2.4 Hz, 0.4H), 4.10 -4.03 (m, 0.6H), 3.92 (s, 3H), 3.86 -3.77 (m, 0.4H), 3.63
(s, 1.2H),
3.60 (s, 1.8H), 3.01 -2.95 (m, 1H), 2.36 - 2.10 (m, 2.6H), 2.05 - 2.01 (m,
1.4H), 1.92 -
1.71 (m, 3H), 1.68 - 1.61 (m, 1H).
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Assembles of dihydropyrimidines of general formula VH/VIII incorporated with
acids of general formula III- 1 or 111-2, aryl aldehydes (P1) and
carboxamidines (P2)
via sequential two reaction steps are shown below in Table 1:
Table 1:
acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VHI
formula formula
111- 1/111-2 IV- 1/IV-2
Al KT 1 AL9 Cal
0 CI
0 N
trans H 11\_)
0
0-
Compound VII- 1-X
Al KT2 AL9 Cal
0 CI
ON
trans N
0
0_
Compound VII-2-Y
Al KT 1 AL5 Cal
0
0 te H
0
0¨
Compound VII-3-H
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
Al KT 1 AL1 Cal
0 01
ULN
ie. NH
0
2
Compound VII-4-N
Al KT 1 AL2 Cal
0 01
I IN
et's
0
4
Compound VII-5-Q
Al KT 1 AL7 Cal
0
ss s
0 er
4 Compound VII-6-Q
Al KT 1 AL9 Ca2
01
N F
I
0
H
S--
0
0
Compound VII-7-N
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
A2 KT3 AL9 Cal
0 CI
N
0
0\(
Compound VII-8-N
Al KT2 AL2 Cal
0 CI
Ns
trans H
0
0
0¨
Compound VII-9-F
Al KT2 AL 1 Cal
0 CI
trans
0
0
Compound VII- 10-P
Al KT2 AL5 Cal
o
CO IN1
4
Compound VII- 1 1 -Q
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
Al KT2 AL7 Cal
0
I IA
NrS
trans H
0
0
0
Compound VII- 12-P
A3 KT4 AL9 Cal
0 CI
* N
0 H
IN
0
0
Compound VII- 13-P
Compound VII- 13-Q
A4 KT5 AL9 Cal
0 CI
Ns\
trans H j
0
0
Compound VII- 14-N
A5 KT6 AL9 Cal F
0 CI
I
ans
0 N''.-"==
Compound VII- 15-M
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
A6 KT7 AL9 Cal
0 40 c,
s
El-
es'
0
r
Compound VII- 16-N
A6 KT7 AL1 Cal
o
o
sr,
Compound VII- 17-M
A6 KT7 AL4 Cal
0 Br
,s I 3r
N S\
t ans H rsLI
00_0
Compound VII- 18-M
A6 KT7 AL8 Cal
0 Br
0
s
0_0 IN
FO
Compound VII- 19-M
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
F
A6 KT7 AL2 Cal
0 ci
O N
,1 )r
0
0--IN
0
/---0
Compound VII-20-N
F
A6 KT7 AL5 Cal
0 ,
,0 N
tran H NO
0
r
Compound VII-2 1 -N
F
A7 KT8 AL9 Cal F
O CI
0 N
trans H 0
0
\ IN
0.
0
Compound VII-22 -S
A8 KT9 AL9 Cal F
40 F
O CI
0 N
I ),S
N
trans H r\ j
\01,.
0
ro
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV-1/IV-2
Compound VII-23-Y
A9 KT10 AL9 Cal
O CI
II _
0
\
0
0¨
Compound VII-24-M
A10 KT1 1 AL9 Cal
O CI
(T/s,==
0
0
Compound VII-25-N
All KT12 AL9 Cal
O CI
II _
=410,
$11
ofo
Compound VII-26-8
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
Al2 KT13 AL9 Cal F
0 CI
N jIrSµ
,te H
0
Compound VII-27-R
Al3 KT14 AL9 Cal F
0 CI
N
I Ns
trans H
0
Compound VII-28-N
Al4 KT15 AL1 Cal
0 CI
N
N*T,S
t ans H
Compound VII-29-P
Al5 KT16 AL9 Cal
0 CI
N
trans H
0
Compound VII-30-10
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A16 KT17 AL9 Cal
0 CI
N
H
N-
0
Compound VII-31
Al7 KT18 AL9 Cal
0 CI
1\1
N)rs
trans H
IN,
Compound VII-32-N
A18 KT19 AL9 Cal
CI
N
I I
1\1)S
trans H NI)
Compound VII-33-10
Al9 KT20 AL9 Cal
0 01
N
I
0 111
Compound VII-34
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A20 KT21 AL9 Cal
0 CI
)S
\N trans H (
N'\
0
0¨
Compound VII-35-P
A21 KT22 AL9 Cal
0 CI
s
0_
Compound VII-36-N
A22 KT23 AL9 Cal F
11,
0 CI
(7)
trans
Niasµ.
--1/
o
Compound VII-37-4C
A23 KT24 AL9 Cal
0 CI
/0 JIL\I
yS
trans H 11_)
N,
0
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
Compound VII-38-N
F
A24 KT25 AL9 Cal F
O CI
0 N
M 0
0 N S
H Li
¨IV
Compound VII-39-N
F
A24 KT25 AL9 Cal F
O CI
0 N
MO ONS
/ N trans H ri_j
--...
-11
Compound VII-39-P
F
A25 KT26 AL9 Cal F
0 CI
..-"O
N
N trans
I
Or,N
Compound VII-40-M
F
A26 KT27 AL9 Cal F
O CI
J(3 N
trans H ri j
S
5--IN
EtO2C
Compound VII-41-N
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV- 1/IV-2
A27 KT28 AL9 Cal
0 CI
N)S
t ans H
N'x I
(R: -CH38.-CH2CH3)
P
R
Compound VII-42- 11
A28 KT29 AL9 Cal
0 CI
trans
0'
0
0
Compound VII-43-N
A30 KT31 AL9 Cal
CI
os
N
trans H
0
0
Compound VII-44-X
A31 KT32 AL9 Cal
0 CI
N
trans H
N
EtO2C
Compound VII-45-R
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A36 KT39 AL9 Cal
o 10' c,
NKrS
trans H
N
)0.zU
Compound VII-46-P
A37 KT40 AL6 Cal
0 Br
' N
trans H '
0 0"
Compound VII-47-N
A38 KT41 AL1 Cal
o 1.1 CI
Ns
trans H
H3 C r
N
0
¨0
Compound VII-48-B
A39 KT42 AL9 Cal
0 I. CI
N
I N S N
t ans H
0
Compound VII-49-A
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A39 KT42 AL1 Cal
0 a
,0
=
s
N-
0
Compound VII-50-A
A32 KT33 AL10 Cal
0
s
H
Boc,N
Compound VIII-1-B
A32 KT34 AL5 Cal
0
I
T1) BocN
Compound VIII-2-B
A32 KT34 AL3 Cal
o
Ns
H
>0iN
0
Compound VIII-3-B
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A32 KT33 AL5 Cal
0
I
H
Boc'N
Compound VIII-4-A
A32 KT33 AL7 Cal
0
)rs
Boc'N
Compound VIII-5-B
A32 KT33 AL2 Cal çI
0 CI
H
BocN
Compound VIII-6-B
A32 KT33 AL1 Cal
a
Boc' N
Compound VIII-7-B
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A32 KT34 AL1 Cal
0 CI
N
N
Boc, N H s
Compound VIII-8-B
A32 KT34 AL2 Cal
0 CI
H
Boc, N
Compound VIII-9-B
A32 KT33 AL9 Cal
0 CI
I
H
Boc, N
Compound VIII-10-B
A33 KT35 AL9 Cal
0 CI
KO
I )s
H jBocN
Compound VIII-11-6
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV-1/IV-2
A32 KT34 AL9 Cal F
F
O CI
0 N
IN
N --
H
Boc,N S----
Compound VIII- 12-B
A32 KT33 AL11 Cal Br
O CI
o N
I )r s
N
H \ j
Boc,N N
Compound VIII- 13-2b
A32 KT33 AL6 Cal F
F
O Br
o N
I s
N
H NJ
Boc,N
Compound VIII- 14-B
A32 KT33 AL8 Cal F
O Br
(7) N
I s
N
H \ j
Boc,N N
Compound VIII- 15-B
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
111- 1/111-2 IV-1/IV-2
A32 KT33 AL11 Cal F
0 Br
0 N
1 Kis
N
13oc'N H ri_si
VIII- 16-2B
A34 KT36 AL9 Cal F
F
1 0 CI
0 N
I s
N
H \ 1
BocN N j Compound VIII-
17
A29 KT37 AL9 Cal F
F
1 0 CI
0 N
I s
N
BocN H \\ j
N
Compound VIII- 18-2
A35 KT38 AL1 Cal F
0 CI
o N
I )s
N
13oc'N
N
Compound VIII- 19-4
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acid of ketoester P1 P2 dihydropyrimidine of
general of general general formula VII/VIII
formula formula
III-1/11I-2 IV-1/1V-2
A40 KT43 AL1 Cal
0 L-,171-01
\O 'N
j NN
H
NN
Compound VIII-20-6B
A32 KT34 AL8 Cal
0 Br
)s
H )
Boc,N
Compound VIII-21-B
A32 KT34 AL11 Cal
0 Br
H )
Boc, N
Compound VIII-22-2
A41 KT44 AL1 Cal
0 CI
0 N
N
N N H
A
Compound VIII-23-B
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Spectral analyses of assembled dihydropyrimidines of general formula VII/VIII
Compound VII-2-Y:
(trans) -methyl 2-(44642-chloro-3,4-difluoropheny0-5-(ethoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a single
stereoisomer)
Intermediates VII-2-P and VII-2-Q:
(cis)-Methyl 2444642-chloro-3,4-difluoropheny1)-5-(ethoxycarbonyl)-2-(thiazol-
2-y1)-
3,6-dihydropyrimidin-4-y0cydohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers) and (trans)-methyl 2444642-chloro-3,4-difluoropheny1)-5-
(ethoxycarbony0-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-yl)cydohexyDoxazole-4-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
Compound VIE-2-P: LC-MS (ESI): RT = 3.919 min, mass calcd. for C27H25C1F2N405S
590.1, m/z found 591.1 [M+111 . 111 NMR (400 MHz, CDC13) 6 8.26 (s, 1H), 8.17
(s,
1H), 7.80 - 7.78 (m, 1H), 7.45 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 2.8 Hz,
0.7H), 7.09 -
6.96 (m, 2H), 6.20 (s, 0.7H), 6.06 (d, J= 2.8 Hz, 0.3H), 4.11 - 3.99 (m, 3H),
3.94 (s,
2.1H), 3.92 (s, 0.9H), 3.38 - 3.33 (m, 0.7H), 3.31 - 3.26 (m, 0.3H), 2.57 -
2.43 (m, 2H),
2.1 - 1.65 (m, 6H), 1.14 (t, J= 7.2 Hz, 3H).
Compound VIE-2-Q: LC-MS (ESI): RT = 4.351 min, mass calcd. for C27H25C1F2N405S
590.1, m/z found 591.1 [M+111 . 111 NMR (400 MHz, CDC13) 6 8.18 (s, 1H), 8.14
(s,
0.5H), 7.83 - 7.82 (m, 1H), 7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 3.2 Hz,
0.6H), 7.33
(s, 0.5H), 7.12 - 6.99 (m, 2H), 6.21 (s, 0.6H), 6.08 (d, J= 2.8 Hz, 0.4H),
4.10 - 4.00 (m,
2.6H), 3.92 (s, 3H), 3.85 - 3.78 (m, 0.4H), 3.02 - 2.93 (m, 1H), 2.38 - 2.21
(m, 2.8H),
2.15 - 2.01 (m, 1.2H), 1.91 - 1.65 (m, 4H), 1.17 - 1.12 (m, 3H).
A stereoisomeric mixture of (trans)- methyl 2-(4-(6-(2-chloro-3,4-
difluoropheny0-5-
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)oxazole-
4-
carboxylate VII-2-Q (160 mg, 0.270 mmol, 98.6 % purity) was separated by
chiral
Prep. HPLC (Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
:
DEA = 50 : 50 : 0.2 at 25 mL/min; Temp: 30 C; Wavelength: 230 nm) to give
compounds VII-2-X (70 mg, 43 % yield, 100 % stereopure) and VII-2-Y (65 mg, 40
%
yield, 99.6 % stereopure).
Compound VII-2-X: LC-MS (ESI): RT = 2.878 min, mass calcd. for C27H25C1F2N405S
590.1, m/z found 591.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm
4.6 *
250 mm; Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/min;
Wavelength:
230 nm, RT = 5.865 min). 111 NMR (400 MHz, CDC13) 6 8.18 (s, 1H), 8.14 (s,
0.6H),
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7.83 (d, J= 3.6 Hz, 1H), 7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 3.2 Hz, 0.6H),
7.33 (s,
0.4H), 7.12 - 6.99 (m, 2H), 6.21 (s, 0.6H), 6.08 (d, J= 2.8 Hz, 0.4H), 4.12 -
3.98 (m,
2.8H), 3.92 (s, 3H), 3.86 - 3.77 (m, 0.2H), 3.03 - 2.92 (m, 1H), 2.36 - 2.17
(m, 2.6H),
2.10 - 2.01 (m, 1.2H), 1.93 - 1.65 (m, 4.2H), 1.17 - 1.12 (m, 3H).
Compound VII-2-Y: LC-MS (ESI): RT = 2.849 min, mass calcd. for C27H25C1F2N405S
590.1, m/z found 591.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm
4.6 *
250 mm; Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/min;
Wavelength:
230 nm, RT = 6.610 min). 1H NMR (400 MHz, CDC13) 68.18 (s, 1H), 8.15 (s,
0.5H),
7.83 - 7.82 (m, 1H), 7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 2.8 Hz, 0.6H),
7.33 (s,
0.5H), 7.12- 6.99(m, 2H), 6.21 (s, 0.6H), 6.08 (d, J= 2.4 Hz, 0.4H), 4.10-
4.00(m,
2.8H), 3.92 (s, 3H), 3.85 - 3.78 (m, 0.2H), 3.01 - 2.92 (m, 1H), 2.38 - 2.17
(m, 2.8H),
2.10 - 1.98 (m, 1.2H), 1.92 - 1.65 (m, 4H), 1.17 - 1.12 (m, 3H).
Compound VII-3-H:
(trans)-Methyl 2-446-(3-fluoro-2-methylpheny1)-5-(methoxycarbony1)-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a single
stereoisomer)
Intermediate VII-3-1:
Methyl 2-4-(3-(3-fluoro-2-methylpheny0-2-
(methoxycarbonyOacryloyl)cyclohexy0oxazole-4-carboxylate
To a solution of methyl 2-(4-(3-methoxy-3-oxopropanoyl)cyclohexyl)oxazole-4-
carboxylate KT1 (700 mg, 1.86 mmol) and 3-fluoro-2-methylbenzaldehyde AL5 (307
mg, 2.22 mmol) in propan-2-ol (30 mL) was added one drop of piperidine and one
drop of acetic acid at room temperature. After stirred at 70 C under nitrogen
atmosphere overnight, the reaction mixture was cooled down and concentrated
under reduced pressure to give a residue, which was purified by C18 column
(acetonitrile : water = 62 % to 69 %) to give the title compound (510 mg, 64 %
yield)
as yellow soilds. LC-MS (ESI): RT = 1.72 min, mass calcd. for C23H24FN06
429.1, m/z
found 429.9 [M+111 . 1H NMR (400 MHz, CDC13) 68.18 - 8.11 (m, 1H), 7.97-7.94
(m,
0.7H), 7.79-7.75 (m, 0.3H), 7.15 - 6.94 (m, 3H), 3.91 (s, 2H), 3.89 (s, 1H),
3.85 (s,
1.3H), 3.83 (s, 0.7H), 3.70 (s, 0.7H), 3.68 (s, 0.3H), 3.13 - 3.05 (m, 0.3H),
2.97 - 2.78
(m, 0.7H), 2.73 - 2.66 (m, 0.3H), 2.30 - 1.63 (m, 9.711), 1.46 - 1.24 (m, 2H).
Intermediate VII-3-Q and VII-3-P:
(trans)-Methyl 2-446-(3-fluoro-2-methylpheny1)-5-(methoxycarbony1)-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers) and (ci0-Methyl 2-4-(643-fluoro-2-methylpheny1)-5-
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(methoxycarbony0-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-370cyclohexyl)oxazole-
4-
carboxylate (a mixture of 2 stereoisomers)
To a solution of methyl 2-(4-(3-(3-fluoro-2-methylpheny1)-2-
(methoxycarbonyl)acryloyl)cyclohexyl)oxazole-4-carboxylate VII-3-1 (500 mg,
1.08
mmol) and thiazole-2-carboximidamide hydrochloride Cal (212 mg, 1.30 mmol) in
N,N-dimethylformamide (26 mL) was added sodium bicarbonate (273 mg, 3.25 mmol)
at room temperatue. After stirred at 90 C under nitrogen atmosphere
overnight, the
reaction mixture was cooled down and diluted with water (100 mL), extracted
with
ethyl acetate (100 mL) twice. The combined organic layers were washed with
water
(30 ml), brine (50 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under reduced pressure and purified by silica gel column
chromatography (petroleum ether : ethyl acetate = 4: 1 to 3 : 1 to 2 :1) to
give the
compound W1-3-P (53 mg, 8 % yield) as yellow soilds and VII-3-Q (82 mg, 14 %
yield)
as yellow soilds.
VII-3-P: LC-MS (ESI): RT = 1.78 min, mass calcd. for C27H27FN405S 538.2, m/z
found
539.0 [M+Hi . 1H NMR (400 MHz, CDC13) 68.27 (s, 1H), 8.13 (s, 0.8H), 7.76 (d,
J =
3.2 Hz, 1H), 7.52 (s, 0.2H), 7.40 (d, J = 2.8 Hz, 1H), 7.08 - 7.00 (m, 2H),
6.91 - 6.85(m,
1H), 5.98 (s, 1H), 4.10 - 4.04 (m, 0.8H), 3.94 (s, 3H), 3.76 - 3.73 (m, 0.2H),
3.59 (s, 3H),
3.38 - 3,31 (m, 1H), 2.58 - 2.49 (m, 5H), 2.05 - 1.77 (m, 6H).
VII-3-Q: LC-MS (ESI): RT = 1.76 min, mass calcd. for C27H27FN405S 538.2, m/z
found 539.0 [M+111 . 1H NMR (400 MHz, CDC13) 68.18 (d, J= 3.2 Hz, 1H), 8.11
(s,
0.7H), 7.80 (d, J= 2.8 Hz, 1H), 7.52 (s, 0.3H), 7.50 (d, J= 3.2 Hz, 0.2H),
7.43 (d, J=
3.6 Hz, 0.8H), 7.15 - 7.00 (m, 2H), 6.95 - 6.88 (m, 1H), 6.01 (s, 0.8H), 5.91
(d, J= 2.0
Hz, 0.2H), 4.09 - 4.05 (m, 0.8H), 3.93 (s, 2.4H), 3.92 (s, 0.6H), 3.75 - 3.70
(m, 0.2H),
3.60 (s, 2.4H), 3.59 (s, 0.6H), 3.02 - 2.94 (m, 1H), 2.55 (d, J= 2.0 Hz,
2.4H), 2.40 -
2.21 (m, 3.6H), 2.10 - 1.62 (m, 5H).
A stereoisomeric mixture of trans-methyl 2-(4-(6-(3-fluoro-2-methylpheny1)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)oxazole-4-
carboxylate VII-3-Q (98 mg, 0.164 mmol) was separated by chiral Prep. HPLC
(the
separation condition: Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase:
Hex:
Et0H : DEA = 80 : 20 : 0.3 at 15 mL/ min; Temp: 30 C; Wavelength: 214 nm) to
afford the compounds VII-3-G (41 mg, 42 % yield, 100 % stereopure) and VII-3-H
(38
mg, 39 % yield, 97.7 % stereopure) as yellow solids.
VII-3-G: LC-MS (ESI): RT = 1.72 min, mass calcd. for C27H27FN405S 538.2, m/z
found 539.2 [M+1-11 . Chiral HPLC (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/ min; Temp: 30 0C;
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Wavelength: 230 nm, RT = 18.513 min). 1H NMR (400 MHz, CDC13) 6 8.18 (d, J=
3.2
Hz, 1H), 8.11 (s, 0.8H), 7.80 (d, J= 3.2 Hz, 1H), 7.50 (d, J= 3.2 Hz, 0.2H),
7.43 (d, J
= 3.6 Hz, 1H), 7.17 - 7.00 (m, 2H), 6.95 - 6.88 (m, 1H), 6.01 (s, 0.8H), 5.91
(d, J= 2.0
Hz, 0.2H), 4.13 - 4.04 (m, 0.8H), 3.93 (s, 2.4H), 3.92 (s, 0.6H), 3.75 - 3.69
(m, 0.2H),
3.60 (s, 2.4H), 3.59 (s, 0.6H), 3.03 - 2.94 (m, 1H), 2.55 (d, J= 2.0 Hz,
2.4H), 2.40 -
2.22 (m, 3.6H), 2.10 - 1.62 (m, 5H).
VII-3-H: LC-MS (EST): RT = 1.72 min, mass calcd. for C27H27FN405S 538.2, m/z
found 539.2 [M+111 . Chiral HPLC (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/ min; Temp: 30 oC;
Wavelength: 230 nm, RT = 20.813 min). 1H NMR (400 MHz, CDC13) 6 8.18 (d, J=
3.2
Hz, 1H), 8.11 (s, 0.8H), 7.80 (d, J= 2.8 Hz, 1H), 7.50 (d, J= 2.8 Hz, 0.2H),
7.43 (d, J
= 2.8 Hz, 1H), 7.17 - 7.00 (m, 2H), 6.95 - 6.88 (m, 1H), 6.01 (s, 0.8H), 5.91
(d, J= 2.0
Hz, 0.2H), 4.13 - 4.04 (m, 0.8H), 3.93 (s, 3H), 3.74 - 3.69 (m, 0.2H), 3.60
(s, 3H), 3.02 -
2.94 (m, 1H), 2.55 (d, J= 2.0 Hz, 2.4H), 2.41 - 2.22 (m, 3.6H), 2.10 - 1.62
(m, 5H).
Compound VII-4-N:
(trans) -methyl 2-(4-(6-(2-chloro-4-fluoropheny0-5-(methoxycarbony1)-2-
(thiazol-2-y0-
3,6-dihydropyrimidin-4-y0cyclohexyDoxazole-4-carboxylate (a single
stereoisomer)
Intermediate VII-4-R:
Methyl 2-(4-(6-(2-chloro-4-fluoropheny1)-5-(methoxycarbony0-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-ypcydohexyl)oxazole-4-carboxylate (a mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. 1HN1VIR (400 MHz, CDC13) 6 8.26 (s, 0.5H), 8.18
(s,
0.5H), 7.86 (t, J= 2.8 Hz, 1H), 7.54 (d, J= 2.8 Hz, 1H), 7.33 - 7.28 (m, 1H),
7.16 -
7.11 (m, 1H), 6.96 - 6.89 (m, 1H), 6.20 (s, 0.5H), 6.17 (s, 0.5H), 3.93 (s,
1.5H), 3.92 (s,
1.5H), 3.62 (s, 1.5H), 3.61 (s, 1.5H), 3.39 - 3.30 (m, 1H), 2.38 - 2.19 (m,
2H), 2.00 -
1.64 (m, 6H), 1.36 - 1.14 (m, 1H).
Intermediates VII-4-M, VII-4-N and VIE-4-P:
(trans) Methyl 2-(4-(6-(2-chloro-4-fluoropheny1)-5-(methoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-ypcydohexyl)oxazole-4-carboxylate (a single
stereoisomer), (trans)-methyl 2-(4-(6-(2-chloro-4-fluorophenyl)-5-
(methoxycarbonyl)-
2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cydohexyl)oxazole-4-carboxylate (a
single
stereoisomer)
and (cis)-methyl 2-(4-(6-(2-chloro-4-fluoropheny1)-5-(methoxycarbony0-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyDoxazole-4-carboxylate (a mixture of 2
stereoisomers)
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A stereoisomeric mixture of methyl 2-(4-(6-(2-chloro-4-fluoropheny1)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)oxazole-4-
carboxylate VII-4-R (710 mg, 1.27 mmol) was separated by chiral Prep. HPLC
(Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 60:
40 : 0.2 at 13 mL/min; Temp: 30 C; Wavelength: 214 nm) to give the title
compounds
VII-4-M (100 mg, 14 % yield, 100 % stereopure), VII-4-N (100 mg, 14 % yield,
100 %
stereopure) and VII-4-P (190 mg, 27 % yield) as a yellow solids.
VII-4-M: LC-MS (ESI): RT = 1.72 min, mass calcd. for C26H24C1FN405S 558.1, m/z
found 559.0 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
.. Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.2 at 1 mL/min; Wavelength: 230
nm,
RT = 10.485 min). 1H NMR (400 MHz, DMSO-d6) 6 9.48 - 9.44 (m, 0.6H), 9.02 (s,
0.4H), 8.79 (s, 0.4H), 8.78 (s, 0.6H), 8.01 - 7.99 (m, 1.5H), 7.95 - 7.94 (m,
0.4H), 7.46 -
7.40 (m, 1H), 7.39 - 732 (m, 1H), 7.26 - 7.18 (m, 1H), 6.02 (s, 0.4H), 5.92
(d, J= 3.6
Hz, 0.6H), 3.94 - 3.85 (m, 0.4H), 3.80 (s, 3H), 3.70 - 3.61 (m, 0.7H), 3.53
(d, J= 5.2 Hz,
3H), 3.10 - 3.01 (m, 0.4H), 2.95 - 2.85 (m, 0.6H), 2.24- 2.16 (m, 2H), 2.07 -
1.76 (m,
3.4H), 1.73 - 1.51 (m, 2.6H).
VII-4-N: LC-MS (ESI): RT = 1.73 min, mass calcd. for C26H24C1FN405S 558.1, m/z
found 559.0 [M+Hi . Chiral analysis (Column: Chiralpak OJ - H 5 i.tm 4.6 * 250
mm;
Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.2 at 1 mL/min; Wavelength: 230
nm,
RT = 13.163 min). 1H NMR (400 MHz, DMSO-de) 69.47 - 9.46 (m, 0.6H), 9.01 (s,
0.4H), 8.79 (s, 0.4H), 8.78 (s, 0.6H), 8.00 - 7.99 (m, 1.6H), 7.95 - 7.94 (m,
0.4H), 7.45 -
7.41 (m, 1H), 7.38 - 7.33 (m, 1H), 7.25 - 7.19 (m, 1H), 6.02 (s, 0.4H), 5.92
(d, J= 3.2
Hz, 0.6H), 3.96 - 3.86 (m, 0.4H), 3.80 (s, 3H), 3.71 - 3.61 (m, 0.6H), 3.53
(d, J= 5.6 Hz,
3H), 3.11 - 3.00 (m, 0.4H), 2.95 - 2.85 (m, 0.6H), 2.25 - 2.12 (m, 2H), 2.09 -
1.77 (m,
3.4H), 1.73 - 1.50 (m, 2.6H).
VII-4-P: LC-MS (ESI): RT = 1.74 min, mass calcd. for C26H24C1FN405S 558.1, m/z
found 559.0 [M+Hi . Chiral analysis (Column: Chiralpak OJ - H 5 i.tm 4.6 * 250
mm;
Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.2 at 1 mL/min; Wavelength: 230
nm,
RT = 7.430 min and 7.778 min). 1H NMR (400 MHz, DMSO-de) 6 9.43 (s, 0.7H),
9.42
.. (s, 0.3H), 8.86 - 8.85 (m, 1H), 7.97 - 7.92 (m, 2H), 7.42 - 7.39 (m, 1H),
7.32 - 7.29 (m,
1H), 7.20 - 7.19 (m, 1H), 6.01 (s, 0.3H), 5.88 (d, J= 3.6 Hz, 0.7H), 3.83 (s,
3H), 3.75 -
3.66 (m, 1H), 3.53 (s, 2.1H), 3.52 (s, 0.9H), 3.29 - 3.25 (m, 1H), 2.44- 2.29
(m, 2H),
2.00 - 1.78 (m, 4H), 1.72 - 1.58 (m, 1.3H), 1.52 - 1.38 (m, 0.7H).
Compound VII-5-Q:
(trans)-methyl 2-(44642-chloro-3-fluoropheny0-5-(methoxycarbony1)-2-(thiazol-2-
y0-
3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a single
stereoisomer)
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Intermediates VII-5-M and VII-5-N:
(cis)-Methyl-24446-(2-chloro-3-fluoropheny1)-5-(methoxycarbony0-2-(thiazol-2-
y1)-
3,6-dihydropyrimidin-4-370cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
and (trans) -methy1-2-4-(6-(2-chloro-3-fluorophenyl)-5-(methoxycarbony0-2-
(thiazol-
270-3,6-dihydropyrimidin-4-yl)cyclohexypoxazole-4-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
VII-5-M: 11-1 NMR (400 MHz, CDC13) 68.29 - 8.24 (m, 1H), 8.20 - 8.13 (m,
0.7H), 7.83
- 7.74 (m, 1H), 7.48 - 7.44 (m, 0.4H), 7.43 - 7.41 (m, 0.6H), 7.38 - 7.35 (m,
0.3H), 7.19
- 7.08 (m, 2H), 7.07 - 6.99 (m, 1H), 6.25 (s, 0.6H), 6.09 (d, J= 2.8 Hz,
0.4H), 4.15 -
4.02 (m, 1H), 3.94 (s, 1.9H), 3.92 (s, 1.1H), 3.61 (s, 1.1H), 3.59 (s, 1.9H),
3.89 - 3.33
(m, 0.6H), 3.31 - 3.26 (m, 0.4H), 2.58 - 2.43 (m, 2H), 2.00 - 1.90 (m, 3H),
1.89 - 1.83
(m, 2H), 1.77 - 1.65 (m, 1H).
VII-5-N: 11-1 NMR (400 MHz, CDC13) 68.20 - 8.14 (m, 1.5H), 7.81 (d, J= 2.8 Hz,
1H),
7.49 (d, J= 3.2 Hz, 0.5H), 7.45 - 7.42 (m, 1H), 7.22 - 7.10 (m, 2H), 7.08 -
6.99 (m, 1H),
6.24 (s, 0.5H), 6.10 (d, J= 2.8 Hz, 0.5H), 4.09 - 4.02 (m, 0.5H), 3.91 (s,
3H), 3.86 -
3.78 (m, 0.5H), 3.60 (s, 1.4H), 3.58 (s, 1.6H), 3.04 - 2.94 (m, 1H), 2.37 -
2.26 (m, 2H),
2.23 - 2.20 (m, 1H), 2.12 - 2.03 (m, 2H), 1.98 - 1.85 (m, 2H), 1.72 - 1.58 (m,
1H).
A stereoisomeric mixture of (trans)-methyl 2-(4-(6-(2-chloro-3-fluoropheny1)-
5(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)oxazole-4-
carboxylate VII-5-N (300 mg, 90 % purity, 0.483 mmol) was separated by chiral
HPLC (separation condition: Column: Chiralpak IA 5 pm 20 * 250 mm, Mobile
Phase: Hex : Et0H : DEA = 60 : 40 : 0.3 at 20 ml/min; Temp: 30 C ;
Wavelength:
214 nm) to afford the title compounds VII-5-P (119 mg, 95 % purity from NMR,
42 %
yield, 99.8 % stereopure) and VII-5-Q (129 mg, 95 % purity from NMR, 45 %
yield,
96.9 % stereopure) as yellow solids.
11-1 NMR (400 MHz, CDC13) 6 8.18 (s, 1H), 8.14 (s, 0.5H), 7.86 - 7.80 (m, 1H),
7.50 (d, J= 3.2 Hz, 0.5H), 7.45 (d, J= 2.8 Hz, 0.5H), 7.43 (m, 0.5H), 7.22 -
7.20 (m,
0.6H), 7.16 - 7.11 (m, 1.4H), 7.10- 7.00(m, 1H), 6.26(s, 0.5H), 6.12 (d, J=
2.4 Hz,
0.5H), 4.12 - 4.03 (m, 0.5H), 3.92 (s, 3H), 3.87 - 3.79 (m, 0.5H), 3.62 (s,
1.5H), 3.60 (s,
1.5H), 3.03 - 2.92 (m, 1H), 2.38 - 2.26 (m, 1.7H), 2.26 - 2.14 (m, 1.2H), 2.11
- 1.97 (m,
1.7H), 1.86 - 1.71 (m, 3.4H). Chiral analysis (Column: Chiralpak IA 5 pm 4.6 *
250
mm; Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.2 at 1 ml/min; Col. Temp: 30
C;
Wavelength: 230 nm, Back pressure: 100 bar; RT = 6.960 min).
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VII-5-Q: 1H NMR (400 MHz, CDC13) 6 8.19 - 8.18 (m, 1.5H), 7.84 - 7.82 (m, 1H),
7.50
(d, J= 3.2 Hz, 0.5H), 7.46 (d, J= 3.2 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.10 -
7.02 (m, 1H),
6.26 (s, 0.5H), 6.12 (s, 0.5H), 4.10 - 4.04 (m, 0.5H), 3.92 (s, 3H), 3.86 -
3.81 (m, 0.5H),
3.62 (s, 1.4H), 3.60 (s, 1.6H), 3.01 - 2.95 (m, 1H), 2.35 - 2.28 (m, 1.6H),
2.24 - 2.18 (m,
1.1H), 2.10 - 2.01 (m, 1.7H), 1.92 - 1.77 (m, 3.6H). Chiral analysis (Column:
Chiralpak IA 5 pm 4.6 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.2
at
1 ml/min; Col. Temp: 30 C; Wavelength: 230 nm, Back pressure: 100 bar; RT =
9.952
min).
Compound VII-6-Q:
(trans)-methyl 2-(4-(6-(4-fluoro-2-methylpheny1)-5-(methoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-470eydohexyl)oxazole-4-earboxylate (a single
stereoisomer)
Intermediates: VII-6-M and VII-6-N
(cis)-Methyl 2-(4-(6-(4-fluoro-2-methylphenyl)-5-(methoxycarbony0-2-(thiazol-2-
y1)-
3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers) and (trans)-methyl 2-(4-(6-(4-fLuoro-2-methylpheny0-5-
(methoxycarbony0-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-
4-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
VII-6-M: 1H NMR (400 MHz, CDC13) 68.27 (s, 1H), 8.12 (s, 0.8H), 7.76 (d, J=
3.2 Hz,
1H), 7.43 (d, J= 3.2 Hz, 0.2H), 7.39 (d, J= 3.2 Hz, 0.8H), 7.32 - 7.28 (m,
0.2H), 7.18 -
7.10 (m, 0.8H), 7.00 - 6.96 (m, 0.2H), 6.92 - 6.82 (m, 1.2H), 6.79 - 6.72 (m,
0.8H), 5.94
(s, 0.8H), 5.85 - 5.81 (m, 0.2H), 4.14 - 4.03 (m, 0.811), 3.94 (s, 2.3H), 3.93
(s, 0.7H),
.. 3.81 - 3.73 (m, 0.2H), 3.60 (s, 2.3H), 3.59 (s, 0.7H), 3.40 - 3.33 (m,
0.8H), 3.31 - 3.26
(m, 0.2H), 2.62 (s, 2.5H), 2.58 - 2.49 (m, 2H), 2.47 (s, 0.5H), 2.08 - 1.91
(m, 3H), 1.90 -
1.79 (m, 2H), 1.75 - 1.68 (m, 1H).
VII-6-N: 1H NMR (400 MHz, CDC13) 68.21 - 8.17 (m, 1H), 8.12 (s, 0.7H), 7.82 -
7.79
(m, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.43 (d, J= 3.2 Hz, 0.7H), 7.35 - 7.29 (m,
0.3H),
.. 7.20 - 7.15 (m, 0.7H), 7.09 - 7.05 (m, 0.3H), 6.92 - 6.83 (m, 1.3H), 6.82 -
6.75 (m,
0.7H), 5.96 (s, 0.7H), 5.88 - 5.85 (m, 0.3H), 4.12 - 4.02 (m, 0.7H), 3.93 (s,
2.2H), 3.92
(s, 0.8H), 3.73 - 3.70 (m, 0.3H), 3.61 (s, 2.2H), 3.60 (s, 0.8H), 3.02 - 2.97
(m, 1H), 2.64
(s, 2.2H), 2.49 (s, 0.8H), 2.41 - 2.30 (m, 1.8H), 2.25 - 2.22 (m, 1.4H), 2.12 -
2.01 (m,
1.2H), 1.97 - 1.84 (m, 2H), 1.71 - 1.57 (m, 1.6H).
.. A stereoisomeric mixture of (trans)-methyl 2-(4-(6-(2-chloro-3-
fluoropheny1)-5-
(methoxycarb
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ony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)oxazole-4-
carboxylate VII-
6-N (365 mg, 80 % purity, 0.542 mmol) was separated by chiral Prep. HPLC
(separation condition: Column: Chiralpak IA 5 pm 20 * 250 mm, Mobile Phase:
Hex:
Et0H : DEA = 60 : 40 : 0.3 at 22 mL/ min; Temp: 30 0C; Wavelength: 214 nm) to
afford the title compounds VII-6-P (105 mg, 95 % purity from 1H NMR, 34 %
yield,
100 % stereopure) and VII-6-Q (110 mg, 95 % purity from 1H NMR, 36 % yield,
94.5 %
stereopure) as yellow solids.
VII-6-P: 1H NMR (400 MHz, CDC13) 68.23 - 8.16 (m, 1H), 8.11 (s, 0.7H), 7.80
(d, J=
3.2 Hz, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 2.8 Hz, 0.7H), 7.35 - 7.30
(m,
0.3H), 7.21 - 7.14 (m, 0.7H), 7.02 (s, 0.3H), 6.92 - 6.87 (m, 1.2H), 6.84-
6.75 (m,
0.8H), 5.96 (s, 0.7H), 5.89 - 5.83 (m, 0.3H), 4.12 - 4.02 (m, 0.7H), 3.93 (s,
3H), 3.74 -
3.67 (m, 0.3H), 3.60 (s, 3H), 3.03 - 2.92 (m, 1H), 2.64 (s, 2.2H), 2.49 (s,
0.8H), 2.39 -
2.33 (m, 1.7H), 2.27 - 2.17 (m, 1.3H), 2.12 - 1.99 (m, 1.4H), 1.97 - 1.83 (m,
2H), 1.82 -
1.65 (m, 1.6H). Chiral analysis: (column : Chiralpak IA 5 pm 4.6 * 250 mm;
Mobile
Phase: Hex : Et0H : DEA = 60 : 40 : 0.2 at 1 mL/ min; Col. Temp: 30 C;
Wavelength:
230 nm; RT = 6.321 min).
VII-6-Q: 1H NMR (400 MHz, CDC13) 68.20 - 8.16 (m, 1H), 8.10 (s, 0.7H), 7.80
(d, J=
2.8 Hz, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.34 - 7.29
(m,
0.3H), 7.18 - 7.15 (m, 0.7H), 7.01 (s, 0.3H), 6.91 - 6.87 (m, 1.2H), 6.83 -
6.75 (m, 0.8H),
.. 5.95 (s, 0.7H), 5.88 - 5.85 (m, 0.3H), 4.12 - 4.02 (m, 0.7H), 3.92 (s, 3H),
3.72 - 3.66 (m,
0.3H), 3.60 (s, 3H), 3.02 - 2.93 (m, 1H), 2.64 (s, 2.2H), 2.49 (s, 0.8H), 2.40
- 2.33 (m,
1.7H), 2.27 - 2.22 (m, 1.3H), 2.11 - 1.99 (m, 1.4H), 1.95 - 1.83 (m, 2H), 1.80
- 1.62 (m,
1.6H). Chiral analysis: (column: Chiralpak IA 5 pm 4.6 * 250 mm; Mobile Phase:
Hex : Et0H : DEA = 60 : 40 : 0.2 at 1 mL/ min; Col. Temp: 30 C; Wavelength:
230
11.M; RT = 8.167 min).
Compound VII-7-N:
(trans)-methyl 2-(44642-chloro-3,4-difluoropheny0-243,5-difluoropyridin-2-y1)-
5-
(methoxycarbony1)-3,6-dihydropyrimidin-4-y1)cydohexyl)oxazole-4-carboxylate (a
single stereoisomer)
Intermediate VII-7-S:
(trans)-Methyl 2-(4-(6-(2-chloro-3,4-difluoropheny0-2-(3,5-difluoropyridin-2-
y1)-5-
(methoxycarbony1)-3,6-dihydropyrimidin-4-yl)cydohexyl)oxazole-4-carboxylate (a
mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.052 min, mass calcd. for C281-123C1F4N405 606.0, m/z found
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607.1 [M+1-11 . 11-1 NMR (300 MHz, CDC13) 68.70 (s, 1H), 8.34 - 8.20 (m, 2H),
7.09 -
6.97 (m, 2H), 6.30 (d, J= 6.0 Hz, 0.8H), 6.05 - 6.02 (m, 0.2H), 4.17 - 4.08
(m, 1H),
3.95 (s, 2.4H), 3.93 (s, 0.6H), 3.61 (s, 3H), 3.41 - 3.34 (m, 1H), 2.54 - 2.46
(m, 1H),
2.38 - 2.11 (m, 1H), 2.05 - 1.91 (m, 3H), 1.86 - 1.82 (m, 2H), 1.71 - 1.58 (m,
1H).
A stereoisomeric mixture of (trans)-methyl 2-(4-(6-(2-chloro-3,4-
difluoropheny1)-2-
(3,5-difluoropyridin-2-y1)-(methoxycarbony1)-3,6-dihydropyrimidin-4-
yl)cyclohexyl)oxazole-4-carboxylate VII-7-S (340 mg, 90 % purity, 0.504 mmol)
was
separated by chiral Prep. HPLC (separation condition: Column: Chiralpak IC 5
pm
20 * 250 mm; Mobile Phase: Hex : Et0H = 50 : 50 at 11 mL/ mm; Temp: 30 C;
Wavelength: 214 nm) to afford the desired compounds V11-7-M (36 mg, 90 %
purity
from 11-I NMR, 11 % yield, 100 % stereopure) and VII-7-N (101 mg, 90 % purity
from
11-1 NMR, 30 % yield, 98.5 % stereopure) as yellow solids.
VII-7-M: Chiral analysis: (Column: Chiralpak IC 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA= 50: 50 : 0.2 at 1 mL/ mm; Temp: 40 C; Wavelength: 230 nm,
Back pressure: 100 bar, RT = 7.887 min). 11-1 NMR (400 MHz, DMSO-de) 6 9.32
(s,
0.7H), 9.21 (s, 0.3H), 8.79 (s, 0.7H), 8.77 (s, 0.3H), 8.58 (d, J= 7.2 Hz,
1H), 8.10 - 8.04
(m, 1H), 7.54 - 7.44 (m, 1H), 7.25 - 7.16 (m, 1H), 6.04 (s, 0.7H), 5.94 (d, J=
2.4 Hz,
0.3H), 4.00 - 3.92 (m, 0.6H), 3.80 (s, 3H), 3.70 - 3.64 (m, 0.4H), 3.53 (s,
2H), 3.51 (s,
1H), 2.95 - 2.84 (m, 1H), 2.29 - 2.16 (m, 2H), 1.98 - 1.77 (m, 4H), 1.68 -
1.54 (m, 2H).
VII-7-N: Chiral analysis: (Column: Chiralpak IC 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H = 50 : 50 at 1 mL/ mm; Temp: 30 C; Wavelength: 230 nm, Back
pressure: 100 bar, RT = 12.115 min). 11-1 NMR (400 MHz, DMSO-de) 6 9.31 (s,
0.7H),
9.21 (s, 0.3H), 8.79 (s, 0.7H), 8.77 (s, 0.3H), 8.59 - 8.57 (m, 1H), 8.10 -
8.05 (m, 1H),
7.53 - 7.44 (m, 1H), 7.25 - 7.17 (m, 1H), 6.05 (s, 0.7H), 5.94 (d, J= 3.2 Hz,
0.3H), 3.99
- 3.93 (m, 0.7H), 3.80 (s, 3H), 3.71 - 3.63 (m, 0.3H), 3.54 (s, 2H), 3.51 (s,
1H), 2.95 -
2.85 (m, 1H), 2.23 - 2.13 (m, 2H), 1.97 - 1.80 (m, 4H), 1.70 - 1.53 (m, 2H).
Compound VII-8-N:
methyl 2-046-(2-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-ylThicydo[1.1.1]pentan-1-ypoxazole-4-carboxylate (a single
stereoisomer)
Intermediate VII-8-R:
Methyl 2-(3-(6-(2-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-ylkicydo[1.1.1]pentan-1-ypoxazole-4-carboxylate (a mixture
of
2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 1.77 min, mass calcd. for
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C25Hi9C1F2N405S 560.1, m/z found 561.2 [M+1-11 . 1H NMR (400 MHz, DMSO-d6) 6
9.62 (d, J= 3.2 Hz, 0.6H), 8.83 (s, 0.4H), 8.80 (s, 0.6H), 8.49 (s, 0.4H),
8.03 - 8.01 (m,
1.6H), 7.97 - 7.96 (m, 0.4H), 7.51 - 7.44 (m, 1H), 7.23 - 7.17 (m, 1H), 6.00
(s, 0.4H),
5.91 (d, J= 3.2 Hz, 0.6H), 3.80 (s, 3H), 3.58 - 3.57 (m, 3H), 2.68 (s, 2.3H),
2.52 (s,
3.7H).
A stereoisomeric mixture of methyl 2-(3-(6-(2-chloro-3,4-difluoropheny0-5-
(methoxycarbonyl) -2- (thiazol-2 - yl) -3, 6 - dihydropyrimidin- 4-yl)bicyclo
[1. 1. li pentan- 1-
yl)oxazole -4-carboxylate VII-8-R (150 mg, 95 % purity, 0.254 mmol) was
separated
by chiral Prep. HPLC (separation condition: Column: Chiralpak IE 5 pm 20 * 250
.. mm; Mobile Phase: Hex : Et0H : DEA= 70 : 30 : 0.2 at 12 mL/min; Temp: 30
C;
Wavelength: 230 nm) to afford the title compounds VII-8-M (60 mg, 95 % purity,
40 %
yield, 100 % stereopure) and VII-8-N (60 mg, 95 % purity, 40 % yield, 100 %
stereopure) as yellow solids.
VII-8-M: LC-MS (EST): RT = 1.80 min, mass calcd. for C25Hi9C1F2N405S 560.1,
m/z
found 561.0 [M+Hi . Chiral HPLC (Column: Chiralpak IE 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 11.217 min). 1H NMR (400 MHz, CDC13) 6 8.19 (d, J=
2.0
Hz, 1H), 7.93 (s, 0.7H), 7.84 - 7.82 (m, 1H), 7.51 (d, J= 3.2 Hz, 0.3H), 7.46
(d, J= 3.2
Hz, 0.7H), 7.42 (s, 0.3H), 7.10 - 7.01 (m, 2H), 6.17 (s, 0.7H), 6.05 (d, J=
1.6 Hz, 0.3H),
.. 3.93 (s, 3H), 3.66 (s, 1H), 3.62 (s, 2H), 2.76 (s, 4H), 2.70 (s, 2H).
VII-8-N: LC-MS (EST): RT = 1.80 min, mass calcd. for C25Hi9C1F2N405S 560.1,
m/z
found 561.0 [M+Hi . Chiral HPLC (Column: Chiralpak IE 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 15.313 min). 1H NMR (400 MHz, CDC13) 6 8.19 (d, J=
2.0
Hz, 1H), 7.93 (s, 0.7H), 7.84 - 7.82 (m, 1H), 7.51 (d, J= 3.2 Hz, 0.3H), 7.46
(d, J= 3.2
Hz, 0.7H), 7.42 (s, 0.3H), 7.10 - 7.01 (m, 2H), 6.17 (s, 0.7H), 6.05 (d, J=
2.4 Hz, 0.3H),
3.93 (s, 3H), 3.66 (s, 1H), 3.62 (s, 2H), 2.76 (s, 4H), 2.70 (s, 2H).
Compound VII-9-F:
(trans)-methyl 2-(44642-chloro-3-fluorophenyp-5-(ethoxycarbony1)-2-(thiazol-2-
y1)-
3,6-dihydropyrimidin-4-ypcydohexyl)oxazole-4-carboxylate (a single
stereoisomer)
Intermediates VII-9-M and VII-9-N:
(cis)-methyl 2-(4-(6-(2-chloro-3-fluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-y1)cydohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
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And (trans)-methyl 244-(642-chloro-3-fluoropheny0-5-(ethoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-9-M: LC-MS (ESI): RT = 4.322 min, mass calcd. for C27H26C1FN405S 572.1,
m/z
found 572.9 [M+Hi . 1H NMR (400 MHz, CDC13) 68.29 (s, 0.6H), 8.26 (s, 0.4H),
8.14
(s, 0.6H), 7.81 - 7.76 (m, 1H), 7.44 (d, J= 3.2 Hz, 0.4H), 7.41 (d, J= 3.2 Hz,
0.6H),
7.31 - 7.29 (m, 0.4H), 7.21 - 7.09 (m, 2H), 7.09 - 6.98 (m, 1H), 6.27 (s,
0.6H), 6.14 -
6.09 (d, J= 8.0 Hz, 0.4H), 4.14 - 3.97 (m, 3H), 3.94 (s, 2H), 3.92 (s, 1H),
3.38 - 3.33 (m,
0.6H), 3.31 - 3.26 (m, 0.4H), 2.58 - 2.43 (m, 2H), 2.15 - 2.03 (m, 0.5H), 1.99
- 1.89 (m,
2.5H), 1.89 - 1.77 (m, 2H), 1.77 - 1.63 (m, 1H), 1.16 - 1.08 (m, 3H).
W1-9-N: LC-MS (ESI): RT = 4.420 min, mass calcd. for C27H26C1FN405S 572.1, m/z
found 573.1 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.50 (d, J= 3.6 Hz, 0.6H),
8.98
(s, 0.4H), 8.79 (s, 0.4H), 8.78 (s, 0.6H), 8.01 - 7.94 (m, 2H), 7.42 - 7.28
(m, 2H), 7.24 -
7.17 (m, 1H), 6.09 (s, 0.4H), 5.98 (d, J= 3.6 Hz, 0.6H), 4.01 - 3.94 (m, 2H),
3.93 - 3.88
(m, 0.3H), 3.80 (s, 3H), 3.71 - 3.60 (m, 0.7H), 3.10 - 3.03 (m, 0.4H), 2.94 -
2.85 (m,
0.6H), 2.26 - 2.11 (m, 2H), 2.01 - 1.86 (m, 2.3H), 1.86 - 1.67 (m, 1.7H), 1.66
- 1.48 (m,
2H), 1.11 - 1.00 (m, 3H).
A stereoisomeric mixture of WI-9-N (740 mg, 99.7 % purity, 1.29 mmol) was
separated by chiral Prep. HPLC (Column: Chiralpak IE 5 pm 20 * 250 mm; Mobole
Phase: Hex : Et0H : DEA = 60 : 40 :0.3 at 10 ml/ min; Temp: 30 0C; Wavelength:
214
nm) to afford the title compounds VII-9-E (210 mg, 98.8 % purity, 28 % yield,
100 %
ee) as yellow solids and VII-9-F (229 mg, 98.1 % purity, 31 % yield, 99.7 %
ee) as
yellow solids.
VII-9-E: LC-MS (ESI): RT = 4.253 min, mass calcd. for C27H26C1FN405S 572.1,
m/z
found 573.1 [M+111 . 1H NMR (400 MHz, CDC13) 68.18 (s, 1H), 8.13 (s, 0.5H),
7.83 (s,
0.5H), 7.82 (s, 0.5H), 7.50 (d, J= 3.2 Hz, 0.5H), 7.45 (d, J= 3.2 Hz, 0.5H),
7.36 (s,
0.5H), 7.24 - 7.12 (m, 2H), 7.11 - 6.99 (m, 1H), 6.28 (s, 0.5H), 6.14 (d, J=
2.4 Hz,
0.5H), 4.10 - 3.98 (m, 2.5H), 3.92 (s, 3H), 3.88 - 3.79 (m, 0.5H), 3.03 - 2.93
(m, 1H),
2.38- 2.16 (m, 2.8H), 2.12 - 2.00 (m, 1.5H), 1.94- 1.65 (m, 3.7H), 1.16- 1.09
(m, 3H).
VII-9-F: LC-MS (ESI): RT = 2.265 min, mass calcd. for C27H26C1FN405S 572.1,
m/z
found 573.1 [M+111 . 1H NMR (400 MHz, CDC13) 68.18 (s, 1H), 8.13 (s, 0.5H),
7.84 -
7.81 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.5H), 7.45 (d, J= 2.8 Hz, 0.5H), 7.37 (d,
J= 2.4 Hz,
0.5H), 7.24- 7.13 (m, 2H), 7.10- 7.00 (m, 1H), 6.28 (s, 0.5H), 6.14 (d, J= 2.8
Hz,
0.5H), 4.09 - 4.01 (m, 2.5H), 3.92 (s, 3H), 3.87 - 3.79 (m, 0.5H), 3.03 - 2.93
(m, 1H),
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2.38 - 2.16 (m, 2.811), 2.12 - 2.02 (m, 1.411), 1.96 - 1.74 (m, 3.111), 1.74-
1.64 (m,
0.711), 1.17 - 1.09 (m, 311).
Compound VII-10-P:
(trans)-Methyl 2444642-chloro-4-fluoropheny0-5-(ethoxycarbony1)-2-(thiazol-2-
y1)-
3,6-dihydropyrimidin-4-y0cydohexyl)oxazole-4-carboxylate (a single
stereoisomer)
Intermediates: VII- 10-X and VII- 10-Y
(cis)- Methyl 2444642-chloro-4-fluoropheny1)-5-(ethoxycarbonyl)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-y1)cydohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
& (trans)- methyl 244-(642-chloro-4-fluoropheny1)-5-(ethoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-ypcydohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized as yellow solids.
VII-10-X: LC-MS (ESI): RT = 3.644 min, mass calcd. for C271126C1FN405S 572.1,
miz
found 572.9 [M+111 . 1H NMR (400 MHz, CD30D) 6 8.55 (d, J= 3.2 Hz, 111), 7.86 -
7.84 (m, 111), 7.71 - 6.68 (m, 111), 7.40 - 7.34 (m, 11), 7.25 - 7.20 (m, 11),
7.06 - 7.00
(m, 11), 6.13 (s, 0.51), 6.05 (s, 0.51), 4.07 - 4.01 (m, 2.511), 3.91 - 3.81
(m, 3.511),
3.37 - 3.31 (m, 0.511), 3.30 - 3.24 (m, 0.511), 2.55 - 2.42 (m, 211), 2.10 -
1.79 (m, 41),
1.77 - 1.72 (m, 1.511), 1.57 - 1.53 (m, 0.511), 1.14 (t, J= 7.2 Hz, 311).
VII-10-Y: LC-MS (ESI): RT = 2.496 min, mass calcd. for C271126C1FN405S 572.1,
miz
found 572.9 [M+111 . 1H NMR (400 MHz, CD30D) 6 8.48 (s, 11), 8.29 - 8.26 (m,
21),
7.57 - 7.53 (m, 11), 7.4- 2 7.40 (m, 111), 7.24 - 7.19 (m, 11), 6.32 (s, 11),
4.17 - 4.10
(m, 21), 3.99 - 3.92 (m, 111), 3.88 (s, 311), 3.05 - 2.97 (m, 11), 2.32 - 2.29
(m, 21),
2.06 - 1.83 (m, 41), 1.76 - 1.68 (m, 21), 1.18 (t, J= 7.2 Hz, 311).
A stereoisomeric mixture of (trans)- methyl 2-(4-(6-(2-chloro-4-fluoropheny1)-
5-
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)oxazole-
4-
carboxylate VII-10-Y (200 mg, 90 % purity, 0.314 mmol) was separated by chiral
Prep. HPLC (Column: Chiralpak S-OJ 5 gm 21 * 250 mm; Mobile Phase: Hex:
Et0H : DEA = 70: 30 : 0.05 at 20 mLimin; Temp: 35 C; Wavelength: 254 nm) to
give
the title compounds VII-10-P (80 mg, 99 % purity, 44 % yield, 98.6 %
stereopure) as
yellow solids and VII-10-Q (75 mg, 99.2 % purity, 41 % yield, 99.9 %
stereopure) as
yellow solids.
VII-10-P: LC-MS (ESI): RT = 4.289 min, mass calcd. for C271126C1FN405S 572.1,
miz
found 572.9 [M+Hi . Chiral analysis (Column: Chiralpak S-OJ 5 gm 4.6 * 150 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.05 at 1 mLimin; Wavelength: 254
nm,
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RT = 5.657 min). 111 NMR (400 MHz, CD30D) 6 8.37 (s, 0.511), 8.36 (s, 0.511),
7.84 -
7.83 (m, 0.511), 7.80 - 7.79 (m, 0.511), 7.66 - 7.65 (m, 111), 7.34- 7.29 (m,
111), 7.16 -
7.11 (m, 111), 6.99 - 6.92 (m, 111), 6.06 (s, 0.511), 5.99 (s, 0.511), 3.98 -
3.92 (m, 2.511),
3.79 (s, 311), 3.74 - 3.67 (m, 0.511), 2.98 - 2.80 (m, 1H), 2.24 - 2.03 (m,
211), 1.93 - 1.60
(m, 611), 1.07 - 1.02 (m, 311).
VII-10-Q: LC-MS (EST); RT = 4.289 min, mass calcd. for C271126C1FN405S 572.1,
miz
found 572.9 [M+Hi . Chiral analysis (Column; Chiralpak S-OJ 5 i.tm 4.6 * 150
mm;
Mobile Phase; Hex : Et0H : DEA = 70 : 30 ; 0.05 at 1 mL/min; Wavelength; 254
nm,
RT = 7.812 min). 1H NMR (400 MHz, CD30D) 6 8.50 (s, 0.511), 8.49 (s, 0.511),
7.97 -
7.96 (m, 0.511), 7.92 - 7.92 (m, 0.511), 7.78 - 7.77 (m, 0.511), 7.46 - 7.42
(m, 111), 7.28 -
7.23 (m, 111), 7.11 - 7.04 (m, 111), 6.18 (s, 0.511), 6.11 (s, 0.511), 4.10 -
4.05 (m, 2.511),
3.91 (s, 311), 3.86 - 3.80 (m, 0.511), 3.14- 2.93 (m, 1H), 2.37 - 2.21 (m,
211), 2.14- 1.73
(m, 611), 1.17 (t, J= 7.2 Hz, 311).
Compound VII-11-Q:
(trans) -methyl 2-445-(ethoxycarbony0-6-(3-fluoro-2-methylpheny1)-2-(thiazol-2-
y0-
3,6-dihydropyrimidin-4-y0cyclohexyDoxazole-4-carboxylate (a single
stereoisomer)
Intermediates VII-11-M and WI-11-N:
(cis)-Methyl 244-0-(ethoxycarbony0-643-fluoro-2-methylphenyl)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-ypcyclohexyDoxazole-4-carboxylate (a mixture of 2
stereoisomers) and (trans) methyl 244-0-(ethoxycarbony1)-6-(3-fluoro-2-
methylpheny0-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexypoxazole-4-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-11-M: 1H NMR (400 MHz, CDC13) 6 8.27 (s, 1H), 8.12 (s, 111), 7.76 (d, J=
3.2 Hz,
111), 7.46 - 7.43 (m, 0.211), 7.42 - 7.37 (m, 0.811), 7.14 - 6.99 (m, 211),
6.97 - 6.84 (m,
111), 6.01 (s, 0.811), 5.90 (s, 0.211), 4.16 - 3.98 (m, 311), 3.94 (s, 311),
3.40 - 3.33 (m,
0.811), 3.31 - 3.25 (m, 0.211), 2.57 - 2.45 (m, 4.511), 2.41 - 2.36 (m,
0.511), 1.98 - 1.91
(m, 111), 1.86 - 1.80 (m, 211), 1.75 - 1.67 (m, 311), 1.13 (t, J= 7.2 Hz,
311).
VII-11-N: 1H NMR (300 MHz, CDC13) 6 8.24 (s, 111), 8.19 - 8.11 (m, 111), 7.89 -
7.83
(m, 111), 7.57 - 7.45 (m, 111), 7.19 - 7.05 (m, 211), 7.01 - 6.91 (m, 111),
6.07 (s, 0.811),
5.99 (s, 0.211), 4.13 - 4.04 (m, 311), 3.98 (s, 311), 3.02 - 2.99 (m, 111),
2.64 - 2.55 (m,
211), 2.52 - 2.22 (m, 411), 2.03 - 1.83 (m, 311), 1.81 - 1.58 (m, 211), 1.81
(t, J= 7.2 Hz,
311).
A stereoisomeric mixture of (trans)-methyl 2-(4-(5-(ethoxycarbony1)-6-(3-
fluoro-2-
methylpheny1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-
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carboxylate Vu-1-N (376 mg, 90 % purity, 0.612 mmol) was separated by chiral
Prep. SFC (Column: Chiralpak IC 5 pm 20 * 250 mm; Mobile Phase: CO2 : Et0H
DEA = 70 : 30 : 0.3 at 50 g/min; Col. Temp: 40 0C; Wavelength: 214 nm; Back
pressure: 100 bar) to afford the compounds VIE-11-P (165 mg, 95 % purity from
1H
NMR, yield 46 %, 100 % stereopure) and VII-11-Q (150 mg, 95 % purity from 1H
NMR, yield 42 %, 100 % stereopure) as yellow solids.
VII-11-P: Chiral analysis (Column: Chiralpak IC 5 pm 4.6 * 250 mm; Mobile
Phase:
CO2 Et0H : DEA = 70 : 30 : 0.2 at 3 g/min; Col. Temp: 40 C; Wavelength: 280
nm,
Back pressure: 100 bar; RT = 4.38 min). 1H NMR (300 MHz, CDC13) 6 8.19 (s,
1H),
.. 8.10 (s, 0.7H), 7.83 - 7.78 (m, 1H), 7.52 - 7.40 (m, 1H), 7.16 - 7.00 (m,
2.3H), 6.96 -
6.87 (m, 1H), 6.02 (s, 0.8H), 5.97 - 5.91 (m, 0.2H), 4.09 - 4.02 (m, 2.8H),
3.92 (s, 3H),
3.77 - 3.69 (m, 0.2H), 2.94 - 2.91 (m, 1H), 2.54 (s, 2.5H), 2.45 - 2.41 (m,
0.5H), 2.37 -
2.18 (m, 3H), 2.13 - 2.08 (m, 0.5H), 1.94- 1.79 (m, 2.5H), 1.76 - 1.54 (m,
2H), 1.13 (t,
J= 7.2 Hz, 3H).
WI-11-Q: Chiral analysis (Column: Chiralpak IC 5 pm 4.6 * 250 mm; Mobile
Phase:
CO2 : Et0H : DEA = 70 : 30 : 0.2 at 3 g/min; Col. Temp: 40 C; Wavelength: 280
nm,
Back pressure: 100 bar; RT = 5.03 min). 1H NMR (300 MHz, CDC13) 6 8.19 (s,
1H),
8.10 (s, 0.7H), 7.83 - 7.78 (m, 1H), 7.53 - 7.49 (m, 0.2H), 7.49 - 7.41 (m,
0.8H), 7.18 -
7.15 (m, 0.3H), 7.13 - 7.01 (m, 2H), 6.99 - 6.86 (m, 1H), 6.03 (s, 0.8H), 5.96
- 5.91 (m,
0.2H), 4.11 - 4.03 (m, 2.7H), 3.93 (s, 3H), 3.78 - 3.67 (m, 0.3H), 2.97 - 2.94
(m, 1H),
2.55 (s, 2.5H), 2.42 - 2.41 (m, 0.5H), 2.37 - 2.18 (m, 3H), 2.13 - 2.05 (m,
1.3H), 1.95 -
1.78 (m, 2.7H), 1.71 - 1.60 (m, 1H), 1.14 (t, J= 7.2 Hz, 3H).
Compound VII-12-P:
(trans)-Methyl 244-(5-(ethoxycarbony0-644-fluoro-2-methylpheny1)-2-(thiazol-2-
370-
3,6-dihydropyrimidin-4-0cyclohexyl)oxazole-4-carboxylate (a single
stereoisomer)
Intermediates VII-12-X & VII 12Y
(cis)-Methyl 244-0-(ethoxycarbony0-644-fluoro-2-methylpheny1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-y1)cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
& (trans)-methyl 2-(445-(ethoxycarbony1)-644-fluoro-2-methylpheny1)-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-370cyclohexyl)oxazole-4-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-12-X: LC-MS (ESI): RT = 3.737 min, mass calcd. for C281129FN405S 552.2,
m/z
found 553.0 [M+111 . 1H NMR (400 MHz, CDC13) 68.27 (s, 1H), 8.10 (s, 0.7H),
7.76 (d,
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J= 3.2 Hz, 1H), 7.45 (d, J= 3.2 Hz, 0.3H), 7.39 (d, J= 3.2 Hz, 0.8H), 7.30 -
7.26 (m,
0.2H), 7.17 - 7.14 (m, 0.8H), 6.92 - 6.74 (m, 2.2H), 5.95 (s, 0.8H), 5.84 (d,
J= 2.0 Hz,
0.2H), 4.11 - 3.99 (m, 3H), 3.94 (s, 2H), 3.93 (s, 1H), 3.36 (s, 0.8H), 3.28
(s, 0.2H),
2.62 (s, 2.3H), 2.55 - 2.47 (m, 2.7H), 2.04 - 1.69 (m, 6H), 1.15 - 1.10 (m,
3H).
VII-12-Y: LC-MS (ESI): RT = 4.521 min, mass calcd. for C281-129FN405S 552.2,
m/z
found 553.1 [M+1-11 . 1H NMR (400 MHz, CDC13) 6 8.19 (s, 0.7H), 8.18 (s,
0.3H), 8.08
(s, 0.7H), 7.81 - 7.80 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 2.8 Hz,
0.7H),
7.33 - 7.29 (m, 0.3H), 7.20 - 7.17 (m, 0.7H), 6.97 - 6.90 (m, 0.3H), 6.84-
6.77 (m, 2H),
5.97 (s, 0.7H), 5.87 (d, J= 2.0 Hz, 0.3H), 4.11 - 4.01 (m, 3H), 3.92 (d, J=
2.0 Hz, 3H),
3.02 - 2.94 (m, 1H), 2.64 (s, 2H), 2.49 (s, 1H), 2.38 - 2.22 (m, 2.7H), 2.10 -
1.62 (m,
5.3H), 1.13 (d, J= 7.2 Hz, 3H).
A stereoisomeric mixture of (trans)-methyl 2-(4-(5-(ethoxycarbony1)-6-(4-
fluoro-2-
methylpheny1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-0cyclohexyl)oxazole-4-
carboxylate VII-12-Y (120 mg, 95 % purity, 0.206 mmol) was separated by chiral
Prep. HPLC (Column: Chiralpak IC 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
:
DEA = 80 : 20 : 0.3 at 25 mL/min; Temp: 30 C; Wavelength: 214 nm) to give the
title
compounds VII-12-P (65 mg, 95.5 % purity, 54 % yield, 100 % stereopure) and
VII-
12Q (50 mg, 97.8 % purity, 43 % yield, 95.3 % stereopure) as yellow solids.
VII-12-P: LC-MS (ESI): RT = 2.037 min, mass calcd. for C281-129FN405S 552.2,
m/z
found 553.1 [M+Hi . Chiral analysis (Column: Chiralpak IC 5 i.tm 4.6 *250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/min; Wavelength: 230
nm,
RT = 12.418 min). 1H NMR (400 MHz, CDC13) 6 8.18 (d, J= 2.8 Hz, 1H), 8.08 (s,
0.7H), 7.81 - 7.80 (m, 1H), 7.50 (d, J= 2.8 Hz, 0.3H), 7.42 (d, J= 3.6 Hz,
0.7H), 7.34 -
7.30 (m, 0.3H), 7.20 - 7.17 (m, 0.8H), 6.98 - 6.97 (m, 0.2H), 6.89 - 6.75 (m,
2H), 5.97 (s,
0.7H), 5.87 (d, J= 2.0 Hz, 0.3H), 4.12 - 4.00 (m, 3H), 3.93 (s, 2H), 3.92 (s,
1H), 3.03 -
2.93 (m, 1H), 2.63 (s, 2H), 2.49 (s, 1H), 2.37 - 2.21 (m, 3H), 2.04 - 1.67 (m,
5H), 1.13 (t,
J= 7.2 Hz, 3H).
VII-12-Q: LC-MS (ESI): RT = 2.037 min, mass calcd. for C281-129FN405S 552.2,
m/z
found 553.1 [M+Hi . Chiral analysis (Column: Chiralpak IC 5 i.tm 4.6 *250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/min; Wavelength: 230
nm,
RT = 13.758 min). 1H NMR (400 MHz, CDC13) 6 8.18 (d, J= 3.2 Hz, 1H), 8.08 (s,
0.7H), 7.81 - 7.80 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz,
0.7H), 7.34 -
7.30 (m, 0.3H), 7.20 - 7.17 (m, 0.8H), 6.97 - 6.95 (m, 0.2H), 6.90 - 6.77 (m,
2H), 5.97 (s,
0.7H), 5.87 (d, J= 2.0 Hz, 0.3H), 4.11 - 4.00 (m, 3H), 3.93 (s, 2H), 3.92 (s,
1H), 3.01 -
2.93 (m, 1H), 2.63 (s, 2.2H), 2.49 (s, 0.8H), 2.37 - 2.22 (m, 3H), 2.10 - 1.65
(m, 5H),
1.13 (d, J= 7.2 Hz, 3H).
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Compound VII-13-P and compound VII-13-Q:
244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-471)cyclohex- 1-en- 1-yl)oxazole-4-carboxylate (a single
stereoisomer) and 2-446-(2-chloro-3,4-difluoropheny0-5-(ethoxycarbony0-2-
(thiazol-
270-3, 6-dihydropyrimidin-4-yl)cydohex- 1-en- 1 -yl)oxazole-4-carboxylate (a
single
stereoisomer)
Intermediates VII-13-R:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-yl)cydohex- 1-en- 1-yl)oxazole-4-carboxylate (a mixture of
4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
Intermediate VII-13-R: LC-MS (ESI): RT = 4.032 min, mass calcd. for
C281125C1F2N405S 602.1, m/z found 602.9 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6
9.64 - 9.61 (m, 0.8H), 9.15 (s, 0.1H), 9.08 (s, 0.1H), 8.81 - 8.78 (m, 1H),
8.00 - 7.94 (m,
2H), 7.51 - 7.45 (m, 1H), 7.28 - 7.20 (m, 1H), 6.94 - 6.90 (m, 1H), 6.07 (s,
0.1H), 6.05
(s, 0.1H), 5.97 - 5.95 (m, 0.8H), 4.29 (q, J= 7.2 Hz, 2H), 4.14 (hr s, 0.2H),
4.00 - 3.89
(m, 2.8H), 2.75 - 2.58 (m, 2H), 2.49 - 2.26 (m, 2H), 2.08 - 1.83 (m, 2H), 1.30
(t, J= 7.2
Hz, 3H), 1.08 - 1.01 (m, 3H).
A stereoisomeric mixture of ethyl 2-(4-(6-(2-chloro-3,4-difluoropheny1)-5-
(ethoxycarbony1)-2 - (thiazol-2 -y1) -3,6- dihydropyrimidin- 4-yl)cyclohex- 1-
en- 1-
yl)oxazole -4-carboxylate VIE-13-R (420 mg, 99.7 % purity, 0.69 mmol) was
separated
by chiral prep. HPLC (the first separation condition: Column: Chiralpak ID 5
pm 20
* 250 mm; Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.3 at 15 mL/ min;
Wavelength: 214 nm; the second separation condition: Column: Chiralpak IF 5 pm
20 * 250 mm; Mobile Phase: CO2 : Me0H = 60 : 40 at 45 g/ min; Col. Temp 40 C;
Wavelength: 254 nm; Back pressure: 100 bar; the third separation condition:
Column:
Chiralpak ID 5 pm 20 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.3
at
15 mL/ min; Wavelength: 214 nm) to give the title compounds VII-13-M (60 mg,
96.5 %
purity, 34 % yield, 98.2 % de), VII-13-N (80 mg, 95.2 % purity, 45 % yield,
98.4 % de),
VII-13-P (60 mg, 99.1 % purity, 38 % yield, 100 % de) and VII-13-Q (70 mg,
99.7 %
purity, 44 % yield, 99.5 % de).
VII-13-M: LC-MS (ESI): RT = 4.227 min, mass calcd. for C281125C1F2N405S 602.1,
m/z
found 603.1 [M+111 . Chiral HPLC (Column: Chiralpak IF 5 gm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 60 : 40 at 3 g/min; Temp: 40 C; Wavelength: 254
nm,
RT = 3.85 min). 111 NMR (400 MHz, DMSO-d6) 6 9.63 (d, J= 3.2 Hz, 0.7H), 9.17
(s,
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0.3H), 8.81 - 8.79 (m, 1H), 8.01 - 7.93 (m, 2H), 7.51 - 7.45 (m, 1H), 7.26 -
7.20 (m, 1H),
6.93 - 6.90 (m, 1H), 6.07 (s, 0.3H), 5.97 (d, J= 3.6 Hz, 0.7H), 4.29 (q, J=
7.2 Hz, 2H),
4.13 (hr s, 0.3H), 4.00 - 3.88 (m, 2.7H), 2.78 - 2.59 (m, 2H), 2.46 - 2.36 (m,
2H), 2.10 -
1.82 (m, 2H), 1.29 (t, J= 7.2 Hz, 3H), 1.08 - 1.01 (m, 3H).
VII-13-N: LC-MS (ESI): RT = 4.113 min, mass calcd. for C281125C1F2N405S 602.1,
m/z
found 602.9 [M+Hi . Chiral HPLC (Column: Chiralpak IF 5 i.tm 4.6 *250 mm;
Mobile Phase: CO2 : Me0H = 60 : 40 at 3 g/min; Temp: 40 C; Wavelength: 254
nm,
RT = 5.43 min). 1H NMR (400 MHz, DMSO-d6) 6 9.65 (d, J= 3.2 Hz, 0.7H), 9.09
(s,
0.3H), 8.81 - 8.79 (m, 1H), 8.02 - 7.94 (m, 2H), 7.53 - 7.47 (m, 1H), 7.28 -
7.25 (m, 1H),
6.91 - 6.88 (m, 1H), 6.05 (s, 0.2H), 5.96 (d, J= 3.2 Hz, 0.8H), 4.29 (q, J=
7.2 Hz, 2H),
4.13 (hr s, 0.3H), 4.00 - 3.89 (m, 2.7H), 2.76 - 2.58 (m, 2H), 2.44 - 2.26 (m,
2H), 2.20 -
1.99 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.08 - 1.01 (m, 3H).
VII-13-P: LC-MS (ESI): RT = 3.346 min, mass calcd. for C281125C1F2N405S 602.1,
m/z
found 603.1 [M+111 . Chiral HPLC (Column: Chiralpak ID 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 :0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 8.847 min). 1H NMR (400 MHz, DMSO-d6) 6 9.62 (d, J=
3.2 Hz, 0.6H), 9.16 (s, 0.4H), 8.81 - 8.78 (m, 1H), 8.01 - 7.93 (m, 2H), 7.51 -
7.45 (m,
1H), 7.26 - 7.20 (m, 1H), 6.93 - 6.89 (m, 1H), 6.07 (s, 0.3H), 5.97 (d, J= 2.8
Hz, 0.7H),
4.29 (q, J= 7.2 Hz, 2H), 4.16 - 4.09 (m, 0.3H), 4.00- 3.87 (m, 2.7H), 2.79 -
2.58 (m,
2H), 2.46 - 2.33 (m, 2H), 2.08 - 1.82 (m, 2H), 1.29 (t, J= 7.2 Hz, 3H), 1.08 -
1.01 (m,
3H).
VII-13-Q: LC-MS (ESI): RT = 3.604 min, mass calcd. for C281125C1F2N405S 602.1,
m/z
found 603.1 [M+111 . Chiral HPLC (Column: Chiralpak ID 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 13.800 min). 1H NMR (400 MHz, DMSO-d6) 6 9.64 (d, J=
3.2 Hz, 0.7H), 9.08 (s, 0.3H), 8.81 - 8.78 (m, 1H), 8.01 - 7.93 (m, 2H), 7.53 -
7.45 (m,
1H), 7.28 - 7.25 (m, 1H), 6.91 - 6.88 (m, 1H), 6.05 (s, 0.2H), 5.96 (d, J= 3.6
Hz, 0.8H),
4.29 (q, J= 7.2 Hz, 2H), 4.16 - 4.10 (m, 0.3H), 4.00- 3.89 (m, 2.7H), 2.75 -
2.57 (m,
2H), 2.44 - 2.26 (m, 2H), 2.19 - 1.99 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.08 -
1.01 (m,
3H).
Compound VII-14-N:
(trans)-methyl 2-(4-(6-(2-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)-5-methyloxazole-4-carboxylate (a
single
stereoisomer)
Intermediate VII-14-8:
(trans)-Methyl 2444642-chloro-3,4-difluoropheny0-5-(ethoxycarbony1)-2-(thiazol-
2-
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y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)-5-methyloxazole-4-carboxylate (a
mixture
of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized as yellow solids. LC-MS (ESI): RT = 1.723 min, mass calcd. for
C281-127C1F2N405S 604.1, m/z found 605.1 [M+1-11 . 1H NMR (400 MHz, CDC13) 6
8.14
(s, 0.6H), 7.83 (d, J= 2.8 Hz, 1H), 7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 3.2
Hz,
0.6H), 7.32 (s, 0.4H), 7.12 - 7.01 (m, 2H), 6.21 (s, 0.6H), 6.08 (d, J= 2.8
Hz, 0.4H),
4.10 - 4.02 (m, 2.6H), 3.91 (s, 3H), 3.81 (hr s, 0.4H), 2.93 - 2.87 (m, 1H),
2.61 (s, 3H),
2.29 - 1.63 (m, 8H), 1.17 - 1.12 (m, 3H).
A stereoisomeric mixture of (trans)-methyl 2-(4-(6-(2-chloro-3,4-
difluoropheny1)-5-
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)-5-
methyloxazole-4-carboxylate VII-14-8 (630 mg, 99 % purity, 1.03 mmol) was
separated by chiral Prep. HPLC (separation condition: Column: Chiralpak IA 5
pm
30 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.3 at 22 mL/min;
Wavelength: 214 nm) to give the title compound VII-14-M (200 mg, 98.7 %
purity,
32 % yield, 100 % stereopure) as yellow solids and another isomer (190 mg, 88
%
stereopure), which was further purified by chiral Prep. HPLC (Column:
Chiralpak
IA 5 pm 30 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.3 at 22
mL/min;
Wavelength: 214 nm) to give the title compound VII-14-N (60 mg, 99.9 % purity,
9.6 %
yield, 99.6 % stereopure) as yellow solids.
VII-14-M: LC-MS (ESI): RT = 3.051 min, mass calcd. for C281-127C1F2N405S
604.1, m/z
found 604.9 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 9.303 min). 1H NMR (400 MHz, DMSO-d6) 6 9.56 (d, J=
3.6 Hz, 0.6H), 9.00 (s, 0.4H), 8.01 - 8.00 (m, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H), 7.51 -
7.43 (m, 1H), 7.22 - 7.17 (m, 1H), 6.04 (s, 0.4H), 5.93 (d, J= 3.6 Hz, 0.6H),
4.02 - 3.87
(m, 2.4H), 3.79 (s, 3H), 3.68 - 3.62 (m, 0.6H), 3.01 - 2.94 (m, 0.4H), 2.84 -
2.78 (m,
0.6H), 2.56 - 2.55 (m, 3H), 2.19 - 1.54 (m, 8H), 1.11 - 1.04 (m, 3H).
VII-14-N: LC-MS (ESI): RT = 4.134 min, mass calcd. for C281-127C1F2N405S
604.1, m/z
found 605.0 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 11.057 min). 1H NMR (400 MHz, DMSO-d6) 6 9.55 (d, J=
3.2 Hz, 0.6H), 9.00 (s, 0.4H), 8.01 - 8.00 (m, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H), 7.51 -
7.43 (m, 1H), 7.23 - 7.17 (m, 1H), 6.04 (s, 0.4H), 5.93 (d, J= 3.6 Hz, 0.6H),
4.02 - 3.86
(m, 2.4H), 3.79 (s, 3H), 3.67 - 3.61 (m, 0.6H), 3.01 - 2.95 (m, 0.4H), 2.84 -
2.77 (m,
0.6H), 2.56 - 2.55 (m, 3H), 2.16 - 1.51 (m, 8H), 1.10 - 1.04 (m, 3H).
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Compound VII-15-M:
(trans)-Methy1-2-04-(6-(2-chloro-3,4-difluoropheny0-5-(ethoxycarbony0-2-
(thiazol-2-
y1)-3,6 -dihydropyrimidin-4-yl)cydohexyl)methyl)oxazole-4-carboxylate (a
single
stereoisomer)
Intermediate VII-15-R:
Methy12-04-(6-(2-ohloro-3,4-difluoropheny1)-5-(ethoxycarbonyl)-2-(thiazol-2-
y1)-3,6-
dihydro pyrimidin-471)cydohexyl)methyl)oxazole-4-carboxylate (a mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized as yellow solids.
LC-MS (ESI): RT = 1.94 min, mass calcd. for C281127C1F2N405S 604.1, m/z found
604.9 [M+11] . 111 NMR (400 MHz, DMSO-d6) 6 9.57 - 9.48 (m, 0.711), 8.96 (s,
0.311),
8.80 - 8.78 (m, 111), 8.03 - 7.93 (m, 211), 7.50 - 7.42 (m, 111), 7.23 - 7.15
(m, 111), 6.03 -
6.02 (m, 0.411), 5.92 - 5.91 (m, 0.611), 3.99 - 3.92 (m, 211), 3.88 - 3.80 (m,
3.511), 3.74 -
3.66 (m, 0.211), 3.62 - 3.54 (m, 0.311), 3.21 - 3.19 (m, 0.311), 3.00 - 0.97
(m, 0.411), 2.75
- 2.74 (m, 1.311), 2.30 - 2.25 (m, 0.311), 2.09 - 1.38 (m, 7.711), 1.17 - 1.11
(m, 111), 1.09
- 1.02 (m, 311).
Intermediates VII-15-X and VII 15Y
(trans)-Methyl 2-04-(6-(2-chloro-3,4-difluoropheny0-5-(ethoxycarbony0-2-
(thiazol-2-
y1)-3,6 -dihydropyrimidin-471)cydohexyl)methyl)oxazole-4-carboxylate (a
mixture of
2 stereoisomers) and (cis)-methyl 2-04-(6-(2-chloro-3,4-difluoropheny0-5-
(ethoxycarbony0-2-(thiazol-2-y0-3,6 -dihydropyrimidin-4-
yl)cydohexyl)methyl)oxazole-4-carboxylate (a mixture of 2 stereoisomers)
A mixture of methyl -2-
252-((4-(6-(2-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1) (thiazol-2-y1)-3,6-
dihydropyrimidin-4-yl)cyclohexyl)methyl)oxazole-4-carboxylate
VII-15-R (480 mg, 95 % purity, 0.75 mmol) was separated by chiral prep. HPLC
(Column: Chiralpak IC 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 80:
20 : 0.3 at 15 mL/min; Temp: 30 C; Wavelength: 254 nm) to give the title
compounds
VII 15X (140 mg, 98 % purity, 29 % yield) and VII 15Y (260 mg, 98 % purity, 54
%
yield) as yellow solids.
Intermediate VII-15-X: Chiral analysis (Chiralpak IC 5 i.tm 4.6 * 250 mm;
Mobile
Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/min; Temp: 30 C; Wavelength:
254
nm, RT = 11.072 min and 11.491 min). 111 NMR (400 MHz, DMSO-de) 6 9.53 (d, J=
3.6 Hz, 0.511), 8.96 (br s, 0.511), 8.79 - 8.78 (m, 111), 8.00 - 7.94 (m,
211), 7.49 - 7.42 (m,
111), 7.21 - 7.14 (m, 111), 6.02 (s, 0.511), 5.91 (d, J= 3.6 Hz, 0.511), 3.99 -
3.92 (m, 211),
3.86 - 3.80 (m, 3.511), 3.62 - 3.55 (m, 0.511), 2.79 - 2.70 (m, 211), 2.02 -
1.57 (m, 711),
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1.18- 1.02 (m, 5H).
Intermediate VII-15-Y: Chiral analysis (Chiralpak IC 5 gm 4.6 * 250 mm; Mobile
Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/min; Temp: 30 C; Wavelength:
254
nm, RT = 14.629 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.57 (d, J= 3.2 Hz, 0.5H),
9.48 (s, 0.5H), 8.80 - 8.79 (m, 1H), 8.03 - 7.93 (m, 2H), 7.51 - 7.44 (m, 1H),
7.24 - 7.15
(m, 1H), 6.03 (s, 0.5H), 5.93 - 5.92 (d, J= 3.6 Hz, 0.5H), 3.99 - 3.92 (m,
2H), 3.99 -
3.80 (m, 3.5H), 3.73 - 3.64 (m, 0.5H), 3.21 - 3.19 (m, 1H), 3.04- 3.93 (m,
1H), 2.33 -
2.27 (m, 1H), 2.09 - 1.86 (m, 2H), 1.63 - 1.38 (m, 6H), 1.09 - 1.03 (m, 3H).
A stereoisomeric mixture of (trans)-methyl- 4-(6-(2-chloro-3,4-difluoropheny1)-
5-
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)methyl)oxazole-4-carboxylate VII-15-X (240 mg, 98 % purity,
0.377
mmol) was separated by chiral prep. SFC (Column: Chiralpak IA 5 gm 20 * 250
mm;
Mobile Phase: CO2 : IPA= 75 : 25 at 50 g/min; Col. Temp: 40 C; Wavelength:
214 nm,
Back pressure: 100 bar) to give the compounds VII-15-M (110 mg, 95 % purity,
46 %
yield, 100 % stereopure) and VII-15-N (80 mg, 95 % purity, 33 % yield, 99 %
stereopure) as yellow solids.
VII-15-M: Chiral analysis (Chiralpak IA 5 gm 4.6 * 250 mm; Mobile Phase: c02:
IPA = 75 : 25 at 3 g/min; Col. Temp: 40 0C; Wavelength: 220 nm, Back pressure:
100
bar, RT = 4.98 min).
VII-15-N: Chiral analysis (Chiralpak IA 5 gm 4.6 * 250 mm; Mobile Phase: c02:
IPA = 75 : 25 at 3 g/min; Col. Temp: 40 0C; Wavelength: 220 nm, Back pressure:
100
bar, RT = 5.87 min).
Compound VII-16-N:
(trans)-Methyl 442-chloro-3,4-difluoropheny1)-644-(442-ethoxy-2-oxoethypoxazol-
2-
yl)cydohexyl)-2-(thiazol-270-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediates VII-16-X and VII-16-Y:
(trans)-Methyl 442-chloro-3,4-difluoropheny1)-644-(442-ethoxy-2-oxoethypoxazol-
2-
y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 2
stereoisomers) and (cig)-methyl 4-(2-chloro-3,4-difluoropheny1)-644-(442-
ethoxy-2-
oxoethyl)oxazol-2-yl)cydohexyD-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
(a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
Intermediate VII-16-X: 11-1 NMR (400 MHz, DMSO-d6) 6 9.59 (d, J= 3.6 Hz,
0.7H),
9.07 (s, 0.3H), 8.01 - 8.00 (m, 1.5H), 7.96 - 7.95 (m, 0.5H), 7.86 - 7.85 (m,
1H), 7.50 -
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7.43 (m, 1H), 7.22 - 7.15 (m, 1H), 6.02 (s, 0.4H), 5.93 (d, J= 3.6 Hz, 0.6H),
4.13 - 4.08
(m, 2H), 3.94 - 3.89 (m, 0.5H), 3.69 - 3.62 (m, 2.5H), 3.54 (s, 1.8H), 3.53
(m, 1.2H),
3.00 - 2.94 (m, 0.4H), 2.83 - 2.76 (m, 0.6H), 2.18 - 2.10 (m, 2H), 2.06 - 1.66
(m, 4H),
1.62- 1.48 (m, 2H), 1.22 - 1.18 (m, 3H).
.. Intermediate VII-16-Y: 11-1 NMR (400 MHz, DMSO-d6) 6 9.54 (d, J= 3.6 Hz,
0.7H),
8.49 (s, 0.3H), 7.98 - 7.91 (m, 3H), 7.48 - 7.40 (m, 1H), 7.18 - 7.14 (m, 1H),
6.02 (s,
0.3H), 5.89 (d, J= 3.6 Hz, 0.7H), 4.12 - 4.06 (m, 2H), 3.93 - 3.88 (m, 0.3H),
3.71 - 3.66
(m, 1.4H), 3.62 (s, 1.3H), 3.53 (s, 1.8H), 3.52 (s, 1.2H), 3.29 - 2.27 (m,
0.3H), 3.18 -
3.16 (m, 0.7H), 2.34 - 2.24 (m, 2H), 1.97 - 1.58 (m, 5.3H), 1.44- 1.41 (m,
0.7H), 1.19 -
.. 1.15 (m, 3H).
A stereoisomeric mixture of (trans)-methyl 4-(2-chloro-3,4-difluoropheny1)-6-
(4-(4-(2-
ethoxy-2-oxoethyl)oxazol-2-yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate VII-16-X (300 mg, 95 % purity, 0.471 mmol) was separated by chiral
prep. HPLC (Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
:
DEA = 50: 50: 0.3 at 10 mLimin, Temp: 30 C, Wavelength: 230 nm) to afford VII-
16-
M (110 mg, 95 % purity from 11-1 NMR, 37 % yield, 100 % stereopure) and VII-16-
N
(110 mg, 95 % purity from 11-1 NMR, 37 % yield, 99.8 % stereopure) as yellow
solids.
VII-16-M: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 *250 mm; Mobile
Phase:
Hex : Et0H : DEA= 50: 50 : 0.2 at 1.0 mLimin; Temp: 30 C; Wavelength: 230 nm,
RT = 6.781 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.58 - 9.57 (m, 0.6H), 9.05 (s,
0.4H),
8.01 (s, 1.5H), 7.96 - 7.95 (m, 0.5H), 7.86 - 7.84 (m, 1H), 7.50 - 7.43 (m,
1H), 7.21 -
7.14 (m, 1H), 6.02 (s, 0.4H), 5.93 - 5.92 (m, 0.6H), 4.10 (q, J= 7.2 Hz, 2H),
3.94- 3.88
(m, 0.5H), 3.68 - 3.61 (m, 0.5H), 3.57 (s, 2H), 3.54 (s, 1.8H), 3.53 (s,
1.2H), 3.00 - 2.94
(m, 0.4H), 2.84- 2.76 (m, 0.6H), 2.18 - 2.10 (m, 2H), 2.04- 1.66 (m, 4H), 1.61
- 1.51
(m, 2H), 1.20 (t, J= 7.2 Hz, 3H).
VII-16-N: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 *250 mm; Mobile
Phase:
Hex : Et0H : DEA= 50: 50 : 0.2 at 1.0 mLimin; Temp: 30 C; Wavelength: 230 nm,
RT = 12.009 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.58 - 9.57 (m, 0.6H), 9.05
(s,
0.4H), 8.01 (s, 1.5H), 7.96 - 7.95 (m, 0.5H), 7.85 - 7.84 (m, 1H), 7.50 - 7.43
(m, 1H),
.. 7.22 - 7.16 (m, 1H), 6.02 (s, 0.4H), 5.93 - 5.92 (m, 0.6H), 4.10 (q, J= 7.2
Hz, 2H), 3.95
- 3.88 (m, 0.5H), 3.67 - 3.61 (m, 0.5H), 3.57 (s, 2H), 3.54 (s, 1.8H), 3.53
(s, 1.2H)õ 3.00
- 2.94 (m, 0.4H), 2.83 - 2.76 (m, 0.6H), 2.18 - 2.11 (m, 2H), 2.04- 1.67 (m,
4H), 1.61 -
1.51 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H).
Compound VII-17-M:
(trans)-Methyl 442-chloro-4-fluoropheny1)-6-(44442-ethoxy-2-oxoethyDoxazol-2-
yDcydohexy0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a single
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stereoisomer)
Intermediates VII-17-X and VII-17-Y
(trans)-Methyl 442-chloro-4-fluoropheny1)-6-(44442-ethoxy-2-oxoethy0oxazol-2-
yl)cydohexyl)-2-(thiazol-270-1,4-dihydropyrimidine-5-carboxylate (a mixture of
2
stereoisomers) and (cis)-methyl 442-chloro-4-fluoropheny1)-6-(44442-ethoxy-2-
oxoethyl)oxazol-2-y1)cydohexy0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
(a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
VII-17-X: 1H NMR (400 MHz, CDC13) 6 8.16 (s, 0.4H), 7.83 - 7.82 (m, 1H), 7.56 -
7.54
(m, 1H), 7.50 (d, J= 3.2 Hz, 0.4H), 7.46 - 7.45 (d, J= 2.8 Hz, 0.6H), 7.40 (hr
s, 0.6H),
7.32 - 7.28 (m, 1H), 7.14- 7.12 (m, 1H), 6.96 - 6.89 (m, 1H), 6.19 (s, 0.6H),
6.06 - 6.05
(m, 0.4H), 4.23 - 4.18 (m, 2H), 4.08 - 4.01 (m, 0.6H), 3.84 - 3.78 (m, 0.4),
3.62 - 3.60
(m, 4H), 2.93 - 2.86 (m, 1H), 2.33 - 2.14 (m, 3H), 2.10 - 2.07 (m, 1H), 1.88 -
1.64 (m,
4H), 1.31- 1.24 (m, 3H).
VII 17Y 1H NMR (400 MHz, CDC13) 6 8.27 (s, 0.7H), 7.83 - 7.82 (d, J= 3.2 Hz,
0.7H),
7.80 - 7.79 (d, J= 2.8 Hz, 0.3H), 7.65 (s, 0.7H), 7.63 (s, 0.3H), 7.47 - 7.46
(d, J= 3.2
Hz, 0.3H), 7.43 - 7.42 (d, J= 3.2 Hz, 0.7H), 7.35 (hr s, 0.3H), 7.30 - 7.25
(m, 1H), 7.13
- 7.10 (m, 1H), 6.94- 6.86 (m, 1H), 6.18 (s, 0.7H), 6.04 - 6.03 (d, J= 3.2 Hz,
0.3H),
4.23 - 4.16 (m, 2H), 4.13 - 4.05 (m, 0.7H), 3.89 - 3.83 (m, 0.3H), 3.73 (s,
1.4H), 3.66 (s,
0.6H), 3.61 (s, 0.5H), 3.60 (s, 2.5H), 3.29 (s, 0.7H), 3.22 - 3.21 (m, 0.3H),
2.50 - 2.35
(m, 2H), 2.13 - 2.07 (m, 0.3H), 1.98 - 1.78 (m, 5.7H), 1.30 - 1.26 (m, 3H).
A stereoisomeric mixture of (trans)-methyl -5-
254-(2-chloro-4-fluoropheny1)-6-(4-(4-(2-
ethoxy-2-oxoethyl)oxazol-2-yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine carboxylate VII-17-X (130 mg, 0.221 mmol) was seperated by
chiral Prep. SFC
(Column: Chiralpak IG 5 i.tm 20 * 250 mm; Mobile Phase: CO2 : Et0H : DEA= 65:
35 : 0.3 at 50 g/min; Col. Temp: 40 C; Wavelength: 230 nm; Back pressure: 100
bar)
to give the compounds VII-17-M (50 mg, 38 % yield, 100 % stereopure) and VII-
17-N
(60 mg, 46 % yield, 99.2 % stereopure).
VII-17-M: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
CO2 Et0H : DEA = 65 : 35 : 0.3 at 3 g/min; Col. Temp: 40 C; Wavelength: 230
nm,
Back pressure: 100 bar, RT = 3.51 min).
VII-17-N: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
CO2 : Et0H : DEA = 65 : 35 : 0.3 at 3 g/min; Col. Temp: 40 C; Wavelength: 230
nm,
Back pressure: 100 bar, RT = 4.28 min).
Compound VII-18-M:
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(trans)-Methyl 442-bromo-4-fluoropheny1)-6-(44442-ethoxy-2-oxoethy0oxazol-2-
yl)cydohexy0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediates VII-18-X and VII-18-Y:
(trans)-Methyl 442-bromo-4-fluoropheny1)-6-(44442-ethoxy-2-oxoethyl)oxazol-2-
y1)cydohexyl)-2-(thiazol-270-1,4-dihydropyrimidine-5-carboxylate (a mixture of
2
stereoisomers) and (cis)-methyl 442-bromo-4-fluoropheny1)-6444442-ethoxy-2-
oxoethyl)oxazol-2-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
(a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
Intermediate VII-18-Y: 1H NMR (400 MHz, CDC13) 6 8.25 (s, 0.7H), 7.82 (d, J=
3.2
Hz, 0.7H), 7.80 (d, J= 3.2 Hz, 0.3H), 7.65 (s, 0.7H), 7.63 (s, 0.3H), 7.46 (d,
J= 3.2 Hz,
0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.41 - 7.38 (m, 0.3H), 7.32 - 7.30 (m, 1H),
7.00 - 6.91
(m, 1H), 6.15 (s, 0.7H), 5.99 (d, J= 2.8 Hz, 0.3H), 4.23 - 4.16 (m, 2H), 4.13 -
4.07 (m,
0.7H), 3.89 - 3.84 (m, 0.3H), 3.73 (s, 1.3H), 3.66 (s, 0.7H), 3.61 (s, 1H),
3.60 (s, 2H),
3.30 (br s, 0.7H), 3.22 - 3.21 (m, 0.3H), 2.43 - 2.34 (m, 1.8H), 2.13 - 2.07
(m, 0.3H),
1.96 - 1.87 (m, 4.5H), 1.83 - 1.76 (m, 1.4H), 1.30 - 126 (m, 3H).
Intermediate VII-18-X: 1H NMR (400 MHz, CDC13) 6 8.16 (s, 0.5H), 7.83 (t, J=
3.2
Hz, 1H), 7.59 - 7.56 (m, 1H), 7.53 - 7.50 (m, 0.5H), 7.49 - 7.46 (m, 0.5H),
7.45 - 7.43
(m, 0.5H), 7.35 - 7.30 (m, 2H), 7.03 - 6.91 (m, 1H), 6.17 (s, 0.5H), 6.02 (d,
J= 2.4 Hz,
0.5H), 4.20 (q, J= 7.2 Hz, 2H), 4.10 - 4.02 (m, 0.5H), 3.86 - 3.77 (m, 0.5H),
3.62 (s,
2H), 3.60 (s, 3H), 2.95 - 2.82 (m, 1H), 2.37 - 2.25 (m, 1.5H), 2.19 - 2.16 (m,
1H), 2.08 -
2.01 (m, 1.5H), 1.86 - 1.75 (m, 3H), 1.70 - 1.57 (m, 1H), 1.33 - 1.26 (m, 3H).
A stereoisomeric mixture of (trans)- methyl 4-(2-bromo-4-fluoropheny1)-6-(4-(4-
(2-
ethoxy-2-oxoethyl)oxazol-2-yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate VII-18-X (560 mg, 95 % purity, 0.842 mmol) was separated by chiral
Prep. SFC (Column: Chiralpak IF 5 i.tm 20 * 250 mm, Mobile Phase: CO2 : Et0H
DEA = 70 : 30 : 0.3 at 50 g/min; Col. Temp: 40 0C; Wavelength: 214 nm; Back
pressure: 100 bar) to afford the title compunds VII-18-M (103 mg, 90 % purity,
17 %
yield, 100 % stereopure) and VII-18-N (145 mg, 90 % purity, 25 % yield, 99.5 %
stereopure) as yellow solids.
VII-18-M: LC-MS (EST): RT = 1.92 min, mass calcd. for C281-128BrFN405S 631.5,
m/z
found 632.8 [M+Hi . Chiral analysis (Column: Chiralpak IF 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2: Et0H DEA = 70 30 0.2 at 5 g/min; Col. Temp: 40 C;
Wavelength: 214 nm, Back pressure: 100 bar, RT = 5.82 min). 1H NMR (400 MHz,
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CDC13) 6 8.14 (s, 0.5H), 7.83 - 7.82 (m, 1H), 7.56 (s, 1H), 7.50 - 7.49 (m,
0.5H), 7.44 (d,
J= 3.2 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.03 - 6.90 (m, 1H), 6.17 (s, 0.5H), 6.02
(d, J=
2.8 Hz, 0.5H), 4.20 (q, J= 7.2 Hz, 2H), 4.10 - 4.00 (m, 0.5H), 3.86 - 3.76 (m,
0.5H),
3.62 - 3.60 (m, 5H), 2.96 - 2.83 (m, 1H), 2.37 - 2.02 (m, 4H), 1.92 - 1.64 (m,
4H), 1.29
(t, J= 7.2 Hz, 3H).
VII-18-N: LC-MS (ESI): RT = 1.90 min, mass calcd. for C281-128BrFN405S 631.5,
m/z
found 632.8 [M+Hi . Chiral analysis (Column: Chiralpak IF 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2: Et0H : DEA = 70 : 30 : 0.2 at 5 g/min; Col. Temp: 40 C;
Wavelength: 214 nm, Back pressure: 100 bar, RT = 8.02 min). 1H NMR (400 MHz,
CDC13) 6 8.15 (s, 0.5H), 7.83 - 7.82 (m, 1H), 7.56 (s, 1H), 7.50 - 7.49 (m,
0.5H), 7.44 (d,
J= 3.2 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.01 - 6.91 (m, 1H), 6.17 (s, 0.5H), 6.02
(d, J=
2.8 Hz, 0.5H), 4.20 (q, J= 7.2 Hz, 2H), 4.10 - 4.01 (m, 0.5H), 3.86 - 3.76 (m,
0.5H),
3.62 - 3.60 (m, 5H), 2.94 - 2.84 (m, 1H), 2.36 - 2.02 (m, 4H), 1.93 - 1.64 (m,
4H), 1.29
(t, J= 7.2 Hz, 3H).
Compound VII 19M:
(trans)-Methyl 442-bromo-3-fluoropheny1)-6-(44442-ethoxy-2-oxoethypoxazol-2-
y1)cydohexyl)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediate VII- 19-1:
(trans)-Methyl 442-bromo-3-fluoropheny1)-6-(44442-ethoxy-2-oxoethypoxazol-2-
0cydohexyl)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a mixture of
2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized.
LC-MS (ESI): RT = 2.097 min, mass calcd. for C281-128BrFN405S 630.1, m/z found
631.0 [M+1-11 . 1H NMR (400 MHz, CD30D) 6 7.92 (s, 0.5H), 7.88 (s, 0.5H), 7.75
- 7.72
(m, 2H), 7.34 - 7.28 (m, 1H), 7.21 (d, J= 8.0 Hz, 111), 7.14 - 7.07 (m, 1H),
6.20 (s,
0.5H), 6.10 (s, 0.5H), 4.18 (q, J= 6.8 Hz, 2H), 4.09 - 4.03 (m, 0.5H), 3.85 -
3.81 (m,
0.5H), 3.60 - 3.58 (m, 5H), 3.00 - 2.84 (m, 1H), 2.29 - 2.18 (m, 2H), 2.13 -
2.06 (m, 1H),
1.88 - 1.67 (m, 5H), 1.29 - 1.23 (m, 3H).
A stereoisomeric mixture of (trans)-methyl 4-(2-bromo-3-fluoropheny1)-6-(4-(4-
(2-
ethoxy-2-oxoethyl)oxazol-2-y1)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate WI-19-1 (352 mg, 95 % purity, 0.530 mmol) was separated by chiral
Prep. HPLC (Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
DEA = 50 : 50 : 0.3 at 12 mL/min; Temp: 30 0C; Wavelength: 214 nm) to afford
the
title compounds VII-19-M (148 mg, 95 % purity from 1H NMR, 42 % yield) and VII-
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19-N (144 mg, 95 % purity from 11-1 NMR, 41 % yield) as yellow solids.
VII-19-M:111NMR (400 MHz, DMSO-d6) 6 9.49 (hr s, 0.5H), 9.03 (s, 0.5H), 8.00
(d, J
= 3.2 Hz, 1.5H), 7.94 (d, J= 3.2 Hz, 0.5H), 7.85 (d, J= 4.8 Hz, 1H), 7.44 -
7.39 (m,
1H), 7.31 - 7.25 (m, 1H), 7.21 (d, J= 8.0 Hz, 0.5H), 7.16 (d, J= 8.0 Hz,
0.5H), 6.06 (s,
0.5H), 5.97 (s, 0.5H), 4.11 (q, J= 7.2 Hz, 2H), 3.95 - 3.90 (m, 0.5H), 3.68 -
3.62 (m,
0.5H), 3.58 (s, 2H), 3.53 (s, 1.5H), 3.52 (s, 1.5H), 3.00 - 2.94 (m, 0.5H),
2.84 - 2.78 (m,
0.5H), 2.18 - 2.11 (m, 2H), 2.05 - 2.02 (m, 0.5H), 1.94- 1.89 (m, 2H), 1.82 -
1.76 (m,
1H), 1.70 - 1.67 (m, 0.5H), 1.63 - 1.51 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H).
VII-19-N:111NMR (400 MHz, DMSO-d6) 6 9.49 (hr s, 0.5H), 9.05 (s, 0.5H), 8.00
(d, J
.. = 2.8 Hz, 1.5H), 7.95 (d, J= 2.8 Hz, 0.5H), 7.86 (d, J= 4.8 Hz, 1H), 7.45 -
7.39 (m,
1H), 7.32 - 7.25 (m, 1H), 7.21 (d, J= 7.6 Hz, 0.5H), 7.16 (d, J= 7.6 Hz,
0.5H), 6.06 (s,
0.5H), 5.97 (s, 0.5H), 4.11 (q, J= 7.2 Hz, 2H), 3.96 - 3.90 (m, 0.5H), 3.69 -
3.63 (m,
0.5H), 3.58 (s, 2H), 3.53 (s, 2H), 3.52 (s, 1H), 3.00 - 2.94 (m, 0.5H), 2.84 -
2.78 (m,
0.5H), 2.18 - 2.10 (m, 2H), 2.06 - 2.00 (m, 0.5H), 1.94- 1.88 (m, 2H), 1.82 -
1.77 (m,
.. 1H), 1.70 - 1.67 (m, 0.5H), 1.60 - 1.51 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H).
Compound VII-20-N:
(trans)-Methyl 4-(2-chloro-3-fluoropheny1)-6-(44442-ethoxy-2-oxoethypoxazol-2-
0cydohexy0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediate VII-20-3:
(trans)-Methyl 442-chloro-3-fluoropheny1)-6-(44442-ethoxy-2-oxoethypoxazol-2-
y1)cydohexy0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a mixture of
2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (EST): RT = 1.89 min, mass calcd. for C281128C1FN405S 586.2, m/z found
586.9
[M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.17 (s, 0.5H), 7.83 (d, J= 3.2 Hz, 1H),
7.56 (s,
1H), 7.51 - 7.50 (m, 0.5H), 7.46 - 7.45 (m, 0.5H), 7.42 (s, 0.5H), 7.23 - 7.12
(m, 2H),
7.10 - 7.00 (m, 1H), 6.26 (s, 0.6H), 6.11 (s, 0.4H), 4.20 (q, J= 7.2 Hz, 2H),
4.10 - 4.02
(m, 0.5H), 3.89 - 3.78 (m, 0.5H), 3.62 - 3.60 (m, 5H), 2.95 - 2.87 (m, 1H),
2.36 - 1.99
(m, 4H), 1.91 - 1.67 (m, 3.6H), 1.61 - 1.54 (m, 0.4H), 1.30 (t, J= 7.2 Hz,
3H).
A stereoisomeric mixture of (trans)-methyl 4-(2-chloro-3-fluoropheny0-6-(4-(4-
(2-
ethoxy-2-oxoethyl)oxazol-2-y1)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate VII-20-3 (400 mg, 90 % purity, 0.613 mmol) was separated by chiral
.. Prep. HPLC (Column: Chiralpak IE 5 pm 20 * 250 mm; Mobile Phase: Hex : Et0H
DEA = 50 : 50 : 0.3 at 13 mL/min; Temp: 30 C; Wavelength: 230 nm) to give the
title
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compounds VII-20-M (148 mg, 90 % purity, 37 % yield, 100 % stereopure) and VII-
20-N (150 mg, 90 % purity, 37 % yield, 99.7 % stereopure) as yellow solids.
VII-20-M: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/min; Temp: 30 C; Wavelength: 230 nm,
RT
= 7.675 min). 1H NMR (400 MHz, CDC13) 6 7.83 (d, J= 3.2 Hz, 1H), 7.56 (s, 1H),
7.47
(br s, 1H), 7.23 - 7.13 (m, 2H), 7.11 - 7.01 (m, 1H), 6.32 - 6.09 (m, 1H),
4.20 (q, J= 7.2
Hz, 2H), 3.98 (br s, 0.6H), 3.86 - 3.73 (m, 0.4H), 3.60 (s, 5H), 2.93 - 2.85
(m, 1H), 2.35
- 2.04 (m, 4H), 2.02 - 1.72 (m, 4H), 1.31 (t, J= 7.2 Hz, 3H).
VII-20-N: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
.. Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/min; Temp: 30 C; Wavelength: 230
nm, RT
= 10.297 min). 1H NMR (400 MHz, CDC13) 6 7.83 (d, J= 3.2 Hz, 1H), 7.56 (s,
1H),
7.47 (br s, 1H), 7.21 - 7.13 (m, 2H), 7.09 - 7.00 (m, 1H), 6.29 - 6.10 (m,
1H), 4.20 (q, J
= 7.2 Hz, 2H), 3.98 (br s, 0.6H), 3.88 - 3.71 (m, 0.4H), 3.60 (s, 5H), 2.94 -
2.84 (m, 1H),
2.36 - 2.07 (m, 4H), 2.04 - 1.74 (m, 3H), 1.68 - 1.57 (m, 1H), 1.30 (t, J= 7.2
Hz, 3H).
Compound VII-21-N:
(trans)-Methyl 6-44442-ethoxy-2-oxoethypoxazol-2-370cydohexyl)-443-fluoro-2-
methylpheny0-2-(thiazol-2-0-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediate WI-21-1:
(trans)-Methyl 6444442-ethoxy-2-oxoethypoxazol-2-370cydohexy0-443-fluoro-2-
methylpheny0-2-(thiazol-2-0-1,4-dihydropyrimidine-5-carboxylate (a mixture of
2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 1.87 min, mass calcd. for C29H3iFN405S 566.2, m/z found
566.9
[M+1-11 . 1H NMR (400 MHz, CDC13) 6 8.12 (s, 1H), 7.80 (d, J= 2.8 Hz, 1H),
7.56 -
7.55 (m, 1H), 7.50 (d, J= 2.8 Hz, 0.2H), 7.42 (d, J= 2.8 Hz, 0.8H), 7.16 -
7.02 (m, 2H),
6.90 - 6.88 (m, 1H), 6.01 (s, 0.8H), 5.91 (d, J= 2.4 Hz, 0.2H), 4.21 (q, J=
7.2 Hz, 2H),
4.12 - 4.04 (m, 1H), 3.60 (s, 5H), 2.93 - 2.87 (m, 1H), 2.54 (d, J= 2.0 Hz,
2.4H), 2.40
.. (d, J= 2.0 Hz, 0.6H), 2.35 - 2.27 (m, 3H), 2.09 - 1.98 (m, 1H), 1.93 - 1.65
(m, 3.5H),
1.59 - 1.55 (m, 0.5H), 1.29 (t, J= 7.2 Hz, 3H).
A stereoisomeric mixture of (trans)- methyl 6-(4-(4-(2-ethoxy-2-
oxoethyl)oxazol-2-
yl)cyclohexyl)-4-(3-fluoro-2-methylpheny1)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate WI-21-1 (400 mg, 90 % purity, 0.635 mmol) was separated by chiral
Prep. HPLC (Column: Chiralpak IE 5 pm 20 * 250 mm; Mobile Phase: Hex : Et0H
DEA = 70 : 30 : 0.3 at 13 mL/min; Temp: 30 C; Wavelength: 230 nm) to give the
title
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compunds VII-21-M (60 mg, 90 % purity, 15 % yield, 100 % stereopure) and VII-
21-N
(100 mg, 90 % purity, 25 % yield, 99.6 % stereopure). as yellow solids
VII-21-M: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp: 30 C; Wavelength: 230 nm,
RT
= 9.911 min). 11I NMR (400 MHz, CDC13) 68.12 (s, 1H), 7.80 (d, J= 2.8 Hz, 1H),
7.56
(s, 1H), 7.50 (d, J= 3.2 Hz, 0.2H), 7.42 (d, J= 3.2 Hz, 0.8H), 7.16 - 7.02 (m,
2H), 6.95
- 6.88 (m, 1H), 6.01 (s, 0.8H), 5.91 (d, J= 2.4 Hz, 0.2H), 4.20 (q, J= 7.2 Hz,
2H), 4.12
- 4.04 (m, 1H), 3.60 (s, 5H), 2.93 - 2.87 (m, 1H), 2.54 (d, J= 2.0 Hz, 2.4H),
2.40 (d, J=
2.0 Hz, 0.6H), 2.35 - 2.17 (m, 3H), 2.09 - 1.98 (m, 1H), 1.93 - 1.65 (m,
3.5H), 1.59 -
.. 1.55 (m, 0.5H), 1.29 (t, J= 7.2 Hz, 3H).
VII-21-N: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp: 30 C; Wavelength: 230 nm,
RT
= 12.043 min). 11I NMR (400 MHz, CDC13) 6 8.12 (s, 1H), 7.80 (d, J= 2.8 Hz,
1H),
7.56 (s, 1H), 7.50 (d, J= 3.2 Hz, 0.2H), 7.42 (d, J= 3.2 Hz, 0.8H), 7.16 -
7.00 (m, 2H),
6.94 - 6.87 (m, 1H), 6.01 (s, 0.8H), 5.91 (d, J= 2.0 Hz, 0.2H), 4.20 (q, J=
7.2 Hz, 2H),
4.11 - 4.03 (m, 1H), 3.60 (s, 5H), 2.94- 2.85 (m, 1H), 2.54 (d, J= 2.0 Hz,
2.4H), 2.40
(d, J= 2.0 Hz, 0.6H), 2.36 - 2.17 (m, 3H), 2.09 - 1.98 (m, 1H), 1.93 - 1.65
(m, 3.5H),
1.58 - 1.55 (m, 0.5H), 1.29 (t, J= 7.2 Hz, 3H).
Compound VII-22-S:
(trans)-Methyl 442-chloro-3,4-difluoropheny0-644-(442-ethoxy-2-oxoethy0-5-
methyloxazol-2-yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-
carboxylate
(a single stereoisomer)
Intermediate VII-22:
Methyl 442-chloro-3,4-difluoropheny0-6-(44442-ethoxy-2-oxoethyl)-5-
methyloxazol-
2-y0cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.172 min, mass calcd. for C29H29C1F2N405S 618.2, m/z found
619.1 [M+111 . 11I NMR (400 MHz, CDC13) 68.18 (s, 0.6H), 7.83 (d, J= 3.2 Hz,
1H),
7.51 (d, J= 3.2 Hz, 0.3H), 7.46 (d, J= 2.8 Hz, 0.7H), 7.37 (s, 0.4H), 7.10 -
7.00 (m,
2H), 6.19 (s, 0.7H), 6.05 (d, J= 2.8 Hz, 0.3H), 4.21 - 4.10 (m, 2H), 4.06 -
4.00 (m,
0.6H), 3.83 - 3.77 (m, 0.4H), 3.63 (s, 1H), 3.60 (s, 2H), 3.47 (s, 2H), 2.86 -
2.80 (m, 1H),
2.32 - 2.30 (m, 1H), 2.28 (s, 3H), 2.16 - 2.13 (m, 1H), 2.07 - 1.99 (m, 2H),
1.86 - 1.62
(m, 4H), 1.28 (t, J= 7.2 Hz, 3H).
A stereoisomeric mixture of methyl 4-(2-chloro-3,4-difluoropheny1)-6-(4-(4-(2-
ethoxy-
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2-oxoethyl)-5-methyloxazol-2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate VII-22 (300 mg, 90 % purity, 0.436 mmol) was separated by chiral
Prep.
HPLC (Colum: Chiralpak IE 5 pm 20 mm * 250 mm; Mobile Phase: Hex : Et0H :
DEA = 75 : 25 : 0.3 at 15 mL/min; Temp: 30 C; Wavelength: 214 nm) to afford
the
title compounds VII-22-R (85 mg, 90 % purity from 111 NMR, 28 % yield, 96.4 %
stereopure) and VII-22-S (90 mg, 90 % purity from 111 NMR, 30 % yield, 98.4 %
stereopure) as yellow solids.
VII-22-R: LC-MS (ESI): RT = 2.281 min, mass calcd. for C29H29C1F2N405S 618.2,
m/z
found 619.1 [M+Hi . Chiral analysis (Colum: Chiralpak IE 5 pm 4.6 mm * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 75 : 25 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 254 nm, RT = 10.938 min). 111 NMR (400 MHz, CDC13) 6 8.18 (s,
0.6H),
7.83 (d, J= 3.2 Hz, 1H), 7.51 (d, J= 3.2 Hz, 0.3H), 7.46 (d, J= 3.2 Hz, 0.7H),
7.38 (s,
0.4H), 7.10 - 7.01 (m, 2H), 6.19 (s, 0.7H), 6.05 (s, 0.3H), 4.18 (q, J= 7.2
Hz, 2H), 4.05
- 4.00 (m, 0.7H), 3.83 - 3.77 (m, 0.3H), 3.63 (s, 1H), 3.60 (s, 2H), 3.47 (s,
2H), 2.86 -
2.80 (m, 1H), 2.31 - 2.28 (m, 1H), 2.26 (s, 3H), 2.19 - 1.99 (m, 2.7H), 1.87 -
1.70 (m,
4.3H), 1.28 (t, J= 7.2 Hz, 3H).
VII-22-S: LC-MS (ESI): RT = 2.241 min, mass calcd. for C29H29C1F2N405S 618.2,
m/z
found 619.1 [M+Hi . Chiral analysis (Colum: Chiralpak IE 5 pm 4.6 mm * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 75 : 25 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 254 nm, RT = 12.525 min). 111 NMR (400 MHz, CDC13) 6 8.18 (s,
0.6H),
7.83 (d, J= 3.6 Hz, 1H), 7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 3.2 Hz, 0.6H),
7.38 (s,
0.4H), 7.10 - 7.00 (m, 2H), 6.19 (s, 0.6H), 6.05 (d, J= 2.0 Hz, 0.4H), 4.18
(q, J= 6.8
Hz, 2H), 4.06 - 4.00 (m, 0.7H), 3.83 - 3.78 (m, 0.3H), 3.63 (s, 1H), 3.60 (s,
2H), 3.47 (s,
2H), 2.86 - 2.80 (m, 1H), 2.30 - 2.28 (m, 1H), 2.26 (s, 3H), 2.16 - 1.98 (m,
2.5H), 1.84 -
1.64 (m, 4.5H), 1.28 (t, J= 6.8 Hz, 3H).
Compound VII-23-Y:
(trans) Ethyl 4(2-chloro-3,4-difluorophenyl) 44-(4-(2-ethoxy-2-oxoethyl)oxazol-
2-
yl)cydohexyl)-2-(thiazol-270-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediates VII-23-M and VII-23-N:
(trans)-Ethyl 4(2-chloro-3,4-difluorophenyl) 44-(4-(2-ethoxy-2-oxoethyl)oxazol-
2-
yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 2
stereoisomers) and (cis)-ethyl 442-chloro-3,4-difluoropheny0-(44442-ethoxy-2-
oxoethyl)oxazol-2-yl)cydohexy0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
(a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
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synthesized.
VII-23-M: LC-MS (ESI): RT = 3.140 min, mass calcd. for C29H29C1F2N405S 618.2,
m/z
found 619.1 [M+1-11 . 1H NMR (400 MHz, DMSO-d6) 6 9.54 (d, J= 2.8 Hz, 0.6H),
8.98
(s, 0.4H), 8.00 (d, J= 3.6 Hz, 0.6H), 7.99 (s, 1H), 7.95 (d, J= 3.2 Hz, 0.4H),
7.84 (d, J
= 4.4 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.23 - 7.17 (m, 1H), 6.03 (s, 0.4H), 5.93
(d, J= 3.6
Hz, 0.6H), 4.13 - 4.08 (m, 2H), 4.01 - 3.94 (m, 2H), 3.93 - 3.86 (m, 0.4H),
3.68 - 3.61
(m, 0.6H), 3.57 (s, 2H), 3.01 - 2.92 (m, 0.4H), 2.83 - 2.76 (m, 0.6H), 2.20 -
2.10 (m,
2H), 2.06 - 1.68 (m, 4H), 1.61 - 1.47 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H) , 1.10 -
1.03 (m,
3H).
VII-23-N: LC-MS (ESI): RT = 3.644 min, mass calcd. for C29H29C1F2N405S 618.2,
m/z
found 619.1 [M+1-11 . 1H NMR (400 MHz, DMSO-d6) 69.48 (d, J= 3.6 Hz, 0.7H),
8.41
(s, 0.3H), 7.97 - 7.90 (m, 3H), 7.48 - 7.40 (m, 1H), 7.19 - 7.14 (m, 1H), 6.03
(s, 0.3H),
5.90 (d, J= 3.6 Hz, 0.7H), 4.12 - 4.04 (m, 2H), 4.01 - 3.94 (m, 2H), 3.97 -
3.94 (m,
0.3H), 3.72 - 3.66 (m, 1.4H), 3.61 (s, 1.3H), 3.28 - 3.26 (m, 0.3H), 3.19 -
3.15 (m, 0.7H),
2.36 - 2.22 (m, 2H), 1.98 - 1.69 (m, 4.7H), 1.64 - 1.59 (m, 0.7H), 1.46 - 1.41
(m, 0.6H),
1.19- 1.13 (m, 3H), 1.10- 1.04(m, 3H).
A stereoisomeric mixture of (trans)- ethyl 4-(2-chloro-3,4-difluoropheny1)-4-
(4-(2-
ethoxy-2-oxoethyl)oxazol-2-yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate VII-23-M (400 mg, 0.647 mmol) was separated by chiral Prep. HPLC
(Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 40:
60 : 0.2 at 25 mL/min; Temp: 30 C; Wavelength: 254 nm) to give the title
compounds
VII-23-X (150 mg, 38 % yield, 99.8 % purity, 100 % stereopure) and VII-23-Y
(150 mg,
38 % yield, 99.9 % purity, 100 % stereopure) as yellow solids.
VII-23-X: LC-MS (ESI): RT = 4.463 min, mass calcd. for C29H29C1F2N405S 618.2,
m/z
found 618.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 40 : 60 : 0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 6.153 min). 1H NMR (400 MHz, DMSO-d6) 6 9.54 (d, J=
3.2 Hz, 0.6H), 8.98 (s, 0.4H), 8.01 - 8.00 (m, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H), 7.85 (d,
J= 4.4 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.23 - 7.17 (m, 1H), 6.03 (s, 0.4H), 5.93
(d, J=
3.6 Hz, 0.6H), 4.13 - 4.08 (m, 2H), 4.01 - 3.94 (m, 2H), 3.93 - 3.86 (m,
0.4H), 3.68 -
3.61 (m, 0.6H), 3.57 (s, 2H), 3.00 - 2.93 (m, 0.4H), 2.83 - 2.77 (m, 0.6H),
2.19 - 2.10 (m,
2H), 2.03 - 1.50 (m, 6H), 1.20 (t, J= 7.2 Hz, 3H) , 1.10 - 1.04 (m, 3H).
VII-23-Y: LC-MS (ESI): RT = 4.466 min, mass calcd. for C29H29C1F2N4055 618.2,
m/z
found 618.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 40 : 60 : 0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 9.894 min). 1H NMR (400 MHz, DMSO-d6) 6 9.54 (d, J=
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3.6 Hz, 0.6H), 8.98 (s, 0.4H), 8.01 - 8.00 (m, 1.6H), 7.95 (d, J= 3.6 Hz,
0.4H), 7.85 (d,
J= 4.0 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.23 - 7.17 (m, 1H), 6.03 (s, 0.4H), 5.93
(d, J=
3.6 Hz, 0.6H), 4.10 (q, J= 7.2 Hz, 2H), 4.01 - 3.94 (m, 2H), 3.93 - 3.87 (m,
0.4H), 3.67
- 3.60 (m, 0.6H), 3.57 (s, 2H), 2.99 - 2.93 (m, 0.4H), 2.83 - 2.76 (m, 0.6H),
2.18 - 2.10
(m, 2H), 2.04 - 1.67 (m, 4H), 1.61 - 1.46 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H) ,
1.10 - 1.03
(m, 3H).
Compound VII-24-M:
(trans)-ethyl 442-chloro-3,4-difluoropheny1)-644-(443-methoxy-3-
oxopropyDoxazol-2-
yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediate VII-24-R:
(trans)-Ethyl 442-chloro-3,4-difLuoropheny1)-6-(444-0-methoxy-3-
oxopropyDoxazol-
2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 3.193 min, mass calcd. for C29H29C1F2N405S 618.2, m/z found
mass 619.1 [M+111 . 11I NMR (400 MHz, DMSO-d6) 6 9.55 - 9.54(d, J4.0 Hz,
0.6H),
8.98 (s, 0.4H), 8.00 - 7.95 (m, 2H), 7.71 - 7.70 (d, J= 4.0 Hz, 1H), 7.50 -
7.43 (m, 1H),
7.22 - 7.17 (m, 1H), 6.03 (s, 0.4H), 5.93 (d, J= 3.6 Hz, 0.6H), 3.99 (q, J=
7.2 Hz, 2H),
3.87 - 3.78 (m, 0.6H), 3.67 - 3.64 (m, 0.4H), 3.60 (s, 3H), 2.97 - 2.91 (m,
0.4H), 2.79 -
2.74 (m, 0.6H), 2.70 - 2.68 (m, 2H), 2.63 - 2.59 (m, 2H), 2.16 - 2.10 (m, 2H),
1.97 -
1.86 (m, 2H), 1.81 - 1.66 (m, 2H) 1.57 - 1.46 (m, 2H), 1.10 - 1.03 (m, 3H).
A stereoisomeric mixture of VII-24-R (396 mg, 0.640 mmol) was separated by
chiral
Prep. SFC (Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: CO2 : Me0H =
60 : 40 at 50 g/min; Temp: 30 C; Wavelength: 230 nm; Back pressure: 100 bar)
to
give the title compounds VII-24-M (80 mg, 20 % yield, 100 % stereopure) and
VII-24-
N (90 mg, 23 % yield, 100 % stereopure) as yellow solids.
VII-24-M: LC-MS (ESI): RT = 4.857 min, mass calcd. for C29H29C1F2N405S 618.2,
m/z
found mass 619.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 *
250
mm; Mobile Phase: CO2: Et0H = 60 : 40 at 3.0 g/min; Col. Temp: 40 C;
Wavelength:
230 nm, Back pressure: 100 bar, RT = 3.92 min). 111 NMR (400 MHz, CD30D) 6
7.93
(d, J= 3.2 Hz, 0.6H), 7.89 (d, J= 2.8 Hz, 0.4H), 7.76 - 7.74 (m, 1H), 7.55 (d,
J= 4.8
Hz, 1H), 7.25 - 7.20 (m, 2H), 6.15 (s, 0.6H), 6.08 (s, 0.4H), 4.06 - 4.03 (m,
2H), 4.03 -
4.02 (m, 0.6H), 3.84 - 3.76 (m, 0.4H), 3.67 (s, 3H), 2.98 - 2.92 (m, 0.6H),
2.88 - 2.85 (m,
0.4H), 2.81 (t, J= 7.6 Hz, 2H), 2.66 (t, J= 7.6 Hz, 2H), 2.29 - 2.15 (m, 2H),
2.12 - 1.97
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(m, 211), 1.94 - 1.79 (m, 211), 1.76 - 1.65 (m, 211), 1.17 - 1.12 (m, 311).
VII-24-N: LC-MS (ESI): RT = 4.860 min, mass calcd. for C291129C1F2N405S 618.2,
m/z
found mass 619.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250
mm; Mobile Phase: CO2 Et0H = 60 : 40 at 3.0 g/min; Col. Temp: 40 C;
Wavelength:
230 nm, Back pressure: 100 bar, RT = 6.65 min). 1H NMR (400 MHz, CD30D) 6 7.93
(d, J= 3.2 Hz, 0.611), 7.89 (d, J= 2.8 Hz, 0.411), 7.76 - 7.74 (m, 111), 7.55
(d, J= 4.8
Hz, 111), 7.27 - 7.18 (m, 211), 6.15 (s, 0.611), 6.08 (s, 0.411), 4.08 - 4.04
(m, 211), 4.03 -
4.02 (m, 0.511), 3.85 - 3.76 (m, 0.511), 3.67 (s, 311), 2.98 - 2.95 (m,
0.611), 2.89 - 2.84 (m,
0.411), 2.81 (t, J= 7.6 Hz, 211), 2.66 (t, J= 7.6 Hz, 211), 2.29 - 2.15 (m,
211), 2.12 - 1.97
(m, 211), 1.94 - 1.88 (m, 211), 1.79 - 1.65 (m, 211), 1.17 - 1.12 (m, 311).
Compound VII-25-N:
(trans)-Methyl 442-chloro-3,4-difluoropheny1)-644-(443-ethoxy-2,2-dimethyl-3-
oxopropy0oxazol-2-0cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a single stereoisomer)
Intermediate VII-25-7:
(trans)-Methyl 442-chloro-3,4-difluoropheny0-644-(443-ethoxy-2,2-dimethyl-3-
oxopropy0oxazol-270cydohexyl)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.10 min, mass calcd. for C311133C1F2N405S 646.2, m/z found
646.9 [M+1-11 . 1H NMR (400 MHz, CDC13) 6 8.18 (s, 0.611), 7.83 (d, J= 3.2 Hz,
111),
7.51 (d, J= 3.2 Hz, 0.411), 7.46 (d, J= 3.2 Hz, 0.611), 7.38 (s, 0.411), 7.28
(s, 111), 7.11
- 6.99 (m, 211), 6.19 (s, 0.611), 6.05 (d, J= 2.8 Hz, 0.411), 4.14 (q, J= 6.8
Hz, 211), 4.04
- 4.00 (m, 0.611), 3.85 - 3.78 (m, 0.411), 3.63 (s, 111), 3.60 (s, 211), 2.90 -
2.81 (m, 111),
2.77 - 2.76 (m, 211), 2.31 - 2.07 (m, 311), 2.05 - 1.98 (m, 111), 1.90 - 1.69
(m, 311), 1.66 -
1.52 (m, 111), 1.28 - 1.23 (m, 911).
A stereoisomeric mixture of (trans)- methyl 4-(2-chloro-3,4-difluoropheny1)-6-
(4-(4-(3-
ethoxy-2,2-dimethy1-3-oxopropyl)oxazol-2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate VII-25-7 (500 mg, 90 % purity, 0.695 mmol) was
separated by chiral Prep. HPLC (Column: Chiralpak IE 5 pm 20 * 250 mm; Mobile
Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 10 mL/min; Temp: 30 C; Wavelength:
230 nm) to give the title compounds VIE-25-M (200 mg, 90 % purity, 40 % yield,
100 %
stereopure) and VII-25-N (210 mg, 90 % purity, 42 % yield, 100 % stereopure)
as
yellow solids.
VII-25-M: Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm; Mobile
Phase:
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Hex : Et0H : DEA = 80 : 20 : 0.2 at 1.0 mLimin; Temp: 30 C; Wavelength: 230
nm,
RT = 8.385 min). 111 NMR (400 MHz, DMSO-d6) 6 9.60 (d, J= 3.6 Hz, 0.6H), 9.06
(s,
0.4H), 8.01 (s, 1.6H), 7.96 - 7.95 (m, 0.4H), 7.67 - 7.66 (m, 1H), 7.50 - 7.43
(m, 1H),
7.24 - 7.13 (m, 1H), 6.02 (s, 0.4H), 5.93 (d, J= 3.6 Hz, 0.6H), 4.06 (q, J=
7.2 Hz, 2H),
3.93 - 3.86 (m, 0.5H), 3.68 - 3.61 (m, 0.5H), 3.53 (s, 1.8H), 3.52 (s, 1.2H),
2.97 - 2.89
(m, 0.5H), 2.79 - 2.72 (m, 0.5H), 2.66 (s, 2H), 2.19 - 1.45 (m, 8H), 1.20 -
1.14 (m, 9H).
VII-25-N: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA = 80 : 20 : 0.2 at 1.0 mLimin; Temp: 30 C; Wavelength: 230
nm,
RT = 10.968 min). 111 NMR (400 MHz, DMSO-d6) 6 9.60 (d, J= 3.2 Hz, 0.6H), 9.06
(s,
0.4H), 8.01 (s, 1.5H), 7.96 - 7.95 (m, 0.5H), 7.67 - 7.66 (m, 1H), 7.51 - 7.43
(m, 1H),
7.26 - 7.13 (m, 1H), 6.02 (s, 0.4H), 5.93 (d, J= 3.6 Hz, 0.6H), 4.06 (q, J=
7.2 Hz, 2H),
3.94 - 3.85 (m, 0.5H), 3.70 - 3.60 (m, 0.5H), 3.53 (s, 1.8H), 3.52 (s, 1.2H),
3.00 - 2.89
(m, 0.5H), 2.83 - 2.72 (m, 0.5H), 2.66 (s, 2H), 2.15 - 1.46 (m, 8H), 1.20 -
1.14 (m, 9H).
Compound VII-26-8:
(trans)-Ethyl 2444642-chloro-3,4-difluoropheny1)-5-(ethoxycarbonyl)-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyDoxazole-5-carboxylate (a single
stereoisomer)
Intermediates WI-26-5 and WI-26-6:
(trans)-Ethyl 2-(44642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony0-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyDoxazole-5-carboxylate (a mixture of 2
stereoisomers) and (cis)-ethyl 2444642-chloro-3,4-difluoropheny1)-5-
(ethoxycarbony0-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-371)cyclohexypoxazole-
5-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
VII-26-5: 111 NMR (400 MHz, DMSO-d6) 6 9.58 - 9.53 (m, 0.7H), 9.00 (s, 0.3H),
8.02 -
7.92 (m, 2H), 7.90 (d, J= 2.8 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.24 - 7.18 (m,
1H), 6.04 -
6.03 (m, 0.4H), 5.95 - 5.90 (m, 0.6H), 4.32 (q, J= 6.8 Hz, 2H), 4.02 - 3.96
(m, 2H),
3.94- 3.87 (m, 0.4H), 3.72- 3.63 (m, 0.6H), 3.15- 3.07 (m, 0.4H), 2.98 - 2.91
(m,
0.6H), 2.23 - 2.04 (m, 2H), 1.99- 1.47 (m, 6H), 1.30 (t, J= 6.8 Hz, 3H), 1.10-
1.03 (m,
3H).
VII-26-6:111 NMR (400 MHz, DMSO-d6) 6 9.53 (d, J= 3.2 Hz, 0.7H), 8.63 (s,
0.3H),
8.01- 7.93 (m, 3H), 7.49- 7.41 (m, 1H), 7.19- 7.16 (m, 1H), 6.04 (s, 0.3H),
5.91 (d, J=
3.6 Hz, 0.7H), 4.34 (q, J= 7.2 Hz, 2H), 4.01- 3.95 (m, 2H), 3.92 - 3.86 (m,
0.3H), 3.75
.. - 3.69 (m, 0.7H), 3.42 - 3.35 (m, 0.3H), 3.33 - 3.27 (m, 0.7H), 2.40 - 2.33
(m, 2H), 1.96
- 1.75 (m, 4H), 1.70- 1.47 (m, 2H), 1.31 (t, J= 6.8 Hz, 3H), 1.11- 1.05 (m,
3H).
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A stereoisomeric mixture of (trans)- ethyl 2-(4-(6-(2-chloro-3,4-
difluoropheny1)-5-
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)oxazole-
5-
carboxylate VII-26-5 (220 mg, 95 % purity, 0.345 mmol) was separated by chiral
Prep. HPLC (Column: Chiralpak IE 5 pm 20 * 250 mm, Mobile Phase: Hex : Et0H :
DEA = 70 : 30 : 0.3 at 15 mL/min, Temp: 30 C, Wavelength: 230 nm) to afford
the
title compounds VII-26-7 (100 mg, 96 % purity from 11-1 NMR, 46 % yield, 100 %
stereopure), VII-26-8 (98 mg, 97 % purity from 11-1 NMR, 45 % yield, 98.7 %
stereopure) as yellow solid.
VII-26-7: LC-MS (ESI): RT = 1.98 min, mass calcd. for C281-127C1F2N405S 604.1,
m/z
found 604.8 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 pm 4.6 * 250 mm,
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1.0 mL/min, Temp: 30 C,
Wavelength: 230 nm, RT = 9.657 min). 11-1 NMR (400 MHz, CD30D) 6 7.93 (d, J=
3.2
Hz, 0.5H), 7.89 (d, J= 3.2 Hz, 0.5H), 7.76 - 7.74 (m, 2H), 7.28 - 7.19 (m,
2H), 6.15 (s,
0.6H), 6.09 (s, 0.4H), 4.37 (q, J= 7.2 Hz, 2H), 4.11 - 4.02 (m, 2.6H), 3.85 -
3.78 (m,
0.4H), 3.12 - 2.93 (m, 1H), 2.36 - 2.22 (m, 2H), 2.15 - 1.71 (m, 6H), 1.37 (t,
J= 6.8 Hz,
3H), 1.17- 1.12 (m, 3H).
VII-26-8: LC-MS (ESI): RT = 1.98 min, mass calcd. for C281-127C1F2N405S 604.1,
m/z
found 604.8 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 pm 4.6 * 250 mm,
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1.0 mL/min, Temp: 30 C,
Wavelength: 230 nm, RT = 11.066 min). 11-1 NMR (400 MHz, CD30D) 6 7.93 (d, J=
3.2 Hz, 0.5H), 7.89 (d, J= 2.8 Hz, 0.5H), 7.76 - 7.74 (m, 2H), 7.28 - 7.19 (m,
2H), 6.15
(s, 0.6H), 6.08 (s, 0.4H), 4.37 (q, J= 7.2 Hz, 2H), 4.11 - 4.02 (m, 2.5H),
3.86 - 3.77 (m,
0.5H), 3.11 - 2.92 (m, 1H), 2.36 - 2.22 (m, 2H), 2.15 - 1.66 (m, 6H), 1.37 (t,
J= 7.2 Hz,
3H), 1.17- 1.12 (m, 3H).
Compound VII-27-R:
(trans)-Ethyl 442-chloro-3,4-difluoropheny1)-6-(444-(1-ethoxy-2-methyl-1-
oxopropan-
270oxazol-271)cydohexyl)-2-(thiazol-270-1,4-dihydropyrimidine-5-carboxylate (a
mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 2.274 min, mass calcd. for C29H28C1F2N504S 646.2, m/z found
647.1 [M+Hl .
Compound VII-28-N:
(trans)-ethyl 4(2-chloro-3,4-difluoropheny1)-6(4-(142-ethoxy-2-oxoethyl)-1H
pyrazol-471)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single stereoisomer)
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Intermediate VII-28-R:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(4-(142-ethoxy-2-oxoethyl)-1H-pyrazol-4-
y1)cydohexyl)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 2.136 min, mass calcd. for C29H30C1F2N504S 617.2, m/z found
618.1 [M+Hi .
The stereoisomeric mixture of VII-28-R (800 mg, 1.29 mmol) was separated by
chiral
Prep. HPLC (the first separation condition: Column: Chiralpak IE (5 i.tm 20 *
250
mm); Mobile Phase: Hex: Et0H: DEA= 60 : 40 : 0.3 at 11 mL/ min; Temp: 30 C;
Wavelength: 214 nm; the second separation condition: Column: Chiralpak IG (5
i.tm
* 250 mm); Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.3 at 15 mL/ min; Temp:
C; Wavelength: 230 nm) to afford VII-28-M (184 mg, 23 % yield, 96.9 %
15 stereopure), VII-28-N (123 mg, 15 % yield, 99.7 % stereopure) VIE-28-P
(143 mg, 18 %
yield, 100 % stereopure) and VII-28-Q (120 mg, 15 % yield, 96.4 % stereopure)
as
yellow solids.
VII-28-M: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA= 50: 50 : 0.2 at 1 mL/ min; Temp: 30 C; Wavelength: 230 nm;
RT
20 .. = 8.072 min). 111 NMR (400 MHz, DMSO-d6) 6 9.54 (d, J= 3.6 Hz, 0.6H),
8.93 (s,
0.4H), 8.01 - 8.00 (m, 1.6H), 7.96 (d, J= 3.2 Hz, 0.4H), 7.55 (d, J= 5.2 Hz,
1H), 7.51 -
7.46 (m, 1H), 7.38 (s, 1H), 7.23 - 7.18 (m, 1H), 6.04 (s, 0.4H), 5.93 (d, J=
2.8 Hz,
0.6H), 4.98 (d, J= 2.0 Hz, 2H), 4.15 - 4.10 (m, 2H), 4.01 - 3.94 (m, 2H), 3.89
- 3.85 (m,
0.4H), 3.70 - 3.65 (m, 0.6H), 2.67 - 2.64 (m, 0.4H), 2.44 - 2.39 (m, 0.6H),
2.06 - 1.81
25 (m, 5.4H), 1.67 - 1.64 (m, 0.6H), 1.45 - 1.34 (m, 2H), 1.23 - 1.19 (m,
3H), 1.10 - 1.05
(m, 3H).
VII-28-N: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA= 50: 50 : 0.2 at 1 mL/ min; Temp: 30 C; Wavelength: 230 nm;
RT
= 10.392 min). 111 NMR (400 MHz, DMSO-d6) 6 9.54 (d, J= 3.6 Hz, 0.6H), 8.93
(s,
30 0.4H), 8.01 - 7.99 (m, 1.6H), 7.96 (d, J= 3.2 Hz, 0.4H), 7.55 (d, J= 5.2
Hz, 1H), 7.50 -
7.43 (m, 1H), 7.38 (s, 1H), 7.23 - 7.18 (m, 1H), 6.04 (s, 0.4H), 5.93 (d, J=
3.6 Hz,
0.6H), 4.98 (d, J= 2.0 Hz, 2H), 4.14 (q, J= 7.2 Hz, 2H), 4.01 - 3.94 (m, 2H),
3.89 -
3.80 (m, 0.4H), 3.70 - 3.62 (m, 0.6H), 2.67 - 2.61 (m, 0.5H), 2.47 - 2.40 (m,
0.5H), 2.06
- 1.80 (m, 5.4H), 1.68 - 1.63 (m, 0.6H), 1.44 - 1.34 (m, 2H), 1.21 (t, J= 7.2
Hz, 3H),
.. 1. 10 - 1.03 (m, 3H).
VII-28-P: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
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Hex : Et0H : DEA= 80 : 20 : 0.2 at 1 mL/ min; Temp: 30 C; Wavelength: 254 nm;
RT
= 10.892 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.50 (hr s, 0.7H), 8.37 (s,
0.3H), 7.99
- 7.94 (m, 2H), 7.70 (s, 0.3H), 7.66 (s, 0.7H), 7.51 (s, 1H), 7.49 - 7.41 (m,
1H), 7.21 -
7.17 (m, 1H), 6.03 (s, 0.3H), 5.91 (s, 0.7H), 5.04 (s, 2H), 4.14 (q, J= 7.2
Hz, 2H), 4.01
- 3.94 (m, 2H), 3.87 - 3.81 (m, 0.3H), 3.76 - 3.70 (m, 0.7H), 3.07 - 3.03 (m,
0.3H), 3.01
- 2.97 (m, 0.7H), 2.10 - 1.59 (m, 7.4H), 1.43 - 1.39 (m, 0.6H), 1.22 - 1.17
(m, 3H), 1.09
- 1.06 (m, 3H).
VII-28-Q: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA= 80 : 20 : 0.2 at 1 mL/ min; Temp: 30 C; Wavelength: 254 nm;
RT = 13.657 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.54 (d, J= 3.2 Hz, 0.7H),
8.37 (s,
0.3H), 7.99 - 7.94 (m, 2H), 7.70 (s, 0.3H), 7.65 (s, 0.7H), 7.50 (s, 1H), 7.49
- 7.40 (m,
1H), 7.20 - 7.16 (m, 1H), 6.03 (s, 0.3H), 5.91 (d, J= 3.6 Hz, 0.7H), 5.04 (s,
1.4H), 5.03
(s, 0.6H), 4.14 (q, J= 7.2 Hz, 2H), 4.00 - 3.97 (m, 211), 3.88 - 3.82 (m,
0.3H), 3.75 -
3.69 (m, 0.7H), 3.07 - 3.03 (m, 0.3H), 3.01 - 2.97 (m, 0.7H), 2.09 - 1.58 (m,
7.3H), 1.42
- 1.39 (m, 0.7H), 1.21 - 1.17 (m, 3H), 1.10 - 1.06 (m, 3H).
Compound VII-29-P:
(trans)-Methyl 4-(2-chloro-4-fluoropheny1)-6-(4-(1-(3-methoxy-3-oxopropyl)-1H
pyrazol-4-ypcydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single stereoisomer)
.. Intermediate WI-29-5:
Methyl 442-chloro-4-fluoropheny1)-644-(143-methoxy-3-oxopropy0-1H-pyrazol-4-
y1)cydohexyl)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 1.87 min, mass calcd. for C281-129C1FN504S 585.2, m/z found
585.9
[M+1-11 . 1H NMR (400 MHz, DMSO-d6) 6 9.44 (d, J= 3.2 Hz, 0.6H), 8.93 (s,
0.2H),
8.38 (s, 0.2H), 8.01 - 7.95 (m, 2H), 7.69 (s, 0.2H), 7.63 (s, 0.5H), 7.54-
7.53 (m, 0.3H),
7.45- 7.31 (m, 3H), 7.24- 7.16 (m, 1H), 6.02 - 6.01 (m, 0.3H), 5.92 - 5.89 (m,
0.7H),
4.36- 4.26 (m, 2H), 3.92 - 3.66 (m, 1H), 3.59 (d, J= 7.6 Hz, 3H), 3.53 (s,
3H), 3.02 -
2.96 (m, 1H), 2.90 - 2.84 (m, 2H), 2.12- 1.54 (m, 7H), 1.39- 1.36 (m, 1H).
A stereoisomeric mixture of methyl 4-(2-chloro-4-fluoropheny1)-6-(4-(1-(3-
methoxy-3-
oxopropy1)-1H-pyrazol-4-y1)cyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-
5-
carboxylate WI-29-5 (350 mg, 0.579 mmol) was separated by chiral Prep. HPLC
(Column: Chiralpak IE 5 pm 20 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 50:
50 : 0.3 at 15 mL/min; Temp: 30 C; Wavelength: 230 nm) to give the title
compounds
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Group 1 (200 mg, 29 % yield), VII-29-P (40 mg, 95 % purity from 1H NMR, 11 %
yield,
99.7 % stereopure) and VII-29-Q (40 mg, 95 % purity from NMR, 11 % yield, 99.6
%
stereopure) as yellow solids. Group 1 (200 mg, 0.34 mmol) was separated by
chiral
Prep. HPLC (Column: Chiralpak OJ-H 5 pm 50 *250 mm; Mobile Phase: Me0H :
DEA = 100 : 0.1 at 60 mL/min; Temp.: 35 C; Wavelength: 254 nm) to afford the
title
compounds VII-29-M (80 mg, 99 % purity, 42 % yield, 100 % stereopure) and VII-
29-
N (80 mg, 99 % purity, 42 % yield, 99.9 % stereopure).
VII-29-M: LC-MS (ESI): RT = 1.974 min, mass calcd. for C281129C1FN504S 585.2,
m/z
found 586.1 [M+Hi . Chiral analysis (Column: Chiralpak OJ-H 5 pm 4.6 * 250 mm;
Mobile Phase: Me0H : DEA= 100 : 0.2 at 1 mL/min; Temp.: 30 C; Wavelength: 230
nm, RT = 5.320 mm). 'H NMR (400 MHz, CDC13) 6 8.07 (s, 0.5H), 7.81 (d, J= 3.2
Hz,
0.4H), 7.78 (d, J= 3.2 Hz, 0.6H), 7.56 (s, 0.6H), 7.49 (d, J= 3.2 Hz, 0.4H),
7.47 - 7.45
(m, 1H), 7.41 (d, J= 3.6 Hz, 0.5H), 7.37 (s, 1H), 7.31 - 7.27 (m, 0.7H), 7.24
(s, 0.3H),
7.14- 7.10 (m, 1H), 6.95 - 6.86 (m, 1H), 6.17 (s, 0.6H), 6.04 (d, J= 2.8 Hz,
0.4H), 4.47
- 4.42 (m, 2H), 4.05 - 3.99 (m, 0.6H), 3.92 - 3.85 (m, 0.4H), 3.67 (s, 3H),
3.61 - 3.59 (m,
3H), 3.11 (s, 0.6H), 3.05 (s, 0.4H), 2.98 - 2.92 (m, 2H), 2.19 - 2.14 (m,
1.6H), 2.06 -
1.80 (m, 3.4H), 1.76 - 1.69 (m, 2H), 1.60 - 1.48 (m, 1H).
VII-29-N: LC-MS (ESI): RT = 1.973 min, mass calcd. for C281129C1FN504S 585.2,
m/z
found 586.1 [M+Hi . Chiral analysis (Column: Chiralpak OJ-H 5 pm 4.6 * 250 mm;
Mobile Phase: Me0H : DEA= 100 : 0.2 at 1 mL/min; Temp.: 30 C; Wavelength: 230
nm, RT = 6.864 min). 1H NMR (400 MHz, CDC13) 6 8.07 (s, 0.5H), 7.81 (d, J= 2.8
Hz,
0.4H), 7.78 (d, J= 2.8 Hz, 0.6H), 7.56 (s, 0.6H), 7.49 (d, J= 2.8 Hz, 0.4H),
7.47 - 7.45
(m, 1H), 7.41 (d, J= 3.2 Hz, 0.5H), 7.37 (s, 1H), 7.31 - 7.27 (m, 0.7H), 7.24
(s, 0.3H),
7.14- 7.10 (m, 1H), 6.95 - 6.86 (m, 1H), 6.17 (s, 0.6H), 6.04 (d, J= 2.8 Hz,
0.4H), 4.47
- 4.43 (m, 2H), 4.06 - 3.98 (m, 0.6H), 3.92 - 3.85 (m, 0.4H), 3.67 (s, 3H),
3.61 - 3.59 (m,
3H), 3.11 (s, 0.6H), 3.05 (s, 0.4H), 2.97 - 2.92 (m, 2H), 2.19 - 2.12 (m,
1.6H), 2.03 -
1.84 (m, 3.4H), 1.76 - 1.67 (m, 2H), 1.61 - 1.48 (m, 1H).
VII-29-P: LC-MS (ESI): RT = 1.83 min, mass calcd. for C281129C1FN504S 585.2,
m/z
found 585.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/min; Temp.: 30 C;
Wavelength: 230 nm, RT = 9.064 min). 1H NMR (400 MHz, DMSO-d6) 6 9.44 (d, J=
3.2Hz, 0.6H), 8.92 (s, 0.4H), 8.01 - 7.98 (m, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H), 7.53 (d,
J= 5.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.38 - 7.33 (m, 2H), 7.24 - 7.19 (m, 1H),
6.02 (s,
0.4H), 5.91 (d, J= 3.2 Hz, 0.6H), 4.30 - 4.26 (m, 2H), 3.93 - 3.84 (m, 0.4H),
3.69 - 3.60
(m, 3.6H), 3.52 (d, J= 4.8 Hz, 3H), 2.87 - 2.83 (m, 2H), 2.68 - 2.55 (m,
0.6H), 2.46 -
2.43 (m, 0.4H), 2.05 - 1.74 (m, 5.4H), 1.65 - 1.61 (m, 0.6H), 1.44 - 1.30 (m,
2H).
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VII-29-Q: LC-MS (ESI): RT = 1.83 min, mass calcd. for C281129C1FN504S 585.2,
m/z
found 585.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/min; Temp.: 30 C;
Wavelength: 230 nm, RT = 12.766 min). 1H NMR (400 MHz, DMSO-d6) 6 9.44 (d, J=
3.2Hz, 0.6H), 8.92 (s, 0.4H), 8.01 - 7.98 (m, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H), 7.53 (d,
J= 5.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.38 - 7.33 (m, 2H), 7.24 - 7.19 (m, 1H),
6.02 (s,
0.4H), 5.91 (d, J= 3.2 Hz, 0.6H), 4.30 - 4.26 (m, 2H), 3.93 - 3.84 (m, 0.4H),
3.69 - 3.60
(m, 3.6H), 3.52 (d, J= 4.8 Hz, 3H), 2.87 - 2.83 (m, 2H), 2.68 - 2.55 (m,
0.6H), 2.46 -
2.43 (m, 0.4H), 2.05 - 1.74 (m, 5.4H), 1.65 - 1.61 (m, 0.6H), 1.44 - 1.30 (m,
2H).
.. Compound VII-30-10:
(trans)-Ethyl 442-chloro-3,4-difluoropheny1)-6-(4-(1-(4-methoxy-2-methyl-4-
oxobutan-2-y1)-1H-pyrazol-4-yDcydohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate (a single stereoisomer)
Intermediates VII-30-5 and VII-30-6:
(cis)-Ethyl 442-chloro-3,4-difluoropheny0-6-(4-(144-methoxy-2-methyl-4-
oxobutan-
2-y0-1H-pyrazol-4-yDcydohexy0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-
carboxylate (a mixture of 2 stereoisomers) and
(trans)-ethyl 442-chloro-3,4-difluoropheny1)-644-(144-methoxy-2-methyl-4-
oxobutan-2-y1)-1H-pyrazol-4-ypcydohexy0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-
5-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-30-5: LC-MS (ESI): RT = 2.327 min, mass calcd. for C311134C1F2N504S 645.2,
m/z
found 646.1 [M+111 . 1H NMR (400 MHz, CDC13) 68.08 (s, 0.7H), 7.81 (d, J= 3.2
Hz,
0.3H), 7.74 (d, J= 3.2 Hz, 0.7H), 7.56 (s, 0.3H), 7.49 - 7.46 (m, 2H), 7.41
(d, J= 3.2
Hz, 0.7H), 7.30 - 7.28 (s, 0.3H), 7.10 - 6.97 (m, 2H), 6.18 (s, 0.7H), 6.06
(d, J= 2.8 Hz,
0.3H), 4.11 - 3.97 (m, 2.8H), 3.91 - 3.83 (m, 0.2H), 3.58 (s, 0.6H), 3.57 (s,
2.4H), 3.15 -
3.10 (m, 0.8H), 3.07 - 3.02 (m, 0.2H), 2.96 (s, 1.6H), 2.93 (s, 0.4H), 2.22 -
2.09 (m, 2H),
2.04 - 1.92 (m, 2.7H), 1.89 - 1.81 (m, 1.3H), 1.78 (s, 4.4H), 1.75 (s, 1.6H),
1.74 - 1.65
(m, 2H), 1.17 - 1.13 (m, 3H).
VII-30-6: LC-MS (ESI): RT = 2.167 min, mass calcd. for C311134C1F2N5045 645.2,
m/z
found 646.1 [M+111 . 1H NMR (400 MHz, CDC13) 68.19 (s, 0.8H), 7.83 (d, J= 3.6
Hz,
1H), 7.52 - 7.49 (m, 0.2H), 7.46 (d, J= 3.2 Hz, 0.8H), 7.43 - 7.41 (m, 1H),
7.33 (s,
1.2H), 7.13 - 6.99 (m, 2H), 6.21 (s, 0.7H), 6.08 (d, J= 2.0 Hz, 0.3H), 4.12 -
3.95 (m,
2.8H), 3.83 - 3.76 (m, 0.2H), 3.58 (s, 3H), 2.89 (s, 2H), 2.66 - 2.55 (m, 1H),
2.18 - 1.92
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(m, 4H), 1.86 - 1.75 (m, 0.7H), 1.71 - 1.68 (m, 6.3H), 1.65 - 1.63 (m, 0.4H),
1.61 - 1.46
(m, 2.6H), 1.14 (t, J= 6.8 Hz, 3H).
A stereoisomeric mixture of (trans)- ethyl 4-(2-chloro-3,4-difluoropheny1)-6-
(4-(1-(4-
metho
xy-2-methy1-4-oxobutan-2-y1)-1H-pyrazol-4-yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate VII-30-6 (265 mg, 90 % purity, 0.369 mmo0 was
separated by chiral Prep. HPLC (separation condition: Column: Chiralpak IC 5
pm
20 * 250 mm; Mobile Phase: Hex: Et0H : DEA= 80 : 20 : 0.1 at 60 mL/min; Temp:
35 C; Wavelength: 214 nm) to give the title compounds VII-30-9 (110 mg, 95 %
purity from 1H NMR, 44 % yield, 99.9 % stereopure) as yellow solids and the
title
compound VII-30-10 (80 mg, 95 % purity from 1H NMR, 32 % yield, 99.9 %
stereopure) as yellow solids.
VII-30-9: LC-MS (EST): RT = 2.156 min, mass calcd. for C311134C1F2N504S 645.2,
m/z
found 646.2 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/min; Wavelength: 230
nm,
RT = 13.343 min). 1H NMR (400 MHz, CDC13) 6 8.20 (s, 0.8H), 7.83 (d, J= 2.8
Hz,
1H), 7.51 (d, J= 3.2 Hz, 0.3H), 7.46 (d, J= 2.8 Hz, 0.7H), 7.44 (s, 0.3H),
7.41 (s,
0.7H), 7.33 - 7.32 (m, 1.2H), 7.13 - 6.98 (m, 2H), 6.21 (s, 0.7H), 6.08 (d, J=
2.0 Hz,
0.3H), 4.11 - 3.98 (m, 2.8H), 3.83 - 3.72 (m, 0.2H), 3.58 (s, 3H), 2.90 (s,
2H), 2.67 -
2.55 (m, 1H), 2.18 - 2.11 (m, 2.5H), 2.05 - 1.92 (m, 2.5H), 1.87 - 1.78 (m,
1H), 1.72 (s,
6H), 1.56 - 1.47 (m, 2H), 1.16 - 1.13 (m, 3H).
VII-30-10: LC-MS (EST): RT = 2.157 min, mass calcd. for C311134C1F2N504S
645.2, m/z
found 646.2 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 : 0.2 at 1 mL/min;; Wavelength: 230
nm,
RT = 15.752 min). 1H NMR (400 MHz, CDC13) 6 8.20 (s, 0.8H), 7.83 (d, J= 3.2
Hz,
1H), 7.51 (d, J= 2.8 Hz, 0.3H), 7.46 (d, J= 3.2 Hz, 0.7H), 7.43 (s, 0.3H),
7.41 (s,
0.7H), 7.33 - 7.31 (m, 1.2H), 7.13 - 6.98 (m, 2H), 6.21 (s, 0.7H), 6.08 (d, J=
2.0 Hz,
0.3H), 4.13 - 3.95 (m, 2.8H), 3.84 - 3.71 (m, 0.2H), 3.58 (s, 3H), 2.89 (s,
2H), 2.66 -
2.54 (m, 1H), 2.18 - 2.09 (m, 2.5H), 2.05 - 1.91 (m, 2H), 1.88 - 1.75 (m,
1.5H), 1.72 (s,
1.8H), 1.71 (s, 4.2H), 1.61 - 1.56 (m, 2H), 1.16 - 1.12 (m, 3H).
Compound VII-31:
Ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(4-(1-(4-methoxy-4-oxobutan-2-y1)- lif
pyrazol-4-yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
mixture of 8 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
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111 NMR (400 MHz, DMSO-d6) 6 9.55 - 9.53 (m, 0.511), 8.93 (s, 0.211), 8.28 -
8.27 (m,
0.311), 8.01 - 7.99 (m, 1.311), 7.96 - 7.94 (m, 0.411), 7.91 - 7.90 (m,
0.311), 7.74 - 7.73
(m, 0.211), 7.66 (s, 0.411), 7.59 - 7.58 (m, 0.411), 7.49 - 7.42 (m, 1.611),
7.32 (s, 0.411),
7.24- 7.16 (m, 111), 6.04- 6.02 (m, 0.411), 5.93 - 5.90 (m, 0.611), 4.78 -
4.64 (m, 111),
4.06 - 3.96 (m, 211), 3.89 - 3.82 (m, 0.411), 3.75 - 3.65 (m, 0.611), 3.56 -
3.53 (m, 311),
3.02 - 2.76 (m, 311), 2.13 - 1.54 (m, 711), 1.48 - 1.32 (m,411), 1.10 - 1.03
(m, 311).
Compound VII-32-N:
(trans)-ethyl 442-chloro-3,4-difluoropheny1)-644-(143-methoxy-3-oxopropy1)-1H-
pyrazol-4-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
single stereoisomer)
Compound VII-32:
ethyl 4-(2-chloro-3,4-difluoropheny1)-644-(143-methoxy-3-oxopropy1)-1H-pyrazol-
4-
y1)cydohexyl)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 2.803 min, mass calcd. for C29H30C1F2N504S 617.2, m/z found
618.1 [M+111 . 111 NMR (400 MHz, CDC13) 68.19 (s, 0.311), 8.06 (s, 0.311),
7.83 - 7.79
(m, 111), 7.56 - 7.36 (m, 2.511), 7.34 - 7.26 (m, 0.411), 7.24 (s, 0.511),
7.13 - 6.97 (m,
211), 6.21 (s, 0.311), 6.19 (s, 0.411), 6.08 - 6.06 (m, 0.311), 4.44 (q, J=
7.2 Hz, 111), 4.39
(q, J= 6.8 Hz, 111), 4.10 - 3.99 (m, 311), 3.70 (s, 111), 3.67 (s, 211), 3.11
(hr s, 0.411),
3.04 (hr s, 0.211), 2.96 (t, J= 6.4 Hz, 111), 2.90 (t, J= 6.8 Hz, 111), 2.64 -
2.55 (m,
0.411), 2.17 - 2.10 (m, 211), 2.03 - 1.84 (m, 311), 1.77 - 1.65 (m, 211), 1.57
- 1.46 (m, 111),
1.16- 1.12 (m, 311).
.. A stereoisomeric mixture of VII-32 (770 mg, 1.25 mmol) was separated by
chiral
Prep. HPLC (the first separation condition: Column: Chiralpak IA 5 gm 20 * 250
mm; Mobile Phase: Hex : Et0H : DEA = 60 : 40 : 0.2 at 25 mL/min; Temp: 30 C;
Wavelength: 214 nm) to afford the VII-32-F (170 mg, 22 % yield) and VII-32E
(280
mg, 36 % yield) as yellow solids.
A stereoisomeric mixture of VII-32-F (170 mg, 0.28 mmol) was separated by
chiral
Prep. HPLC (the second separation condition: Column: Chiralpak IE 5 gm 20 *
250
mm; Mobile Phase: Hex : Et0H : DEA = 40 : 60 : 0.2 at 10 mL/ min; Temp: 30 C;
Wavelength: 230 nm) to afford the VII-32-M (60 mg, 35 % yield, 100 %
stereopure)
and VII-32-N (29 mg, 29 % yield, 100 % stereopure);
Compound VII-32-F: LC-MS (ESI): RT = 2.760 min, mass calcd. for
C291130C1F2N504S
617.2, m/z found 618.2 [M+111 . 111 NMR (400 MHz, CDC13) 6 8.18 (s, 0.711),
7.82 (d,
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J= 3.2 Hz, 1H), 7.50 (d, J= 2.8 Hz, 0.3H), 7.45 (d, J= 3.2 Hz, 0.7H), 7.40 (s,
0.3H),
7.37 (s, 0.7H), 7.32 (s, 0.3H), 7.24 (s, 1H), 7.14 - 7.09 (m, 1H), 7.07 - 6.99
(m, 1H),
6.21 (s, 0.7H), 6.08 (d, J= 2.4 Hz, 0.3H), 4.38 (t, J= 6.4 Hz, 2H), 4.11 -
3.97 (m, 2.8H),
3.83 - 3.76 (m, 0.2H), 3.70 (s, 3H), 2.90 (t, J= 6.4 Hz, 2H), 2.64 - 2.55 (m,
1H), 2.17 -
2.01 (m, 4H), 1.92 - 1.65 (m, 1.5H), 1.59 - 1.44 (m, 2.5H), 1.16 - 1.12 (m,
3H).
Compound VII-32-E: LC-MS (ESI): RT = 4.450 min, mass calcd. for
C29H30C1F2N504S
617.2, m/z found 617.9 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 6 8.06 (s, 0.7H),
7.81 (d,
J= 2.8 Hz, 0.3H), 7.79 (d, J= 3.2 Hz, 0.7H), 7.56 (s, 0.3H), 7.50 (d, J= 3.2
Hz, 0.3H),
7.47 (s, 0.7H), 7.45 (s, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.36 (s, 0.7H),
7.28 (s, 0.3H),
7.12 - 6.97 (m, 1H), 6.19 (s, 0.7H), 6.06 (d, J= 2.4 Hz, 0.3H), 4.44(q, J= 6.8
Hz, 2H),
4.11 - 3.93 (m, 2.7H), 3.90 - 3.85 (m, 0.3H), 3.67 (s, 3H), 3.11 (s, 0.7H),
3.04 (s, 0.3H),
2.94 (q, J= 6.4 Hz, 2H), 2.17 - 2.12 (m, 1.5H), 2.06- 1.83(m, 3.5H), 1.76 -
1.61 (m,
2.5H), 1.56 -1.48 (m, 0.5H), 1.16 -1.12 (m, 3H).
Compound VII-32-M: LC-MS (ESI): RT = 3.872 min, mass calcd. for
C29H30C1F2N504S 617.2, m/z found 618.1 [M+1-11 . 1H NMR (400 MHz, CDC13) 68.22
(s, 0.7H), 7.87 - 7.86 (m, 1H), 7.54 (d, J= 3.2 Hz, 0.3H), 7.49 (d, J= 3.2 Hz,
0.7H),
7.44 (s, 0.3H), 7.42 (s, 0.7H), 7.35 (s, 0.3H), 7.28 (s, 1H), 7.18 - 7.13 (m,
1H), 7.11 -
7.03 (m, 1H), 6.25 (s, 0.7H), 6.12 (d, J= 3.2 Hz, 0.3H), 4.42 (t, J= 6.8 Hz,
2H), 4.15 -
4.02 (m, 2.8H), 3.88 - 3.79 (m, 0.2H), 3.74 (s, 3H), 2.94 (t, J= 6.8 Hz, 2H),
2.68 - 2.59
(m, 1H), 2.21 - 2.02 (m, 4H), 1.96 - 1.65 (m, 2H), 1.61 - 1.50 (m, 2H), 1.20 -
1.16 (m,
3H).
Compound VII-32-N: LC-MS (ESI): RT = 3.876 min, mass calcd. for
C29H30C1F2N504S
617.2, m/z found 618.1 [M+1-11 . 1H NMR (400 MHz, CDC13) 6 8.22 (s, 0.7H),
7.87 -
7.86 (m, 1H), 7.54 (d, J= 3.2 Hz, 0.3H), 7.49 (d, J= 2.8 Hz, 0.7H), 7.44 (s,
0.3H), 7.42
(s, 0.7H), 7.36 (s, 0.3H), 7.28 (s, 1H), 7.18 - 7.13 (m, 1H), 7.11 - 7.03 (m,
1H), 6.25 (s,
0.7H), 6.12 (d, J= 2.8 Hz, 0.3H), 4.42 (t, J= 6.4 Hz, 2H), 4.15 - 4.02 (m,
2.8H), 3.87 -
3.80 (m, 0.2H), 3.74 (s, 3H), 2.94 (t, J= 6.4 Hz, 2H), 2.68 - 2.58 (m, 1H),
2.21 - 2.02
(m, 4H), 1.96 - 1.66 (m, 2H), 1.60 - 1.47 (m, 2H), 1.20 - 1.16 (m, 3H).
Compound VII-33-10:
(trans)-ethyl 442-chloro-3,4-difluoropheny1)-644-(143-methoxy-3-oxopropy1)-3-
methyl-1Hpyrazol-4-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-
carboxylate (a single stereoisomer)
Intermediate VII-33-8:
Ethyl 4(2-chloro-3,4-difluoropheny1)-6-(4-(1-(3-methoxy-3-oxopropyl)-3-methyl-
1H
pyrazol-4-yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
mixture of 4 stereoisomers)
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By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 2.998 min, mass calcd. for
C301132C1F2N504S 631.2, m/z found 632.1 [M+111 . 1H NMR (400 MHz, CDC13) 6
8.21 -
8.20 (m, 0.7H), 7.84 - 7.83 (m, 1H), 7.64 (s, 0.1H), 7.57 - 7.55 (m, 0.2H),
7.51 (d, J=
3.2 Hz, 0.1H), 7.47 - 7.45 (m, 1H), 7.39 - 7.34 (m, 0.3H), 7.14 (s, 0.6H),
7.12 - 6.99 (m,
2H), 6.22 - 6.21 (m, 0.7H), 6.08 (d, J= 2.4 Hz, 0.3H), 4.39 (t, J= 7.2 Hz,
1H), 4.31 (t,
J= 6.8 Hz, 1H), 4.15 - 3.90 (m, 3H), 3.69 (s, 1.5H), 3.67 (s, 1.5H), 3.06 -
3.03 (m,
0.5H), 2.99 - 2.92 (m, 1H), 2.89 - 2.85 (m, 1H), 2.53 - 2.47 (m, 0.5H), 2.26
(s, 0.4H),
2.24 (s, 2.6H), 2.19 - 1.42 (m, 8H), 1.17 - 1.13 (m, 3H).
Intermediates VII-33-9, VIE-33-10 and VII-33-11:
(cis)-Ethyl 4-(2-chloro-3,4-difluorophenyD-6-(4-(1-(3-methoxy-3-oxopropyl)-3-
methyl-
1Hpyrazol-4-y0cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
mixture of 2 stereoisomers), (traneethyl 4-(2-chloro-3,4-difhloropheny1)-6-(4-
(1-(3-
methoxy-3-oxopropyl) -3-methyl- 1Hpyrazol-4-yDcydohexyl)-2-(thiazol-2-y1)- 1,4-
dihydropyrimidine-5-carboxylate (a single stereoisomer) and (trans) ethyl 4-(2-
chloro-3,4-difluoropheny0-6-(4-(1-(3-methoxy-3-oxopropy0-3-methyl-1Hpyrazol-4-
yDcydohexyD-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
A stereoisomeric mixture of ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(4-(1-(3-
methoxy-
3-oxopropy1)-3-methy1-1H-pyrazol-4-y1)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate VII-33-8 (1.26 g, 90 % purity, 1.79 mmol) was
separated by chiral Prep. HPLC (condition: Column: Chiralpak IG 5 i.tm 20 *
250 nm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.3 at 15 mL / min; Temp: 30 C;
Wavelength: 230 nm) to afford the title compounds VII-33-9 (450 mg, 36 %
yield, 90 %
purity, 97.5 % stereopure) as yellow solids, VII-33-10 (220 mg, 17 % yield, 90
%
purity, 95.1 % stereopure) as yellow solids and VII-33-11 (210 mg, 17 % yield,
90 %
purity, 99.2 % stereopure) as yellow solids.
VII-33-9: LC-MS (ESI): RT = 2.866 min, mass calcd. for C30H32C1F2N504S 631.2,
m/z
found 632.2 [M+111 . 1H NMR (400 MHz, CDC13) 6 8.20 (s, 0.6H), 7.84 (d, J= 3.2
Hz,
1H), 7.64 (s, 0.5H), 7.56 (d, J= 2.8 Hz, 0.5H), 7.46 - 7.44 (m, 1H), 7.32 (s,
0.4H), 7.13
- 6.99 (m, 2H), 6.21 (s, 0.6H), 6.08 (d, J= 2.8 Hz, 0.4H), 4.39 (t, J= 7.2 Hz,
2H), 4.15
- 3.88 (m, 3H), 3.67 (s, 3H), 3.05 - 2.99 (m, 0.7H), 2.97 - 2.92 (m, 2.3H),
2.24 (s, 3H),
2.05 - 1.70 (m, 7.4H), 1.60 - 1.41 (m, 0.6H), 1.15 (t, J= 7.2 Hz, 3H).
VII-33-10: LC-MS (ESI): RT = 2.823 min, mass calcd. for C30H32C1F2N5045 631.2,
m/z
found 632.2 [M+111 . 1H NMR (400 MHz, CDC13) 8.19 (s, 0.8H), 7.84 (d, J= 3.2
Hz,
1H), 7.51 (d, J= 2.8 Hz, 0.2H), 7.46 (d, J= 3.2 Hz, 0.8H), 7.33 (s, 0.2H),
7.14- 7.10
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(m, 2H), 7.07 - 6.99 (m, 1H), 6.21 (s, 0.8H), 6.08 (d, J= 2.4 Hz, 0.2H), 4.31
(t, J= 6.4
Hz, 2H), 4.12 - 4.05 (m, 2.8H), 3.98 - 3.85 (m, 0.2H), 3.69 (s, 3H), 2.87 (d,
J= 6.8 Hz,
2H), 2.53 - 2.47 (m, 1H), 2.26 (s, 0.7H), 2.24(s, 2.3H), 2.14 - 1.98 (m, 4H),
1.75 - 1.41
(m, 4H), 1.14 (t, J= 7.2 Hz, 3H).
VII-33-11: LC-MS (ESI): RT = 2.819 min, mass calcd. for C301132C1F2N504S
631.2, m/z
found 632.2 [M+111 .111 NMR (400 MHz, CDC13) 8.20 (s, 0.8H), 7.84 (d, J= 2.8
Hz,
1H), 7.51 (d, J= 2.4 Hz, 0.2H), 7.46 (d, J= 3.2 Hz, 0.8H), 7.32 (s, 0.2H),
7.14 (s, 1H),
7.12 - 7.10 (m, 1H), 7.07 - 6.99 (m, 1H), 6.22 (s, 0.8H), 6.08 (s, 0.2H), 4.31
(t, J= 6.8
Hz, 2H), 4.15 - 3.98 (m, 2.8H), 3.85 - 3.77 (m, 0.2H), 3.69 (s, 3H), 2.87 (d,
J= 6.4 Hz,
2H), 2.53 - 2.47 (m, 1H), 2.26 (s, 0.7H), 2.24(s, 2.3H), 2.14 - 1.95 (m, 4H),
1.75 - 1.42
(m, 4H), 1.14 (t, J= 7.2 Hz, 3H).
Compound VII-34:
Ethyl 644-(1-(3-(tert-butoxycarbonyl)cydobuty1)-1Hpyrazol-4-y1)cydohexy0-442-
chloro-3,4-difluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a
mixture of 4 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
11-1 NMR (300 MHz, CDC13) 68.19 (hr s, 0.2H), 8.08 (hr s, 0.3H), 7.84 - 7.82
(m, 0.6H),
7.78 - 7.76 (m, 0.4H), 7.57 - 7.33 (m, 3.5H), 7.10 - 6.98 (m, 2H), 6.21 - 6.19
(m, 0.7H),
6.09 - 6.05 (m, 0.3H), 5.06 - 4.93 (m, 0.4H), 4.76 - 4.64 (m, 0.6H), 4.11 -
4.02 (m, 3H),
3.15 - 3.04 (m, 1H), 2.88 - 2.73 (m, 4H), 2.14- 1.89 (m, 5H), 1.78 - 1.72 (m,
2H), 1.52 -
1.46 (m, 11H), 1.17 - 1.12 (m, 3H).
Compound VII-35-P:
(trans) -Ethyl 442-chloro-3,4-difluoropheny1)-6-(4-(3-(methoxycarbony0-1-
methyl-1H-
pyrazol-5-yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
single stereoisomer)
Intermediates VII-35-X and VIE-35-Y
(cis)-Ethyl 442-chloro-3,4-difluoropheny1)-6-(4-(3-(methoxycarbony1)-1-methyl-
1H-
pyrazol-5-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
mixture of 2 stereoisomers) and (trans)-Ethyl 442-chloro-3,4-difluoropheny1)-6-
(443-
(methoxycarbony1)-1-methyl-1H-pyrazol-5-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-35-X: LC-MS (ESI): RT = 1.81 min, mass calcd. for C281128C1F2N504S 603.2,
m/z
found 604.2[M+111 . 11-1 NMR (400 MHz, DMSO-d6) 9.60 (d, J= 3.6 Hz, 0.8H),
8.74 (s,
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0.2H), 8.06 - 7.95 (m, 2H), 7.50 - 7.43 (m, 1H), 7.24 - 7.20 (m, 1H), 6.92 (s,
1H), 6.05
(s, 0.2H), 5.93 (d, J= 3.2 Hz, 0.8H), 4.01 - 3.96 (m, 2H), 3.88 (s, 3H), 3.80
(s, 3H),
3.78 - 3.74 (m, 1H), 3.24- 3.22 (m, 1H), 2.14- 2.11 (m, 1H), 2.00 - 1.92 (m,
3H), 1.85 -
1.76 (m, 2H), 1.67 - 1.62 (m, 1H), 1.52 - 1.48 (m, 111), 1.10 - 1.05 (m, 3H).
.. VII-35-Y: LC-MS (ESI): RT = 1.79 min, mass calcd. for C281-128C1F2N504S
603.2, m/z
found 604.2[M+111 . 1H NMR (400 MHz, DMSO-d6) 9.56 (d, J= 3.6 Hz, 0.6H), 8.92
(s,
0.4H), 8.01 - 7.96 (m, 2H), 7.51 - 7.43 (m, 1H), 7.23 - 7.20 (m, 1H), 6.60 -
6.58 (m, 1H),
6.04 (s, 0.4H), 5.94 (d, J= 3.6 Hz, 0.6H), 4.01 - 3.95 (m, 2H), 3.89 (s, 3H),
3.77 (s, 3H),
3.72 - 3.66 (m, 1H), 2.97 - 2.91 (m, 0.5H), 2.81 - 2.75 (m, 0.5H), 2.04 - 1.85
(m, 5H),
1.82 - 1.79 (m, 0.5H), 1.71 - 1.67 (m, 0.5H), 1.52 - 1.43 (m, 2H), 1.11 - 1.04
(m, 3H).
A stereoisomeric mixture of ethyl 4-(2-chloro-3,4-difluoropheny1)-6-((trans)-
4- (3-
(methoxycarbony1)-1-methy1-1H-pyrazol-5-y1)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate VII-35-Y (180 mg, 90 % purity, 0.268 mmol) was
separated by chiral Prep. HPLC (separation condition: Column: Chiralpak ID 5
gm
30 * 250 mm; Mobile Phase: Hex : Et0H : DEA= 60 : 40 : 0.3 at 13 mL/min; Temp:
30 C; Wavelength: 230 nm) to afford VIE-35-P (63 mg, 95 % purity from 1HNMR,
37 %
yield, 100 % ee) and VIE-35-Q (78 mg, 97 % purity from 1HNMR, 47 % yield, 97 %
ee)
as yellow solids.
VII-35-P: Chiral HPLC (Column: Chiralpak ID 5 gm 4.6 * 250 mm; Mobile Phase:
.. Hex: Et0H: DEA= 60 : 40 : 0.2 at 1.0 mL/ min; Temp: 30 C; Wavelength: 230
nm,
RT = 8.464 min). 1H NMR (300 MHz, CDC13) 8.15 (s, 0.5H), 7.85 - 7.82 (m, 1H),
7.52 -
7.46 (m, 1H), 7.34 (s, 0.5H), 7.10 - 7.01 (m, 2H), 6.62 (s, 1H), 6.21 (s,
0.6H), 6.09 (s,
0.4H), 4.16 - 4.07 (m, 2H), 4.05 - 4.00 (m, 1H), 3.94 - 3.92 (m, 6H), 2.73 -
2.65 (m, 1H),
2.22- 1.99 (m, 5H), 1.91- 1.79 (m, 1H), 1.72- 1.64(m, 2H), 1.16- 1.11 (m, 3H).
VII-35-Q: LC-MS (ESI): RT = 1.79 min, mass calcd. for C281-128C1F2N504S 603.2,
m/z
found 604.1 [M+1-11 . Chiral HPLC (Column: Chiralpak ID 5 gm 4.6 * 250 mm;
Mobile Phase: Hex: Et0H: DEA = 60 : 40 : 0.2 at 1.0 mL/ min; Temp: 30 C;
Wavelength: 230 nm, RT = 10.400 min). 1H NMR (300 MHz, CDC13) 8.15 (s, 0.5H),
7.85 - 7.82 (m, 1H), 7.52 - 7.46 (m, 1H), 7.34 (s, 0.5H), 7.12 - 7.01 (m, 2H),
6.62 (s,
1H), 6.21 (s, 0.6H), 6.08 (s, 0.4H), 4.13 - 4.09 (m, 111), 4.06 - 4.00 (m,
2H), 3.94 - 3.92
(m, 6H), 2.74 - 2.67 (m, 1H), 2.19 - 2.03 (m, 5H), 1.87 - 1.80 (m, 1H), 1.73 -
1.66 (m,
2H), 1.17- 1.11 (m, 3H).
Compound VII-36-N:
(trans)-Ethyl 4-(2-chloro-3,4-difLuoropheny1)-6- (445- (methoxycarbony0-1-
methy1-1H
pyrazol-3-yl)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
single stereoisomer)
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Intermediate VII-36-R:
(trans)-Ethyl 4(2-chloro-3,4-difluoropheny1)-6-(4-(5-(methoxycarbony0-1-methyl-
1H
pyrazol-3-ypcyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
(a
mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 1.95 min, mass calcd. for C281128C1F2N504S 603.2, m/z found
mass 604.0 [M+111 . 1H NMR (400MHz, DMSO-d6) 6 9.53 (hr s, 0.5H), 8.97 (hr s,
0.5H), 8.01 - 7.98 (m, 2H), 7.50 - 7.44 (m, 1H), 7.22 - 7.19 (m, 1H), 6.74 (s,
1H), 5.96
(hr s, 1H), 4.03 (s, 3H), 3.98 (q, J= 7.2 Hz, 2H), 3.82 (s, 3H), 3.69 - 3.63
(m, 0.6H),
3.31 (s, 0.4H), 2.77 - 2.60 (m, 1H), 2.08 - 2.05 (m, 2H), 1.92 - 1.85 (m, 2H),
1.80 - 1.72
(m, 2H), 1.55 - 1.49 (m, 2H), 1.07 (t, J = 7.2 Hz, 311).
A stereoisomeric mixture of VII-36-R (100 mg, 0.166 mg) was separated by
chiral
Prep. HPLC (Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
:
DEA =70 : 30 : 0.3 at 12 mL/min; Temp: 30 C; Wavelength: 230 nm) to give the
compounds VII-36-M (30 mg, 30 % yield) and VII-36-N (30 mg, 30 % yield) as
yellow
solids.
VII-36-M: 1H NMR (400MHz, DMSO-d6) 6 9.53 (hr s, 0.5H), 8.97 (hr s, 0.5H),
8.01-
7.98 (m, 2H), 7.50 - 7. 44 (m, 1H), 7.22 - 7.19 (m, 111), 6.74 (s, 1H), 5.96
(hr s, 1H),
4.03 (s, 3H), 3.98 (q, J= 7.2 Hz, 2H), 3.82 (s, 3H), 3.69 - 3.63 (m, 0.6H),
3.31 (s, 0.4H),
2.77 - 2.60 (m, 1H), 2.08 - 2.05 (m, 2H), 1.93 - 1.85 (m, 2H), 1.80 - 1.72 (m,
2H), 1.55 -
1.45 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H).
VII-36-N: 1H NMR (400MHz, DMSO-d6) 6 9.53 (hr s, 0.5H), 8.97 (hr s, 0.5H),
8.01 -
7.98 (m, 2H), 7.50 - 7. 44 (m, 1H), 7.22 - 7.19 (m, 111), 6.74(s, 1H), 5.96
(hr s, 1H),
4.03 (s, 3H), 3.98 (q, J= 7.2 Hz, 2H), 3.82 (s, 3H), 3.69 - 3.63 (m, 0.6H),
3.31 (s, 0.4H),
2.77- 2.60 (m, 1H), 2.08 - 2.05 (m, 2H), 1.93- 1.85 (m, 2H), 1.80- 1.72 (m,
2H), 1.55 -
1.45 (m, 2H), 1.07 (t, J= 7.2 Hz, 3H).
Compound VII-37-4C:
(trans)-Ethyl 644-(143-(tert-butoxy)-2,2-dimethyl-3-oxopropy1)-1Hpyrazol-3-
yl)cydohexyl)-442-chloro-3,4-difluoropheny1)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate (a single stereoisomer)
Intermediate VII-37:
Ethyl 644-(1-(3-(tert-butoxy)-2,2-dimethyl-3-oxopropyl)-1H-pyrazol-3-
y1)cydohexyl)-
442-chloro-3,4-difluoropheny0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
(a mixture of 4 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
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synthesized as yellow solids.
LC-MS (EST): RT = 1.88 and 1.91 min, mass calcd. for C341140C1F2N504S 687.2,
m/z
found 688.0 [M+111 . 111 NMR (400 MHz, CD30D) 6 7.94 - 7.93 (m, 0.311), 7.90 -
7.85
(m, 0.711), 7.76 - 7.72 (m, 111), 7.54 - 7.53 (m, 0.811), 7.47 (s, 0.311),
7.41 (s, 0.311),
7.39 - 7.36 (m, 0.611), 7.24- 7.18 (m, 211), 6.15 - 6.13 (m, 0.611), 6.08 -
6.06 (m, 0.411),
4.29 - 4.27 (m, 111), 4.22 (s, 111), 4.08 - 3.99 (m, 2.8H), 3.87 - 3.79 (m,
0.211), 3.12 -
3.04 (m, 0.611), 2.69 - 2.57 (m, 0.411), 2.26 - 1.54 (m, 811), 1.47 (s, 411),
1.41 (s, 511),
1.17- 1.12 (m, 911).
A stereoisomeric mixture of ethyl 6-(4-(1-(3-(tert-butoxy)-2,2-dimethy1-3-
oxopropy1)-
1H-pyrazol-3-yl)cyclohexyl)-4-(2-chloro-3,4-difluoropheny1)-2-(thiazol-2-y1)-
1,4-
dihydropyrimidine-5-carboxylate VII-37 (290 mg, 90 % purity, 0.379 mmol) was
separated by chiral Prep. HPLC (the first separation condition: Column:
Chiralpak
IE 5i.tm 20 * 250 mm; Mobile Phase: CO2 : Et011 : DEA = 70 : 30 : 0.3 at 50
g/min;
Col. Temp: 30 C; Wavelength: 230 nm; Back pressure 100 bar; the second
separation condition: Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase:
CO2:
Et011 : DEA = 70: 30 : 0.3 at 50 g/min; Col. Temp: 30 C; Wavelength: 214 nm;
Back
pressure 100 bar; the third separation condition: Column: Chiralpak IA 5 i.tm
20 *
250 mm; Mobile Phase: CO2 : Et011 : DEA = 70 : 30 : 0.3 at 45 g/min; Col.
Temp: 30
C; Wavelength: 214 nm; Back pressure 100 bar) to afford VII-37-4A (55 mg, 90 %
purity from 111 NMR, 19 % yield, 100 % stereopure), VIE-37-4B (68 mg, 90 %
purity
from 111 NMR, 23 % yield, 97.1 % stereopure), VII-37-4C (36 mg, 90 % purity
from
111 NMR, 12 % yield, 100 % stereopure) and VIE-37-4D (45 mg, 90 % purity from
111
NMR, 16 % yield, 93.3 % stereopure) as yellow solids.
VII-37-4A: LC-MS (ESI): RT = 1.93 min, mass calcd. for C341140C1F2N504S 687.2,
m/z
found 687.9 [M+111 . Chiral analysis (Column: Chiralpak IE 5 pm 4.6 * 250 mm;
Mobile Phase: CO2 : Et0H : DEA = 70 : 30 : 0.2 at 3.0 g/min; Col. Temp: 40 C;
Wavelength: 230 nm; Back pressure 100 bar, RT = 4.05 min). 111 NMR (400 MHz,
CD30D) 6 7.88 (d, J= 3.2 Hz, 0.411), 7.86 (d, J= 3.2 Hz, 0.611), 7.75 - 7.73
(m, 111),
7.55 - 7.53 (m, 1.411), 7.47 (s, 0.611), 7.24 - 7.16 (m, 211), 6.13 (s,
0.611), 6.06 (s, 0.411),
4.29 - 4.27 (m, 211), 4.08 - 4.01 (m, 2.611), 3.88 - 3.81 (m, 0.411), 3.15 -
3.09 (m, 0.611),
3.07 - 3.02 (m, 0.411), 2.26 - 1.65 (m, 7.511), 1.50 - 1.43 (m, 0.511), 1.41
(s, 911), 1.17 -
1.12 (m, 911).
VII-37-4B: LC-MS (ESI): RT = 1.92 min, mass calcd. for C341140C1F2N504S 687.2,
m/z
found 687.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 pm 4.6 * 250 mm;
Mobile Phase: CO2 : Et0H : DEA = 70 : 30 : 0.2 at 3.0 g/min; Col. Temp: 40 C;
Wavelength: 230 nm; Back pressure 100 bar, RT = 4.77 min). 111 NMR (400 MHz,
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CD30D) 6 7.88 (d, J= 3.2 Hz, 0.4H), 7.86 (d, J= 2.8 Hz, 0.6H), 7.75 - 7.73 (m,
1H),
7.55 - 7.53 (m, 1.4H), 7.47 (s, 0.6H), 7.24 - 7.15 (m, 2H), 6.13 (s, 0.6H),
6.06 (s, 0.4H),
4.29 - 4.27 (m, 2H), 4.08 - 4.00 (m, 2.6H), 3.89 - 3.81 (m, 0.4H), 3.15 - 3.09
(m, 0.6H),
3.06 - 3.01 (m, 0.4H), 2.25 - 1.65 (m, 7.5H), 1.50 - 1.44 (m, 0.5H), 1.41 (s,
9H), 1.17 -
1.12 (m, 9H).
VII-37-40: LC-MS (EST): RT = 1.88 min, mass calcd. for C34H40C1F2N504S 687.2,
m/z
found 687.9 [M+Hi . Chiral analysis (Column: Chiralpak IA5 pm 4.6 * 250 mm;
Mobile Phase: CO2 Et0H : DEA= 80 : 20 : 0.2 at 3.0 g/min; Col. Temp: 40 C;
Wavelength: 230 nm; Back pressure 100 bar, RT = 5.03 min). 111 NMR (400 MHz,
CD30D) 6 7.94 (d, J= 3.2 Hz, 0.7H), 7.90 (d, J= 3.2 Hz, 0.3H), 7.76 (d, J= 2.8
Hz,
1H), 7.42 (s, 0.7H), 7.39 - 7.36 (m, 1.3H), 7.24 - 7.22 (m, 2H), 6.15 (s,
0.7H), 6.08 (s,
0.3H), 4.22 (s, 2H), 4.08 - 3.99 (m, 2.7H), 3.81 - 3.73 (m, 0.3H), 2.70 - 2.53
(m, 1H),
2.18 - 1.71 (m, 6.3H), 1.62 - 1.50 (m, 1.7H), 1.47 (s, 9H), 1.17 - 1.12 (m,
9H).
VII-37-4D: LC-MS (EST): RT = 1.89 min, mass calcd. for C34H40C1F2N504S 687.2,
m/z
found 687.9 [M+Hi . Chiral analysis (Column: Chiralpak IA5 pm 4.6 * 250 mm;
Mobile Phase: CO2 : Et0H DEA= 80 20 0.2 at 3.0 g/min; Col. Temp: 40 C;
Wavelength: 230 nm; Back pressure 100 bar, RT = 6.37 min). 111 NMR (400 MHz,
CD30D) 6 7.94 (d, J= 3.2 Hz, 0.7H), 7.90 (d, J= 2.8 Hz, 0.3H), 7.76 (d, J= 3.2
Hz,
1H), 7.42 (s, 0.7H), 7.39 - 7.36 (m, 1.3H), 7.26 - 7.22 (m, 2H), 6.15 (s,
0.7H), 6.08 (s,
0.3H), 4.22 (s, 2H), 4.08 - 3.98 (m, 2.7H), 3.81 - 3.74 (m, 0.3H), 2.70 - 2.54
(m, 1H),
2.17 - 1.70 (m, 6.2H), 1.62 - 1.51 (m, 1.8H), 1.47 (s, 9H), 1.18 - 1.11 (m,
9H).
Compound VII-38-N:
(trans)-ethyl 4(2-chloro-3,4-difluoropheny1)-644- (4-(ethoxycarbony0- 1H-
pyrazol- 1-
yl)cydohexyl)-2-(thiazol-270- 1, 4-dihydropyrimidine- 5-carboxylate (a single
stereoisomer)
Intermediates VII-38-X and VIE-38-Y:
(cis)-Ethyl 4(2-chloro-3,4-difluoropheny0-644-(4-(ethoxycarbony1)- 1Hpyrazol-
1-
yl)cydohexyl)-2-(thiazol-270- 1, 4-dihydropyrimidine- 5-carboxylate (a mixture
of 2
stereoisomers) and (trans) ethyl 4(2-chloro- 3,4-difluoropheny1)-64444-
(ethoxycarbony0-1H-pyrazol-1-yl)cydohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-38-X: LC-MS (ESI): RT = 4.266 min, mass calcd. for C281128C1F2N504S 603.2,
m/z
found 604.1 [M+111 . 111 NMR (400 MHz, CDC13) 68.34 (s, 0.5H), 8.21 (s, 0.5H),
8.08
(s, 0.5H), 8.05 (s, 0.5H), 7.98 (s, 0.5H), 7.83 (d, J= 3.2 Hz, 0.6H), 7.80 (d,
J= 3.2 Hz,
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0.4H), 7.47 (d, J= 3.2 Hz, 0.5H), 7.43 (d, J= 3.2 Hz, 0.5H), 7.35 - 7.29 (m,
0.5H), 7.12
- 6.97 (m, 2H), 6.20 (s, 0.5H), 6.08 (d, J= 2.4 Hz, 0.5H), 4.55 - 4.45 (m,
1H), 4.36 -
4.28 (m, 2H), 4.24- 4.13 (m, 0.5H), 4.08 - 3.97 (m, 2.5H), 2.68 - 2.44 (m,
2H), 2.19 -
1.78 (m, 6H), 1.39 - 1.33 (m, 3H), 1.14 (t, J= 7.2 Hz, 3H).
.. VII-38-Y: LC-MS (ESI): RT = 4.148 min, mass calcd. for C281128C1F2N504S
603.2, m/z
found 604.1 [M+111 . 1H NMR (400 MHz, CDC13) 68.15 (s, 0.5H), 7.98 (s, 0.5H),
7.95
(s, 0.5H), 7.93 (s, 1H), 7.86 - 7.82 (m, 1H), 7.52 (d, J= 3.2 Hz, 0.6H), 7.47
(d, J= 2.8
Hz, 0.4H), 7.34 (d, J= 2.0 Hz, 0.5H), 7.13 - 7.00 (m, 2H), 6.21 (s, 0.4H),
6.09 (d, J=
2.8 Hz, 0.6H), 4.34 - 4.26 (m, 3H), 4.16 - 3.98 (m, 2.4H), 3.92 - 3.82 (m,
0.6H), 2.43 -
2.21 (m, 2.6H), 2.17 - 2.09 (m, 1.4H), 2.03 - 1.79 (m, 3.2H), 1.74 - 1.66 (m,
0.8H), 1.36
(t, J= 6.4 Hz, 3H), 1.18- 1.11 (m, 3H).
A stereoisomeric mixture of (trans)- ethyl 4-(2-chloro-3,4-difluoropheny1)-6-
(4-(4-
(ethoxycarbonyl) - 1H-pyrazol- 1 -yl)cyclohexyl) -2- (thiazol-2 - yl) - 1,4-
dihydropyrimidine -
5-carboxylate VII-38-Y (150 mg, 97 % purity, 0.249 mmol) was separated by
chiral
Prep. HPLC (the separation condition: Column: Chiralpak IA 5 pm 20 * 250 mm;
Mobile Phase: Hex: Et0H: DEA = 80: 20: 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm), then further purified by C18 column (acetonitrile: water
= 50 %
to 71 %) to give the title compounds VII-38-M (59 mg, 96.7 % purity, 39 %
yield, 100 %
stereopure) and VII-38-N (54 mg, 98.6 % purity, 36 % yield, 96.9 % stereopure)
as
yellow solids.
VII-38-M: LC-MS (ESI): RT = 4.475 min, mass calcd. for C281128C1F2N504S 603.2,
m/z
found 604.1 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 gm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 :20 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 10.844 min). 1H NMR (400 MHz, CDC13) 6 8.15 (br s,
0.5H), 8.00 - 7.95 (m, 1H), 7.93 (s, 1H), 7.85 (d, J= 3.2 Hz, 1H), 7.57 - 7.44
(m, 1H),
7.37 - 7.32 (m, 0.5H), 7.12 - 7.00 (m, 2H), 6.21 (s, 0.5H), 6.09 (s, 0.5H),
4.33 - 4.28 (m,
3H), 4.17 - 4.10 (m, 2.5H), 3.93 - 3.82 (m, 0.5H), 2.43 - 1.74 (m, 8H), 1.35
(t, J= 6.8
Hz, 3H), 1.14 (t, J= 7.2 Hz, 3H).
VII-38-N: LC-MS (ESI): RT = 4.471 min, mass calcd. for C281128C1F2N504S 603.2,
m/z
found 604.0 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 gm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 80 : 20 :0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 13.803 min). 1H NMR (400 MHz, CDC13) 6 8.15 (s,
0.5H),
7.97 (s, 0.5H), 7.95 (s, 0.5H), 7.93 (s, 1H), 7.83 - 7.82 (m, 1H), 7.51 (d, J=
3.2 Hz,
0.5H), 7.47 (d, J= 2.8 Hz, 0.5H), 7.34 (br s, 0.5H), 7.13 - 6.99 (m, 2H), 6.21
(s, 0.5H),
6.09 (d, J= 2.8 Hz, 0.5H), 4.33 - 4.27 (m, 3H), 4.16 - 3.99 (m, 2.5H), 3.93 -
3.82 (m,
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0.5H), 2.45 - 2.03 (m, 4H), 1.97 - 1.67 (m, 4H), 1.36 (t, J= 6.8 Hz, 3H), 1.14
(t, J= 6.8
Hz, 3H).
Compound VII-39-N and compound VII-39-P:
(cis)-ethyl 4-(2-chloro-3,4-difluoropheny1)-644-(5-(ethoxycarbony1)-1Hpyrazol-
1-
yl)cydohexyl)-2-(thiazol-270-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer) and (trans) -Ethyl 442-chloro-3,4-difluoropheny1)-6-(445-
(ethoxycarbonyp-1H-pyrazol-1-y0cydohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate (a single stereoisomer)
Intermediates VII-39-X and VII-39-Y:
(cis)-Ethyl 442-chloro-3,4-difluoropheny0-6-(4-(5-(ethoxycarbony1)-1Hpyrazol-1-
y1)cydohexy1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 2
stereoisomers) and (trane ethyl 442-chloro-3,4-difluoropheny1)-64445-
(ethoxycarbony0-1H-pyrazol-1-y0cydohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate (a mixture of 2 stereoisomers)
.. By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
VII-39-X: LC-MS (ESI): RT = 3.843 min, mass calcd. for C281-128C1F2N504S
603.2, m/z
found 603.9 [M+1-11 . 1H NMR (400 MHz, DMSO-d6) 6 9.57 (d, J= 3.6 Hz, 0.6H),
8.55
(s, 0.4H), 8.07 (d, J= 2.8 Hz, 0.4H), 8.02 - 7.97 (m, 1.6H), 7.75 (d, J= 2.4
Hz, 0.4H),
7.60 (d, J= 2.0 Hz, 0.6H), 7.51 - 7.40 (m, 1H), 7.26- 7.18 (m, 1H), 6.97 (d,
J= 2.0 Hz,
0.4H), 6.92 (d, J= 2.0 Hz, 0.6H), 6.05 (s, 0.4H), 5.94 (d, J= 3.6 Hz, 0.6H),
5.51 - 5.45
(m, 0.4H), 5.28 - 5.21 (m, 0.6H), 4.31 (qd, J= 7.2, 2.8 Hz, 2H), 4.10 - 4.03
(m, 0.4H),
3.98 (q, J= 7.2 Hz, 2H), 3.83 - 3.75 (m, 0.6H), 2.40 - 2.26 (m, 2H), 2.23 -
1.99 (m, 3H),
1.95 - 1.78 (m, 1.4H), 1.74 - 1.65 (m, 1H), 1.59 - 1.50 (m, 0.6H), 1.32 (t, J=
7.2 Hz,
.. 3H), 1.12 - 1.03 (m, 3H).
VII-39-Y: LC-MS (ESI): RT = 4.435 min, mass calcd. for C281-128C1F2N504S
603.2, m/z
found 603.9 [M+1-11 . 1H NMR (400 MHz, DMSO-d6) 6 9.59 (d, J= 3.2 Hz, 0.6H),
9.32
(s, 0.4H), 8.04 - 7.99 (m, 1.6H), 7.95 (d, J= 2.8 Hz, 0.4H), 7.62 - 7.59 (m,
1H), 7.51 -
7.43 (m, 1H), 7.25 - 7.16 (m, 1H), 6.88 (d, J= 1.6 Hz, 1H), 6.04 (s, 0.4H),
5.94 (d, J=
3.6 Hz, 0.6H), 5.31 - 5.22 (m, 0.4H), 5.18 - 5.09 (m, 0.6H), 4.33 (q, J= 7.2
Hz, 2H),
4.04- 3.93 (m, 2.4H), 3.77 - 3.68 (m, 0.6H), 2.25 - 2.15 (m, 0.4H), 2.12 -
1.88 (m,
6.4H), 1.85 - 1.79 (m, 0.6H), 1.77 - 1.71 (m, 0.6H), 1.34 (td, J= 7.2, 2.0 Hz,
3H), 1.13 -
1.03 (m, 3H).
The racemic mixture of (cis)-ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(4-(5 -
(ethoxycarbony1)-1H-pyrazol-1-y1)cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate VII-39-X (390 mg, 99.5 % purity, 0.639 mmol) was separated by
chiral
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prep. SFC (separation condition: Column: Chiralpak IE 5 pm 20 * 250 mm; Mobile
Phase: CO2 : Me0H = 75 : 25 at 50 g/min; Col. Temp: 40 C; Wavelength: 214 nm,
Back pressure: 100 bar) to afford VII-39-M (160 mg, 98.7 % purity, 41 % yield,
100 %
stereopure) and VII-39-N (165 mg, 98.8 % purity, 42 % yield, 100 % stereopure)
as
yellow solids.
VII-39-M: LC-MS (ESI): RT = 4.170 min, mass calcd. for C281-128C1F2N504S
603.2, m/z
found 603.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 75 : 25 at 3.00 g/min; Col. Temp: 40 C;
Wavelength:
230 nm; Back pressure: 100 bar, RT = 6.15 min). 11-1 NMR (400 MHz, DMSO-d6) 6
9.58 (d, J= 3.6 Hz, 0.6H), 8.55 (s, 0.4H), 8.07 (d, J= 2.8 Hz, 0.4H), 8.02 -
7.96 (m,
1.6H), 7.74 (d, J= 2.0 Hz, 0.4H), 7.60 (d, J= 1.6 Hz, 0.6H), 7.50 - 7.40 (m,
1H), 7.26 -
7.17 (m, 1H), 6.96 (d, J= 2.0 Hz, 0.4H), 6.91 (d, J= 2.0 Hz, 0.6H), 6.05 (s,
0.4H), 5.94
(d, J= 3.6 Hz, 0.6H), 5.51 - 5.45 (m, 0.4H), 5.28 - 5.20 (m, 0.6H), 4.30 (qd,
J= 7.2, 2.4
Hz, 2H), 4.11 - 4.02 (m, 0.4H), 3.98 (q, J= 6.8 Hz, 2H), 3.83 - 3.74 (m,
0.6H), 2.40 -
2.26 (m, 2H), 2.22 - 1.98 (m, 2.8H), 1.95 - 1.78 (m, 1.6H), 1.74 - 1.64 (m,
1H), 1.58 -
1.49 (m, 0.6H), 1.31 (t, J= 7.2 Hz, 3H), 1.12 - 1.02 (m, 3H).
WI-39-N: LC-MS (ESI): RT = 4.172 min, mass calcd. for C281-128C1F2N504S 603.2,
m/z
found 603.9 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 75 : 25 at 3.00 g/min; Col. Temp: 40 C;
Wavelength:
230 nm; Back pressure: 100 bar, RT = 7.12 min). 11-1 NMR (400 MHz, DMSO-d6) 6
9.58 (d, J= 3.6 Hz, 0.6H), 8.55 (s, 0.4H), 8.07 (d, J= 3.6 Hz, 0.4H), 8.01 -
7.97 (m,
1.6H), 7.75 (d, J= 2.0 Hz, 0.4H), 7.61 (d, J= 2.0 Hz, 0.6H), 7.51 - 7.40 (m,
1H), 7.25 -
7.19 (m, 1H), 6.97 (d, J= 2.0 Hz, 0.4H), 6.92 (d, J= 2.0 Hz, 0.6H), 6.06 (s,
0.4H), 5.94
(d, J= 3.6 Hz, 0.6H), 5.51- 5.46 (m, 0.4H), 5.28- 5.21 (m, 0.6H), 4.31 (qd, J=
7.2, 2.4
Hz, 2H), 4.11 - 4.03 (m, 0.4H), 3.98 (q, J= 6.8 Hz, 2H), 3.83 - 3.75 (m,
0.6H), 2.40 -
2.26 (m, 2H), 2.23- 1.98 (m, 2.8H), 1.95- 1.78 (m, 1.6H), 1.74 - 1.64 (m, 1H),
1.59 -
1.49 (m, 0.6H), 1.31 (t, J= 7.2 Hz, 3H), 1.12 - 1.03 (m, 3H).
The racemic mixture of (trans)- ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(4-(5-
(ethoxycarbonyl) - 1H -pyrazol- 1 -yl)cyclohexyl) -2 - (thiazol-2 - yl) - 1,4-
dihydropyrimidine -
5-carboxylate VII-39-Y (410 mg, 99.5 % purity, 0.672 mmol) was separated by
chiral
prep. HPLC (separation condition: Column: Chiralpak IG 5 pm 20 * 250 mm;
Mobile
Phase: Hex : IPA : DEA = 90: 10 : 0.3 at 15 mL/min; Wavelength: 230 nm) to
afford
WI-39-P (170 mg, 99.5 % purity, 42 % yield, 100 % stereopure) and VII-39-Q
(175
mg, 99.5 % purity, 43 % yield, 99.8 % stereopure) as yellow solids.
WI-39-P: LC-MS (ESI): RT = 3.868 min, mass calcd. for C281-128C1F2N504S 603.2,
m/z
found 603.9 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 gm 4.6 * 250 mm;
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Mobile Phase: Hex : IPA : DEA = 90 : 10 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 254 nm, RT = 9.987 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.60 (d, J=
3.2 Hz, 0.6H), 9.32 (s, 0.4H), 8.04 - 7.99 (m, 1.6H), 7.95 (d, J= 3.6 Hz,
0.4H), 7.63 -
7.58 (m, 1H), 7.51 - 7.44 (m, 1H), 7.25 - 7.16 (m, 1H), 6.88 (d, J= 2.0 Hz,
1H), 6.04 (s,
0.4H), 5.94 (d, J= 3.6 Hz, 0.6H), 5.32 - 5.22 (m, 0.4H), 5.18 - 5.09 (m,
0.6H), 4.33 (q,
J= 7.2 Hz, 2H), 4.04- 3.93 (m, 2.4H), 3.77 - 3.68 (m, 0.6H), 2.25 - 2.15 (m,
0.4H),
2.12 - 1.88 (m, 6.4H), 1.86 - 1.79 (m, 0.6H), 1.78 - 1.71 (m, 0.6H), 1.34 (td,
J= 7.2, 2.0
Hz, 3H), 1.13- 1.03 (m, 3H).
VII-39-Q: LC-MS (ESI): RT = 3.980 min, mass calcd. for C281-128C1F2N504S
603.2, m/z
found 603.9 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : IPA : DEA = 90 : 10 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 254 nm, RT = 13.321 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.60 (d,
J=
3.2 Hz, 0.6H), 9.32 (s, 0.4H), 8.05 - 7.98 (m, 1.6H), 7.95 (d, J= 2.8 Hz,
0.4H), 7.63 -
7.58 (m, 1H), 7.51 - 7.44 (m, 1H), 7.26 - 7.16 (m, 1H), 6.88 (d, J= 2.0 Hz,
1H), 6.04 (s,
0.4H), 5.94 (d, J= 3.6 Hz, 0.6H), 5.32 - 5.22 (m, 0.4H), 5.18 - 5.08 (m,
0.6H), 4.33 (q,
J= 7.2 Hz, 2H), 4.05 - 3.93 (m, 2.4H), 3.77 - 3.67 (m, 0.6H), 2.26 - 2.14 (m,
0.4H),
2.12 - 1.88 (m, 6.4H), 1.85 - 1.79 (m, 0.6H), 1.78 - 1.71 (m, 0.6H), 1.34 (t,
J= 7.2 Hz,
3H), 1.13 - 1.03 (m, 3H).
Compound VII-40-M:
(trans) -Ethyl 2444642-chloro-3,4-difluoropheny0-5-(methoxycarbony0-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)pyrimidine-5-carboxylate (a single
stereoisomer)
Intermediates VII-40-X and VII-40-Y:
(cis)-Ethyl 2444642-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-
2-y1)-
3,6-dihydropyrimidin-4-0cyclohexyl)pyrimidine-5-carboxylate (a mixture of 2
stereoisomers) and (trans)-ethyl 2444642-chloro-3,4-difluoropheny1)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-0cydohexyppyrimidine-
5-carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compounds were
synthesized as yellow solids.
VII-40-X: LC-MS (ESI): RT = 3.614 min, mass calcd. for C29H28C1F2N504S 615.2,
m/z
found 615.9 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 6 9.37 (s, 1.5H), 9.28 (s,
0.5H), 8.34
(s, 1H), 7.84 (d, J= 3.2 Hz, 0.8H), 7.78 (d, J= 3.2 Hz, 0.2H), 7.44 (d, J= 2.8
Hz, 1H),
7.11 - 6.96 (m, 2H), 6.20 (s, 0.8H), 6.05 (d, J= 3.2 Hz, 0.2H), 4.47 (q, J=
7.2 Hz, 2H),
4.22 - 4.17 (m, 0.8H), 4.11 - 4.00 (m, 2H), 3.96 - 3.91 (m, 0.2H), 3.48 (s,
0.8H), 3.40 -
3.36 (m, 0.2H), 2.70 - 2.62 (m, 0.5H), 2.53 - 2.47 (m, 1.5H), 2.05 - 1.88 (m,
5H), 1.80 -
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1.78 (m, 1H), 1.45 (t, J= 7.2 Hz, 3H), 1.15 (t, J= 7.2 Hz, 3H).
VII-40-Y: LC-MS (ESI): RT = 1.97 min, mass calcd. for C29H28C1F2N504S 615.2,
m/z
found 616.1 [M+1-11 . 1H NMR (400 MHz, CDC13) 69.22 (s, 2H), 8.21 (s, 0.6H),
7.84 (d,
J= 2.8 Hz, 1H), 7.51 (d, J= 2.8 Hz, 0.4H), 7.46 (d, J= 3.2 Hz, 0.6H), 7.32 (s,
0.4H),
7.14 - 6.99 (m, 2H), 6.22 (s, 0.6H), 6.08 (d, J= 2.8 Hz, 0.4H), 4.44 (q, J=
7.2 Hz, 2H),
4.15 - 4.01 (m, 2.8H), 3.91 - 3.85 (m, 0.2H), 3.12 - 3.05 (m, 1H), 2.29 - 2.08
(m, 4H),
1.97- 1.64 (m, 4H), 1.42 (t, J= 7.2 Hz, 3H), 1.15 (t, J= 7.2 Hz, 3H).
A stereoisomeric mixture of (trans)- ethyl 2-(4-(6-(2-chloro-3,4-
difluoropheny1)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)pyrimidine-
5-carboxylate VII-40-Y (210 mg, 95 % purity, 0.324 mmol) was separated by
chiral
Prep. HPLC (Column: Chiralpak ID 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
:
DEA = 40 : 60 : 0.3 at 10 mL/min; Temp: 30 C; Wavelength: 214 nm) to afford
the
title compounds VII-40-M (50 mg, 95.6 % purity, 24 % yield, 100 % stereopure)
and
VII-40-N (55 mg, 99.7 % purity, 27 % yield, 100 % stereopure) as yellow
solids.
VII-40-M: LC-MS (ESI): RT = 4.462 min, mass calcd. for C29H28C1F2N504S 615.2,
m/z
found 616.1 [M+Hi . Chiral analysis (Column: Chiralpak ID 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 40 :60 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 7.153 min). 1H NMR (400 MHz, CDC13) 6 9.27 - 9.26 (m,
2H), 8.26 (s, 0.7H), 7.88 - 7.87 (m, 1H), 7.55 (d, J= 2.8 Hz, 0.3H), 7.50 (d,
J= 3.2 Hz,
0.7H), 7.36 (s, 0.3H), 7.18 - 7.04 (m, 2H), 6.26 (s, 0.6H), 6.13 (d, J= 2.4
Hz, 0.4H),
4.48 (q, J= 6.8 Hz, 2H), 4.19 - 4.05 (m, 2.5H), 3.95 - 3.89 (m, 0.5H), 3.18 -
3.10 (m,
1H), 2.33 - 2.13 (m, 4H), 2.00 - 1.66 (m, 4H), 1.46 (t, J= 6.8 Hz, 3H), 1.22 -
1.17 (m,
3H).
VII-40-N: LC-MS (ESI): RT = 3.396 min, mass calcd. for C29H28C1F2N504S 615.2,
m/z
found 615.9 [M+Hi . Chiral analysis (Column: Chiralpak ID 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 40 :60 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 11.243 min). 1H NMR (400 MHz, CDC13) 6 9.26 - 9.25
(m,
2H), 8.26 (s, 0.6H), 7.88 - 7.87 (m, 1H), 7.55 (d, J= 2.8 Hz, 0.4H), 7.49 (d,
J= 3.2 Hz,
0.6H), 7.36 (s, 0.3H), 7.18 - 7.04 (m, 2H), 6.26 (s, 0.7H), 6.12 (d, J= 2.4
Hz, 0.3H),
4.48 (q, J= 7.2 Hz, 2H), 4.19 - 4.04 (m, 2.7H), 3.95 - 3.89 (m, 0.3H), 3.17 -
3.10 (m,
1H), 2.32 - 2.13 (m, 4H), 2.01 - 1.69 (m, 4H), 1.46 (t, J= 7.8 Hz, 3H), 1.22 -
1.17 (m,
3H).
Compound VII-41-N:
(trans)-ethyl 2444642-chloro-3,4-difluoropheny1)-5-(ethoxycarbonyl)-2-(thiazol-
2-y0-
3,6-dihydropyrimidin-4-y0cyclohexyl)thiazole-4-carboxylate (a single
stereoisomer)
Intermediate VII-41-R:
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(trans)-Ethyl 2444642-chloro-3,4-difluoropheny0-5-(ethoxycarbony0-2-(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)thiazole-4-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 3.965 min, mass calcd. for C281127C1F2N404S2 620.1, m/z
found
621.1 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.55 (d, J= 3.6 Hz, 0.6H), 8.98 (s,
0.4H), 8.42 (d, J= 4.8 Hz, 1H), 8.02 - 8.01 (m, 1.6H), 7.95 (d, J= 2.8 Hz,
0.4H), 7.51 -
7.44 (m, 1H), 7.24 - 7.18 (m, 1H), 6.05 (s, 0.4H), 5.94 (d, J= 3.2 Hz, 0.6H),
4.30 (q, J
.. = 7.2 Hz, 2H), 4.02 - 3.91 (m, 2.4H), 3.73 - 3.65 (m, 0.6H), 3.27 - 3.19
(m, 0.4H), 3.13 -
3.05 (m, 0.6H), 2.27 - 2.18 (m, 2H), 2.10 - 1.82 (m, 3.5H), 1.74- 1.71 (m,
0.5H), 1.64 -
1.56 (m, 2H), 1.31 (t, J= 7.2 Hz, 3H), 1.10 - 1.03 (m, 3H).
A stereoisomeric mixture of VII-41-R (300 mg, 0.48 mmol) was separated by
chiral
Prep. HPLC (Column: Chiralpak AD 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
.. DEA = 70 : 30 : 0.3 at 15 mL/min; Temp: 30 C; Wavelength: 214 nm) to give
the
peak 1 (122 mg, 41 % yiled, about 90 % purity, 100 % stereopure) and the peak
2
(110 mg, 37 % yiled, about 90 % purity, 98.6 % stereopure). Parts of the peak
1(30
mg, 90 % purity) and the peak 2 (30 mg, 90 % purity) were further purified by
Prep.
HPLC (Column: Gilson Xbrige C18 (5 i.tm 19 * 150 mm), Mobile Phase A: water
(0.1 %
.. ammonium bicarbonate), Mobile Phase B: acetonitrile, UV: 214 nm, Flow rate:
15
mL/min, Gradient: 70 - 98 % (%B)) to give the title compounds VII-41-M (6.1
mg, 20 %
yield, 98.3 % purity, 100 % stereopure) and VIE-41-N (6.8 mg, 23 % yiled, 99.7
%
purity, 98.6 % stereopure).
VII-41-M: LC-MS (ESI): RT = 3.001 min, mass calcd. for C281127C1F2N404S2
620.1,
.. m/z found 621.1 [M+Hi . Chiral analysis (Column: Chiralpak AD-H 5 pm 4.6 *
250
mm; Mobile Phase: Hex : Et0H : DEA = 70: 30 : 0.2 at 1 mL/min; Temp:
C;Wavelength: 230 nm; RT = 6.075 min). 1H NMR (400 MHz, DMSO-d6) 6 9.56 (d,
J= 3.2 Hz, 0.6H), 8.99 (s, 0.4H), 8.42 (d, J= 5.2 Hz, 1H), 8.02 - 8.01 (m,
1.6H), 7.96
(d, J= 3.2 Hz, 0.4H), 7.51 - 7.44 (m, 1H), 7.24 - 7.18 (m, 1H), 6.05 (s,
0.4H), 5.94 (d, J
30 .. = 3.6 Hz, 0.6H), 4.30 (q, J= 7.2 Hz, 2H), 4.02 - 3.91 (m, 2.4H), 3.72 -
3.66 (m, 0.6H),
3.27 - 3.19 (m, 0.4H), 3.13 - 3.05 (m, 0.6H), 2.28 - 2.18 (m, 2H), 2.08 - 1.82
(m, 3.5H),
1.75 - 1.71 (m, 0.5H), 1.65 - 1.53 (m, 2H), 1.31 (t, J= 7.2 Hz, 3H), 1.10 -
1.03 (m, 3H).
VII-41-N: LC-MS (ESI): RT = 3.952 min, mass calcd. for C281127C1F2N404S2620.1,
m/z
found 621.1 [M+Hi . Chiral analysis (Column: Chiralpak AD-H 5 pm 4.6 * 250 mm;
.. Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp:
30 C;Wavelength: 230 nm; RT = 8.428 min).1H NMR (400 MHz, DMSO-d6) 6 9.56 (d,
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J= 3.6 Hz, 0.6H), 8.98 (s, 0.4H), 8.42 (d, J= 3.2 Hz, 1H), 8.02 - 8.01 (m,
1.6H), 7.95
(d, J= 3.6 Hz, 0.4H), 7.51 - 7.44 (m, 1H), 7.24 - 7.18 (m, 1H), 6.05 (s,
0.4H), 5.94 (d, J
= 3.2 Hz, 0.6H), 4.30 (q, J= 7.2 Hz, 2H), 4.02 - 3.90 (m, 2.4H), 3.73 - 3.65
(m, 0.6H),
3.27 - 3.20 (m, 0.4H), 3.13 - 3.06 (m, 0.6H), 2.28 - 2.18 (m, 2H), 2.08 - 1.82
(m, 3.5H),
1.75 - 1.71 (m, 0.5H), 1.67 - 1.54 (m, 2H), 1.31 (t, J= 7.2 Hz, 3H), 1.10 -
1.05 (m, 3H).
Compound VII-42-11:
Mixture of (trans)-methyl 5-(4-(6-(2-chloro-3,4-difluorophenyl)-5-
(ethoxycarbony1)-2-
(thiazol-2-y1)-3,6-dihydropyrimidin-4-y0cydohexyl)isoxazole-3-carboxylate (a
single
stereoisomer) and (trans) -ethyl 5-(4-(6-(2-chloro-3,4-difluorophenyl)-5-
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-yDcydohexyDisoxazole-
3-
carboxylate (a single stereoisomer)
Intermediates VII-42-9A and VIE-42-9B:
(trans) -Ethyl 5-(4-(6-(2-chloro-3,4-difluorophenyl)-5-(ethoxycarbonyl)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyDisoxazole-3-carboxylate (a mixture of 2
stereoisomers) and (trans)-methyl 5-(4-(6-(2-chloro-3,4-difluorophenyl)-5-
(ethoxycarbony0-2-(thiazol-2-y0-3,6-dihydropyrimidin-4-ypcydohexyDisoxazole-3-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. Transesterification reaction was observed when
using
ethanol as solvent.
VII-42-9A: LC-MS (ESI): RT = 2.03 min, mass calcd. for C281-127C1F2N405S
604.1, m/z
found 604.8 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 6 9.59 (d, J= 3.2 Hz, 0.6H),
9.04
(s, 0.4H), 8.01 - 7.95 (m, 2H), 7.51 - 7.44 (m, 1H), 7.23 - 7.18 (m, 1H), 6.74
(d, J= 10.0
Hz, 1H), 6.04 (s, 0.4H), 5.94 (d, J= 3.2 Hz, 0.6H), 4.39 - 4.34 (m, 2H), 4.01 -
3.94 (m,
2.5H), 3.71 - 3.65 (m, 0.5H), 3.12 - 3.06 (m, 0.4H), 2.99 - 2.92 (m, 0.6H),
2.19 - 2.12
(m, 2.3H), 2.07 - 1.78 (m, 3H), 1.73 - 1.69 (m, 0.7H), 1.60 - 1.50 (m, 2H),
1.32 (t, J=
7.2 Hz, 3H), 1.10 - 1.03 (m, 3H).
VII-42-9B: LC-MS (ESI): RT = 2.00 min, mass calcd. for C27H25C1F2N405S 590.1,
m/z
found 590.8 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 6 9.59 (s, 0.6H), 9.04 (s,
0.4H),
8.02 - 7.96 (m, 2H), 7.51 - 7.44 (m, 1H), 7.22 - 7.19 (m, 1H), 6.77 - 6.74 (m,
1H), 6.03
(s, 0.4H), 5.95 (s, 0.6H), 4.00 - 3.95 (m, 2.5H), 3.89 (s, 3H), 3.73 - 3.65
(m, 0.5H), 3.13
- 3.07 (m, 0.4H), 3.00 - 2.94 (m, 0.6H), 2.19 - 2.12 (m, 2H), 1.97 - 1.72 (m,
4H), 1.61 -
1.47 (m, 2H), 1.07 - 1.06 (m, 3H).
A stereoisomeric mixture of (trans)- methyl 5-(4-(6-(2-chloro-3,4-
difluoropheny0-5 -
(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)isoxazole-3-
carboxylate VII-42-9B (200 mg, 90 % purity, 0.305 mmol) was separated by
chiral
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Prep. HPLC (Column: Chiralpak IE 5 gm 20 * 250 mm; Mobile Phase: Hex : Et0H :
DEA = 50 : 50 : 0.3 at 11 mL/min; Temp: 30 C; Wavelength: 230 nm) to give the
compounds VII-42-10 (45 mg, 23 % yield, 100 % stereopure) and V1I-42-11 (65
mg,
33 % yield, 99.8 % stereopure) as yellow solids. Transesterification reaction
was
observed when using ethanol as solvent.
VII-42-10: LC-MS (ESI): RT = 1.97 mm and 2.02 mm, mass calcd. for
C27H25C1F2N405S 590.1 and C281127C1F2N405S 604.1, m/z found 590.8 and 604.9
[M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm; Mobile Phase:
Hex : Et0H : TEA= 50 : 50 : 0.2 at 1.0 mL/min; Temp: 30 C; Wavelength: 230
nm,
RT = 7.355 and 8.163 min).
VII-42-11: LC-MS (ESI): RT = 1.97 mm and 2.02 mm, mass calcd. for
C27H25C1F2N405S 590.1 and C281127C1F2N405S 604.1, m/z found 590.9 and 604.9
[M+Hi . Chiral analysis (Column: Chiralpak IE 5 gm 4.6 * 250 mm; Mobile Phase:
Hex : Et0H : TEA= 50 : 50 : 0.2 at 1.0 mL/min; Temp: 30 C; Wavelength: 230
nm,
RT = 11.346 and 13.670 min).
Compound VII-43-N:
(trans)-ethyl 3-4-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony0-2-(thiazol-
2-0-
3,6-dihydropyrimidin-4-y0cyclohexyDisoxazole-5-carboxylate (a single
stereoisomer)
Intermediate VII-43-R:
(trans)-Ethyl 3444642-chloro-3,4-difluoropheny1)-5-(ethoxycarbonyl)-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyDisoxazole-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 3.918 mm, mass calcd. for C281127C1F2N405S 604.1, m/z found
605.1 [M+111 . 11I NMR (400 MHz, DMSO-d6) 6 9.56 (d, J= 3.2 Hz, 0.6H), 9.02
(s,
0.4H), 8.01 (d, J= 3.2 Hz, 1.6H), 7.95 (d, J= 3.2 Hz, 0.4H), 7.51 - 7.46
(m,1H), 7.38 (s,
0.4H), 7.35 (s, 0.6H), 7.24 - 7.18 (m, 1H), 6.04 (s, 0.4H), 5.94 (d, J= 3.6
Hz, 0.6H),
4.36 (q, J= 7.2 Hz, 2H), 3.99 (q, J= 7.2 Hz, 2H), 3.93 - 3.90 (m, 0.4H), 3.74 -
3.66 (m,
0.6H), 3.04 - 2.96 (m, 0.4H), 2.87 - 2.79 (m, 0.6H), 2.10 - 1.81 (m, 6H), 1.72
- 1.54 (m,
2H), 1.32 (t, J= 7.2 Hz, 3H), 1.11 - 1.04 (m, 3H).
A stereoisomeric mixture of VII-43-R (1.20 g, 1.98 mmol) was separated by
chiral
Prep. HPLC (Column: Chiralpak IE 5 gm 20 * 250 mm, Mobile Phase: Hex : Et0H :
DEA = 50 : 50 : 0.2 at 1.0 mL/min, Temp: 30 C, Wavelength: 214 nm) to afford
the
compounds VII-43-M (436 mg, 36 % yield, 100 % stereopure) and VII-43-N (376
mg,
31 % yield, 99.8 % stereopure).
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VII-43-M: LC-MS (ESI): RT = 3.207 min, mass calcd. for C281127C1F2N405604.1,
m/z
found 605.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 6.378 min). 111 NMR (400 MHz, DMSO-d6) 6 9.55 (d, J=
3.6 Hz, 0.6H), 9.02 (s, 0.4H), 8.01 (d, J= 3.2 Hz, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H),
7.51 - 7.43 (m, 1H), 7.38 (s, 0.4H), 7.35 (s, 0.6H), 7.24 - 7.18 (m, 1H), 6.04
(s, 0.4H),
5.94 (d, J= 3.2 Hz, 0.6H), 4.36 (q, J= 7.2 Hz, 2H), 3.99 (q, J= 7.2 Hz, 2H),
3.94 -
3.91 (m, 0.4H), 3.73 - 3.65 (m, 0.6H), 3.03 - 2.95 (m, 0.4H), 2.86 - 2.79 (m,
0.6H), 2.11
- 1.78 (m, 6H), 1.73 - 1.53 (m, 2H), 1.32 (t, J= 7.2 Hz, 3H), 1.11 - 1.04 (m,
3H).
VII-43-N: LC-MS (ESI): RT = 4.047 min, mass calcd. for C281127C1F2N405604.1,
m/z
found 605.1 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1.0 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 9.388 min). 111 NMR (400 MHz, DMSO-d6) 6 9.55 (d, J=
3.6 Hz, 0.6H), 9.02 (s, 0.4H), 8.01 (d, J= 3.2 Hz, 1.6H), 7.95 (d, J= 3.2 Hz,
0.4H),
7.51 - 7.43 (m, 1H), 7.38 (s, 0.4H), 7.35 (s, 0.6H), 7.24 - 7.18 (m, 1H), 6.04
(s, 0.4H),
5.94 (d, J= 3.6 Hz, 0.6H)), 4.36 (q, J= 7.2 Hz, 2H), 3.99 (q, J= 7.2 Hz, 2H),
3.94 -
3.91 (m, 0.4H), 3.73 - 3.66 (m, 0.6H), 3.04 - 2.96 (m, 0.4H), 2.87 - 2.79 (m,
0.6H), 2.11
- 1.72 (m, 6H), 1.60 - 1.53 (m, 2H), 1.32 (t, J= 7.2 Hz, 3H), 1.11 - 1.04 (m,
3H).
Compound VII-44-X:
(trans)-Ethyl 442-chloro-3,4-difluoropheny1)-6-(444-
(methoxycarbonypphenypcydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a mixture of 2 stereoisomers)
Intermediate VII-44-R:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(444-(methoxycarbonyl)phenyl)cydohexyl)-
2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 2.17 min, 2.21 min, mass calcd. for C301128C1F2N304S 599.2,
m/z
found 600.2 [M+111 . 111 NMR (400 MHz, DMSO-d6) 6 9.56 - 9.53 (m, 0.7H), 8.96
(s,
0.3H), 8.02 - 7.89 (m, 4H), 7.60 - 7.44 (m, 3H), 7.23 - 7.19 (m, 1H), 6.05 (s,
0.4H), 5.95
- 5.93 (m, 0.6H), 4.02 - 3.95 (m, 2H), 3.85 - 3.84 (m, 3.5H), 3.75 - 3.68 (m,
0.5H), 2.93
- 2.68 (m, 1H), 1.99 - 1.54 (m, 8H), 1.11 - 1.05 (m, 3H).
A stereoisomeric mixture of ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(4-(4-
(methoxycarbonyl)phenyl)cyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5 -
carboxylate VII-44-R (300 mg, 0.50 mmol) was separated by chiral Prep. SFC
(separation condition: Column: Chiralpak IA 5 pm 20 * 250 mm; Mobile Phase:
CO2:
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Me0H = 70 : 30 at 50 g/min; Col. Temp: 41.1 C; Wavelength: 230 nm; Back
pressure:
100 bar) to afford the compounds VII-44-X (a mixture of 2 stereoisomers) (200
mg,
67 % yield) and VII-44-Y (a mixture of 2 stereoisomers) (85 mg, 28 % yield) as
yellow
solids.
Intermediate VII-44-X: LC-MS (ESI): RT = 2.07 min, mass calcd. for C30I-
128C1F2N304S 599.2,
miz found 600.2 [M+E1] . 1E1 NMR (400 MHz, DMSO-d6) 6 9.54 (d, J= 3.6 Hz,
0.6H), 8.96 (s,
0.4H), 8.02 - 8.00 (m, 1.5H), 7.96 (d, J= 2.8 Hz, 0.5H), 7.92 - 7.89 (m, 2H),
7.51 - 7.42 (m, 3H),
7.24 - 7.18 (m, 1H), 6.05 (s, 0.4H), 5.94 (d, J= 3.2 Hz, 0.6H), 4.02 - 3.95
(m, 2.4H), 3.84 (s, 3H),
3.75 - 3.68 (m, 0.6H), 2.86 - 2.78 (m, 0.4H), 2.72 - 2.63 (m, 0.6H), 2.03 -
1.81 (m, 5.4H), 1.74 -
1.68 (m, 0.6H), 1.63 - 1.53 (m, 2H), 1.10 - 1.04 (m, 3H). Intermediate VII-44-
Y: LC-MS
(ESI): RT = 3.121 min, mass calcd. for C30H28C1F2N304S 599.2, m/z found 600.1
[M+1-11 . 11-1 NMR (400 MHz, DMSO-d6) 6 9.56 (d, J= 4.0 Hz, 0.8 H), 8.52 (s,
0.2H),
7.99 - 7.93 (m, 4H), 7.60 - 7.54 (m, 2H), 7.50 - 7.40 (m, 1H), 7.23 - 7.20 (m,
1H), 6.04
(s, 0.2H), 5.93 (d, J= 3.6 Hz, 0.8 H), 4.01 - 3.94 (m, 2H), 3.86 - 3.85 (m,
4H), 3.13 -
3.10 (m, 0.2H), 2.96 -2.91 (m, 0.8H), 2.35 - 2.25 (m, 2H), 2.03 - 1.59 (m,
6H), 1. 10 -
1.04 (m, 3H).
Compound VII-45-R:
(trans)-Ethyl 5-(-4-(6-(2-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cyclohexyl)-1,2,4-oxadiazole-3-carboxylate (a
mixture
of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 4.364 min, mass calcd. for C27H26C1F2N505S 605.13, m/z found
606.2 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 68.14 (s, 0.5H), 7.84- 7.82 (m, 1H),
7.52
(d, J= 2.8 Hz, 0.5H), 7.47 (d, J= 3.2 Hz, 0.5H), 7.35 (s, 0.5H), 7.12 - 7.00
(m, 2H),
6.21 (s, 0.5H), 6.09 (d, J= 2.4 Hz, 0.5H), 4.52 (q, J= 7.2 Hz, 2H), 4.14- 4.00
(m,
2.5H), 3.89 - 3.82 (m, 0.5H), 3.19 - 3.12 (m, 1H), 2.41 - 2.22 (m, 2.5H), 2.15
- 2.04 (m,
1.5H), 1.97 - 1.83 (m, 3H), 1.75 - 1.62 (m, 1H), 1.45 (t, J= 7.2 Hz, 3H), 1.17
- 1.12 (m,
3H).
Compound VII-46-P:
methyl 4-(2-chloro-3,4-difluoropheny1)-6-arans)-4-(5-(1-
(methoxycarbonyl)cydopropyl)pyrimidin-2-ypcydohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-earboxylate (a single stereoisomer)
Intermediate VII-46-Y:
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methyl 4-(2-chloro-3,4-difluoropheny1)-6-arans)-4-(5-(1-
(methoxycarbonypcyclopropyppyrimidin-2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 1.92 min, mass calcd. for C30H28C1F2N504S 627.2, m/z found
628.4 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 6 8.65 (s, 0.6H), 8.64 (s, 1.4H),
8.24 (s,
0.7H), 7.85 - 7.83 (m, 1H), 7.52 (d, J= 3.2 Hz, 0.3H), 7.47 (d, J= 2.8 Hz,
0.7H), 7.38
(d, J= 2.4 Hz, 0.3H), 7.12 - 7.10 (m, 1H), 7.06 - 6.99 (m, 1H), 6.20 (s,
0.7H), 6.06 (d, J
.. = 2.4 Hz, 0.3H), 4.13 - 4.06 (m, 0.7H), 3.87 - 3.85 (m, 0.3H), 3.67 (s,
3H), 3.64 (s,
0.9H), 3.61 (s, 2.1H), 3.06 - 2.98 (m, 1H), 2.25 - 2.08 (m, 4H), 1.99 - 1.84
(m, 3H), 1.73
- 1.71 (m, 3H), 1.24- 1.21 (m, 2H). A racemic mixture of methyl 4-(2-chloro-
3,4-
difluoropheny1)-6-((trans)- 4- (5-(1- (methoxycarbonyl)cyclopropyl)pyrimidin-2-
yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate VII-46-Y
(170 mg,
0.271 mmol) was separated by chiral Prep. HPLC (separation condition: Column:
Chiralpak IE 5 um 20 * 250mm; Mobile Phase: MeOH: IPA: DEA = 90 : 10 : 0.3 at
10 mL/min; Temp: 30 C; Wavelength: 214 nm) to give VII-46-P (50 mg, 95 %
purity
from 11-I NMR, 28 % yield, 100 % stereopure) and VII-46-Q (50 mg, 95 % purity
from
11-1 NMR, 28 % yield, 99.8 % stereopure) as yellow solids.
WI-46-P: LC-MS (ESI): RT = 1.87 min, mass calcd. for C30H28C1F2N504S 627.2,
m/z
found 628.3 [M+Hi . Chiral analysis (Column: Chiralpak ID 5 um 4.6 * 250mm;
Mobile Phase: MeOH: DCM : DEA = 90 : 10 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 230 nm, Rt = 5.543 min). 11-1 NMR (400 MHz, CDC13) 6 8.65 (s,
0.6H),
8.64 (s, 1.4H), 8.25 (s, 0.6H), 7.84 - 7.83 (m, 1H), 7.51 (d, J= 3.2 Hz,
0.3H), 7.46 (d, J
= 3.2 Hz, 0.7H), 7.39 (br s, 0.4H), 7.12 - 7.09 (m, 1H), 7.05 - 7.01 (m, 1H),
6.20 (s,
0.7H), 6.07 (d, J= 2.4 Hz, 0.3H), 4.11 - 4.06 (m, 1H), 3.67 (s, 3H), 3.64 (s,
0.9H), 3.61
(s, 2.1H), 3.04 - 2.99 (m, 1H), 2.28 - 2.21 (m, 3H), 2.11 - 2.07 (m, 2H), 1.95
- 1.90 (m,
2H), 1.72 - 1.70 (m, 3H), 1.26 - 1.24 (m, 2H).
VII-46-Q: LC-MS (ESI): RT = 1.87 min, mass calcd. for C30H28C1F2N504S 627.2,
m/z
found 628.3 [M+Hi . Chiral analysis (Column: Chiralpak ID 5 um 4.6 * 250mm;
Mobile Phase: MeOH: DCM : DEA = 90 : 10 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 230 nm, Rt = 9.079 min). 11-1 NMR (400 MHz, CDC13) 6 8.64 (s, 2H),
8.24 (s, 0.7H), 7.84 (d, J= 3.2 Hz, 1H), 7.51 (d, J= 2.8 Hz, 0.3H), 7.46 (d,
J= 3.2 Hz,
0.7H), 7.39 (br s, 0.3H), 7.12 - 7.09 (m, 1H), 7.05 - 7.01 (m, 1H), 6.20 (s,
0.7H), 6.07 (s,
0.3H), 4.12 - 4.06 (m, 0.7H), 3.88 - 3.83 (m, 0.3H), 3.67 (s, 3H), 3.64 (s,
0.9H), 3.61 (s,
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2.111), 3.05 - 2.99 (m, 111), 2.28 - 2.22 (m, 311), 2.11 - 2.08 (m, 211), 1.97
- 1.90 (m, 211),
1.73 - 1.70 (m, 311), 1.26 - 1.24 (m, Ha
Compound VII-47-N:
Ethyl 2-((trans) -4-(6-(2-bromo-3,4-difluoropheny0-5-(methoxycarbony0-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-y0cydohexyl)-5-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
Intermediate VII-47-B:
Ethyl 2-qtrans)-4-(6-(2-bromo-3,4-difluoropheny1)-5-(methoxycarbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-ypcydohexyl)-5-methylpyrimidine-4-carboxylate (a
mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 1.97 min, mass calcd. for C29H28BrP2N5O4S 659.1, m/z found
660.1 [M+111 . 1H NMR (400 MHz, CDC13) 6 8.67 (s, 0.411), 8.66 (s, 0.611),
8.25 (s,
0.611), 7.83 (d, J= 3.2 Hz, 111), 7.51 (d, J= 3.2 Hz, 0.411), 7.45 (d, J= 3.2
Hz, 0.611),
7.43 (s, 0.411), 7.12 - 7.02 (m, 211), 6.19 (s, 0.611), 6.03 (d, J = 2.8 Hz,
0.411), 4.52 -
4.46 (m, 211), 4.17 - 4.07 (m, 111), 3.63 (s, 111), 3.61 (s, 211), 3.12 - 3.03
(m, 111), 2.46
(s, 311), 2.28 - 2.18 (m, 211), 2.18 - 2.04 (m, 211), 2.03 - 1.90 (m, 211),
1.87 - 1.64 (m,
211), 1.45 (t, J= 6.8 Hz, 311).
A racemic mixture of Ethyl 2-((trans)- 44642- bromo-3,4-difluorophenyl) -5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-y1)cyclohexyl)-5-
methylpyrimidine-4-carboxylate VII-47-B (127 mg, 95 % purity, 0.183 mmol) was
separated by chiral Prep. HPLC (separation condition: Column: Chiralpak IG 5
um
* 250 mm, Mobile Phase: CO2 : Et0H = 70 : 30 at 60 g/ min; Col. Temp: 40 C;
25 Wavelength: 230 nm, Back pressure: 100 bar) to afford VIE-47-M (40 mg,
90 % purity
from 111 NMR, 30 % yield, 99.6 % stereopure) and VII-47-N (35 mg, 90 % purity
from
111 NMR, 26 % yield, 99.6 % stereopure).
Intermediate VII-47-M: LC-MS (ESI): RT = 1.98 min, mass calcd. for
C29H28BrF2N5O4S 659.1, m/z found 660.2 [M+Hi . Chiral analysis (Column:
30 Chiralpak IG 5 pm 4.6 * 250 mm; Mobile Phase: CO2 : Et0H = 70 : 30 at
3.0 g/min;
Col. Temp: 40 C; Wavelength: 230 nm; Back pressure 100 bar, RT = 7.78 min).
111
NMR (400 MHz, CDC13) 6 8.66 (s, 111), 8.24 (s, 0.611), 7.83 (d, J= 3.2 Hz,
111), 7.52 -
7.51 (m, 0.411), 7.45 (d, J= 2.8 Hz, 0.611), 7.42 (s, 0.411), 7.12 - 7.04 (m,
211), 6.19 (s,
0.711), 6.03 (s, 0.311), 4.48 (q, J= 6.8 Hz, 211), 4.15 - 4.08 (m, 111), 3.63
(s, 0.511), 3.60
(s, 2.51I), 3.13 - 3.03 (m, 111), 2.46 (s, 311), 2.29 - 2.06 (m, 411), 2.03 -
1.89 (m, 211),
1.85 - 1.66 (m, 211), 1.45 (t, J= 6.8 Hz, 311).
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Intermediate VII-47-N: LC-MS (ESI): RT = 1.97 min, mass calcd. for
C29H28BrF2N5O4S 659.1, m/z found 660.2 [M+Hi . Chiral analysis (Column:
Chiralpak IG 5 pm 4.6 * 250 mm; Mobile Phase: CO2 : Et0H = 70 : 30 at 3.0
g/min;
Col. Temp: 40 C; Wavelength: 230 nm; Back pressure 100 bar, RT = 8.83 min).
11-1
NMR (400 MHz, CDC13) 6 8.67 (s, 0.3H), 8.66(s, 0.7H), 8.24 (s, 0.6H), 7.83 (d,
J= 2.8
Hz, 1H), 7.51 (d, J= 6.4 Hz, 0.4H), 7.46 (d, J= 3.2 Hz, 0.6H), 7.43 (s, 0.4H),
7.12 -
7.03 (m, 2H), 6.19 (s, 0.7H), 6.04 (d, J= 2.8 Hz, 0.3H), 4.52 - 4.46 (m, 2H),
4.17 - 4.06
(m, 1H), 3.63 (s, 1H), 3.61 (s, 2H), 3.12 - 3.05 (m, 1H), 2.46 (s, 3H), 2.27 -
2.11 (m,
4H), 2.08 - 1.93 (m, 2H), 1.90 - 1.66 (m, 2H), 1.45 (t, J= 7.2 Hz, 3H).
Compound VII-48-B:
(trans)-Methyl 4-(2-chloro-4-fluoropheny1)-6-(4-(4-(2-methoxy-2-oxoethyl)-5-
methyloxazol-2-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-
carboxylate
(a single stereoisomer)
Intermediate VII-48:
(trans)-Methyl 4-(2-chloro-4-fluoropheny1)-6-(4-(4-(2-methoxy-2-oxoethyl)-5-
methyloxazol-2-y1)cydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-
carboxylate
(a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
LC-MS (ESI): RT = 1.86 min, mass calcd. for C281-128C1FN405S 586.1, m/z found
586.9
[M+1-1] . 11-1 NMR (400 MHz, DMSO-d6) 6 9.41 (d, J= 3.6 Hz, 0.6H), 8.95 (s,
0.4H),
8.00 - 7.93 (m, 2H), 7.44- 7.40 (m, 1H), 7.37 - 7.32 (m, 1H), 7.24- 7.18 (m,
1H), 6.02
(s, 0.4H), 5.91 (d, J= 3.6 Hz, 0.6H), 3.90 - 3.84 (m, 0.4H), 3.65 - 3.60 (m,
3.6H), 3.53 -
3.50 (m, 5H), 2.89 - 2.87 (m, 0.4H), 2.76 - 2.69 (m, 0.6H), 2.23 (s, 3H), 2.17
- 2.07 (m,
2H), 1.94 - 1.77 (m, 3H), 1.68 - 1.62 (m, 1H), 1.58 - 1.45 (m, 2H).
A racemic mixture of (trans)- methyl 4-(2-chloro-4-fluoropheny1)-6-(4-(4-(2-
methoxy-
2-oxoethyl)-5-methyloxazol-2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-
carboxylate VII-48 (180 mg, 95 % purity, 0.291 mmol) was separated by chiral
Prep.
HPLC (separation condition: Superchiral S-AD 5 gm 21 * 250 mm; Mobile phase:
Hex : Et0H : formic acid = 75 : 25 : 0.05 at 20 mL/ min; Temp: 35 C;
Wavelength:
220 nm) to give compound VIE-48-A (65 mg, 95 % purity from 11-1 NMR, 36 %
yield,
98.6 % stereopure) as yellow solids and the title compound VII-48-B (70 mg, 95
%
purity from 11-1 NMR, 39 % yield, 96.4 % stereopure) as yellow solids.
Intermediate VII-48-A: LC-MS (ESI): RT = 1.84 min, mass calcd. for
C281128C1FN4055 586.1, m/z found 587.1 [M+1-11 . Chiral analysis (analytical
condition: Column: Chiralpak column: IE 5 gm 4.6 * 250 mm; Mobile Phase: Hex:
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Et011 : DEA = 70 : 30 : 0.2 at 1 mL/ min; Temp.: 30 C; Wavelength: 254 nm, RT
=
10.302 min). 111 NMR (400 MHz, DMSO-d6) 6 9.44 (hr s, 0.611), 8.97 (s, 0.411),
7.99 (s,
1.61I), 7.94 (s, 0.411), 7.43 - 7.41 (m, 111), 7.37 - 7.32 (m, 111), 7.23 -
7.19 (m, 111), 6.02
(s, 0.411), 5.91 (s, 0.611), 3.91 - 3.85 (m, 0.411), 3.68 - 3.57 (m, 3.61I),
3.53 - 3.50 (m,
511), 2.92 - 2.86 (m, 0.411), 2.75 - 2.69 (m, 0.611), 2.23 (s, 311), 2.14-
2.07 (m, 211), 2.01
- 1.74 (m, 3.411), 1.68 - 1.65 (m, 0.611), 1.59 - 1.45 (m, 211).
Intermediate VII-48-B: LC-MS (ESI): RT = 1.84 min, mass calcd. for
C281128C1FN405S 586.1, m/z found 587.1 [M+Hi . Chiral analysis (analytical
condition: Column: Chiralpak column: IE 5 i.tm 4.6 * 250 mm; Mobile Phase:
Hex:
Et0H : DEA = 70 : 30 : 0.2 at 1 mL/ min; Temp.: 30 C; Wavelength: 254 nm, RT
=
11.581 min). 111 NMR (400 MHz, DMSO-d6) 6 9.43 (hr s, 0.611), 8.97 (s, 0.411),
7.99 (s,
1.61I), 7.94 (s, 0.411), 7.43 - 7.41 (m, 111), 7.37 - 7.32 (m, 111), 7.23 -
7.19 (m, 111), 6.02
(s, 0.411), 5.91 (s, 0.611), 3.90 - 3.85 (m, 0.411), 3.65 - 3.62 (m, 3.61I),
3.53 - 3.50 (m,
511), 2.92 - 2.86 (m, 0.411), 2.75 - 2.69 (m, 0.611), 2.23 (s, 311), 2.14-
2.07 (m, 211), 2.01
- 1.74 (m, 3.411), 1.68 - 1.65 (m, 0.611), 1.59 - 1.46 (m, 211).
Compound VII-49-A:
methyl 4-(2-chloro-3,4-difluoropheny1)-6-((trans)-4-(5-(2-methoxy-2-
oxoethyppyrimidin-2-ypcydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a single stereoisomer)
Intermediate VII-49:
Methyl 4-(2-chloro-3,4-difluoropheny1)-6-qtrans)-4-(5-(2-methoxy-2-
oxoethyppyrimidin-2-ypcydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
111 NMR (400 MHz, CDC13) 6 8.63 - 8.62 (m, 1.71I), 8.60 - 8.58 (m, 0.311),
8.24 (hr s,
0.711), 7.84 - 7.83 (m, 111), 7.52 -7.51 (m, 0.311), 7.46 - 7.45 (m, 0.711),
7.39 - 7.37 (m,
0.311), 7.12 -7.09 (m, 111), 7.05- 7.00 (m, 111), 6.20 (s, 0.711), 6.06 (d,
J=2.4 Hz,
0.311), 4.10 - 4.05 (m, 0.711), 3.87 - 3.84 (m, 0.311), 3.75 (s, 311), 3.64
(s, 111), 3.62 (s,
211), 3.61 (s, 211), 3.07 - 2.97 (m, 111), 2.24- 2.20 (m, 311), 2.12 - 2.07
(m, 111), 1.94 -
1.87 (m, 211), 1.83 - 1.74 (m, 111), 1.69 - 1.64 (m, 111).
A racemic mixture of methyl 4-(2-chloro-3,4-difluoropheny1)-6-((trans)- 4- (5-
(2-
methoxy-2-oxoethyl)pyrimidin-2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate VII-49 (100 mg, 95 % purity, 0.158 mmol) was
separated by chiral Prep. HPLC (separation condition: Column: Chiralpak IG 4.6
i.tm
20 * 250 mm; Mobile Phase: Me0H DCM : DEA = 90 : 10 : 0.3 at 18 mL/min; Temp:
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30 C; Wavelength: 254 nm) to give VII-49-A (40 mg, 95 % purity from 111 NMR,
40 %
yield, 100 % stereopure) and VII-49-B (40 mg, 95 % purity from 111 NMR, 40 %
yield,
100 % stereopure) as yellow solids.
Intermediate VII-49-A: LC-MS (ESI): RT = 1.82 min, mass calcd. for
C281-126C1F2N504S 601.1, m/z found 602.3 [M+111 . Chiral analysis (Column:
Chiralpak IG Sum 4.6 * 250 mm; Mobile Phase: MeOH: DCM : DEA = 90 : 10 : 0.2
at 1 mL/min; Temp: 30 C; Wavelength: 254 nm, RT = 7.300 min). 111 NMR (400
MHz,
CDC13) 6 8.63 - 8.62 (m, 2H), 8.24 (s, 0.7H), 7.84 - 7.83 (m, 1H), 7.52 - 7.50
(m, 0.3H),
7.46 - 7.45 (m, 0.7H), 7.38 - 7.37 (m, 0.3H), 7.12 - 7.09 (m, 1H), 7.03 - 6.98
(m, 1H),
.. 6.20 (s, 0.7H), 6.06 (d, J=2.8 Hz, 0.3H), 4.10 - 4.05 (m, 0.7H), 3.87 -
3.84 (m, 0.3H),
3.75 (s, 3H), 3.64 (s, 1H), 3.62 (s, 2H), 3.61 (s, 2H), 3.07 - 3.04 (m, 1H),
2.28 - 2.20 (m,
3H), 2.12 - 2.07 (m, 1H), 1.96 - 1.89 (m, 2H), 1.84- 1.75 (m, 1H), 1.67 - 1.58
(m, 1H).
Intermediate VII-49-B: LC-MS (ESI): RT = 1.81 min, mass calcd. for
C281126C1F2N504S 601.1, m/z found 602.3 [M+111 . Chiral analysis (Column:
.. Chiralpak IG Sum 4.6 * 250 mm; Mobile Phase: MeOH: DCM : DEA = 90 : 10 :
0.2
at 1 mL/min; Temp: 30 C; Wavelength: 254 nm, RT = 10.123 min). 111 NMR (400
MHz, CDC13) 6 8.63 - 8.62 (m, 2H), 8.24 (br s, 0.7H), 7.84 - 7.83 (m, 1H),
7.52 - 7.50
(m, 0.3H), 7.46 - 7.45 (m, 0.7H), 7.38 - 7.37 (m, 0.311), 7.12 - 7.09 (m, 1H),
7.03 - 6.98
(m, 1H), 6.20 (s, 0.7H), 6.06 (d, J=2.8 Hz, 0.3H), 4.10 - 4.05 (m, 0.7H), 3.87
- 3.84 (m,
.. 0.3H), 3.75 (s, 3H), 3.64 (s, 1H), 3.62 (s, 2H), 3.61 (s, 2H), 3.07 - 3.04
(m, 1H), 2.28 -
2.20 (m, 3H), 2.12 - 2.07 (m, 1H), 1.96 - 1.89 (m, 2H), 1.84- 1.75 (m, 1H),
1.67 - 1.58
(m, 1H).
Compound VII-50-A:
methyl 4-(2-chloro-4-fluoropheny1)-6-((trans)-4-(5-(2-methoxy-2-
oxoethyl)pyrimidin-
.. 2-y0cyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer + acid + ethyl ester)
Intermediate VII-50:
methyl 4-(2-chloro-4-fluoropheny1)-6-((trans)-4-(5-(2-methoxy-2-
oxoethyl)pyrimidin-
2-ypcydohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids.
111 NMR (400 MHz, CDC13) 6 8.63 (s, 0.8H), 8.62 (s, 1.2H), 8.22 (br s, 0.7H),
7.84 -
7.82 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.4H), 7.44 (d, J= 3.2 Hz, 0.6H), 7.40 (br
s, 0.3H),
.. 7.33 - 7.27 (m, 1H), 7.14- 7.12 (m, 1H), 6.96 - 6.89 (m, 1H), 6.20 (s,
0.6H), 6.06 (d, J=
5.2 Hz, 0.4H), 4.09 - 4.03 (m, 0.6H), 3.87 - 3.83 (m, 0.4H), 3.75 (s, 3H),
3.63 (s, 1H),
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3.62 (s, 211), 3.61 (s, 211), 3.07 - 3.00 (m, 111), 2.24 - 2.08 (m, 411), 1.97
- 1.88 (m, 211),
1.82 - 1.76 (m, 111), 1.73 - 1.65 (m, 111).
A racemic mixture of methyl 4-(2-chloro-4-fluoropheny1)-6-((trans)-4-(5-(2-
methoxy-
2-oxoethyl)pyrimidin-2-yl)cyclohexyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate VII-50 (120 mg, 95 % purity, 0.195 mmol) was separated by chiral
Prep.
HPLC (separation condition: Column: Chiralpak IA 4.6 i_tm 20 * 250 mm; Mobile
Phase: Hex : Et0H : DEA = 40 : 60 : 0.3 at 10 mL/min; Temp: 30 C; Wavelength:
254
nm) to give VII-50-A (a mixture of acid and ethyl ester, 30 mg, 25 % yield,
100 %
stereopure) and VII-50-B (50 mg, 95 % purity from 1H NMR, 42 % yield, 98 %
.. stereopure) as yellow solids.
Mixture VII-50-A: Chiral analysis (Column: Chiralpak IA 5 um 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 40 :60 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 254 nm, RT = 3.223 min, 7.171min). LC-MS (ESI): RT = 1.40 min,
1.83
min, mass calcd. for C281127C1FN504S 584.1, m/z found 570.1 [M+11-141+, 598.2
[M+H+141 .
Intermediate VII-50-B: LC-MS (ESI): RT = 1.78 min, mass calcd. for
C281127C1FN504S 583.1, m/z found 584.2 [M+Hi . Chiral analysis (Column:
Chiralpak IA 5 um 4.6 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 40 : 60 : 0.2
at
1 mL/min; Temp: 30 0C; Wavelength: 254 nm, RT = 13.619 min). 1H NMR (400 MHz,
.. CDC13) 6 8.63 (s, 0.811), 8.62 (s, 1.211), 8.22 (br s, 0.711), 7.84 - 7.83
(m, 111), 7.50 (d, J
= 6.0 Hz, 0.411), 7.45 (d, J= 3.2 Hz, 0.611), 7.40 (br s, 0.311), 7.35 - 7.31
(m, 111), 7.14
- 7.12 (m, 111), 6.96 - 6.89 (m, 111), 6.20 (s, 0.611), 6.06 (d, J=2.8 Hz,
0.411), 4.10 -
4.04 (m, 0.611), 3.89 - 3.82 (m, 0.411), 3.75 (s, 311), 3.64 (s, 111), 3.62
(s, 211), 3.61 (s,
211), 3.06 - 2.98 (m, 111), 2.27 - 2.08 (m, 411), 1.97 - 1.67 (m, 411).
.. Compoumd VIII-1:
Methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-(3,4-difluoro-2-
methylpheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 1.96 min, mass calcd. For C261130F2N404S 532.2 m/z found
533.3
[M+1-11 . 1H NMR (400 MHz, DMSO-d6) 69.56 (d, J= 3.2 Hz, 0.811), 9.13 (s,
0.211),
7.99 - 7.91 (m, 211), 7.25 - 7.18 (m, 111), 7.11 - 7.08 (m, 0.811), 6.97 -
6.94 (m, 0.211),
5.82 (s, 0.211), 5.69 (d, J= 3.2 Hz, 0.811), 4.14- 4.00 (m, 2.211), 3.81 -
3.75 (m, 0.811),
3.52 (s, 311), 2.85 - 2.68 (m, 211), 2.43 (s, 311), 1.91 - 1.64 (m, 311), 1.52
- 1.48 (m, 111),
1.44 (s, 911).
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A stereoisomeric mixture of VIII-1 (600 mg, 1.13 mmol) was separated by chiral
Prep. SFC (separation condition: Column: Chiralpak IG 5 pm 20 * 250 mm; Mobile
Phase: CO2: Me0H : DEA = 80 : 20 : 0.2 at 50 g/ min; Col. Temp 40 C;
Wavelength:
214 nm; Back pressure: 100 bar) to afford the title compounds Vu-1-A (260 mg,
43 %
yield, 100 % stereopure) and VIII-1-B (270 mg, 45 % yield, 98.6 % stereopure)
as
yellow solids.
VIII-1-A: LC-MS (ESI): RT = 1.87 min, mass calcd. For C26H30F2N404S 532.2 m/z
found 533.6 [M+Hi . Chiral analysis (Column: Chiralpak IG; Mobile Phase: CO2:
Me0H : DEA = 80 : 20 : 0.2 at 3.0 g/min; Col. Temp: 40.1 C; Wavelength: 230
nm,
Back pressure: 100 bar, RT = 3.08 min). 1H NMR (300 MHz, CDC13) 6 8.10 (s,
0.7H),
7.80 (s, 1H), 7.51 (d, J= 2.1 Hz, 0.3H), 7.43 (d, J= 2.4 Hz, 0.7H), 7.09 -
7.06 (m,
0.3H), 7.04 (s, 0.2H), 6.97 - 6.85 (m, 1.8H), 5.93 (s, 0.8H), 5.85 (s, 0.2H),
4.39 - 4.16
(m, 2.8H), 3.85 - 3.78 (m, 0.2H), 3.60 (s, 3H), 2.94 - 2.79 (m, 2H), 2.57 (s,
2.3H), 2.42
(s, 0.7H), 2.00 - 1.97 (m, 1H), 1.87 - 1.63 (m, 3H), 1.50 (s, 9H).
VIII-1-B: LC-MS (ESI): RT = 1.87 min, mass calcd. For C26H30F2N404S 532.2 m/z
found 533.7 [M+Hi . Chiral analysis (Column: Chiralpak IG; Mobile Phase: CO2:
Me0H : DEA = 80 : 20 : 0.2 at 3.0 g/min; Col. Temp: 39.9 C; Wavelength: 230
nm,
RT = 3.96 min). 1H NMR (300 MHz, CDC13) 6 8.10 (s, 0.7H), 7.80 - 7.79 (m, 1H),
7.51
(d, J= 2.1 Hz, 0.3H), 7.43 (d, J= 2.1 Hz, 0.7H), 7.09 - 7.07 (m, 0.3H), 7.05
(s, 0.2H),
6.95 - 6.87 (m, 1.8H), 5.93 (s, 0.8H), 5.85 (s, 0.2H), 4.37 - 4.15 (m, 2.7H),
3.84- 3.78
(m, 0.3H), 3.60 (s, 3H), 2.94 - 2.80 (m, 2H), 2.57 (s, 2.3H), 2.43 (s, 0.7H),
2.01 - 1.97
(m, 1H), 1.75 - 1.60 (m, 3H), 1.50 (s, 9H).
Compound VIII-2:
Ethyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-(3-fluoro-2-methylpheny0-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.143 min, mass calcd. for C27H33FN404S 528.2, m/z found
529.1
[M+1-11 . 1H NMR (400 MHz, CDC13) 6 8.08 (s, 1H), 7.80 - 7.78 (m, 1H), 7.49
(d, J=
2.8 Hz, 0.3H), 7.42 (d, J= 2.8 Hz, 0.7H), 7.08 - 7.01 (m, 2H), 6.95 - 6.88 (m,
1H), 6.01
(s, 0.7H), 5.92 (d, J= 2.0Hz, 0.3H), 4.31 - 4.17 (m, 3H), 4.08 - 3.99 (m, 2H),
2.89 -
2.82 (m, 2H), 2.54 (d, J= 2.0 Hz, 2H), 2.39 (d, J= 1.6 Hz, 1H), 2.03 - 2.00
(m, 1H),
1.87 - 1.84 (m, 1H), 1.69 - 1.56 (m. 2H), 1.50 (s, 9H), 1.13 - 1.09 (m, 3H).
A stereoisomeric mixture of ethyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-
(3-
fluoro-2-methylpheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
VIII-2
(3.0 g, 85 % purity, 4.82 mmol) was separated by Chiral Prep. HPLC (Column:
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Chiralpak IC 5 i.tm 20 mm * 250 mm; Mobile Phase: Hex : Et0H : DEA = 98 : 2 :
0.3
at 22 mL/ min; Temp: 30 C; Wavelength: 214 nm) to afford the title compounds
VIII-2-A (950 mg, 32 % yield, 90 % purity, 100 % stereopure) and VIII-2-B (650
mg,
23 % yield, 90 % purity, 99.3 % stereopure) as yellow solids.
VIII-2-A: Chiral HPLC (Colum: Chiralpak IC 5 i.tm 4.6 mm * 250 mm; Mobile
Phase:
Hex : Et0H : DEA = 98 : 2 : 0.2 at 1 mL/min; Col. Temp: 40 0C; Wavelength: 254
nm,
RT = 17.28 min). 111 NMR (400 MHz, CDC13) 6 8.06 (s, 0.7H), 7.79 (d, J= 3.2
Hz, 1H),
7.49 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.16 - 7.01 (m, 2.3H),
6.95 - 6.88
(m, 1H), 6.01 (s, 0.7H), 5.92 (d, J= 2.4 Hz, 0.3H), 4.38 - 4.17 (m, 2.7H),
4.09 - 3.99 (m,
2H), 3.86 - 3.80 (m, 0.3H), 2.93 - 2.82 (m, 2H), 2.53 (s, 2.2H), 2.39 (s,
0.8H), 2.06 -
2.00 (m, 1H), 1.87 - 1.68 (m, 2H), 1.62 - 1.55 (m, 1H), 1.50 (s, 9H), 1.13 -
1.09 (m, 3H).
WII-2-B: Chiral HPLC(Colum: Chiralpak IC 5 i.tm 4.6 mm * 250 mm; Mobile Phase:
Hex : Et0H : DEA = 98 : 2 : 0.2 at 1 mL/min; Col. Temp: 40 0C; Wavelength: 254
nm,
RT = 19.61 min). 111 NMR (400 MHz, CDC13) 6 8.06 (s, 0.7H), 7.79 (d, J= 2.8
Hz, 1H),
7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.15 - 7.01 (m, 2.3H),
6.95 - 6.88
(m, 1H), 6.01 (s, 0.7H), 5.92 (d, J= 2.0 Hz, 0.3H), 4.35 - 4.17 (m, 2.7H),
4.10 - 3.99 (m,
2H), 3.86 - 3.81 (m, 0.3H), 2.89 - 2.83 (m, 2H), 2.54 (s, 2.2H), 2.40 (s,
0.8H), 2.03 -
2.00 (m, 1H), 1.87 - 1.84 (m, 1H), 1.73 - 1.68 (m, 1H), 1.62 - 1.56 (m, 1H),
1.50 (s, 9H),
1.14- 1.09 (m, 3H).
Compound WII-3:
Ethyl 6-(1-(tert-butoxycarbonyppiperidin-4-y1)-444-fluoro-2-methylpheny0-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.169 min, mass calcd. for C27H33FN404S 528.2, m/z found
529.1
[M+111 . 111 NMR (400 MHz, CDC13) 6 8.07 (s, 1H), 7.80 - 7.78 (m, 1H), 7.50
(d, J=
3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.06 - 6.79 (m, 3H), 5.96 (s, 0.7H),
5.87 (d, J
= 2.0 Hz, 0.3H), 4.34 - 4.15 (m, 2.7H), 4.07 - 4.00 (m, 2H), 3.85 - 3.79 (m,
0.3H), 2.89 -
2.86 (m, 2H), 2.63 (s, 2H), 2.48 (s, 1H), 2.03 - 2.00 (m, 1H), 1.87- 1.83 (m,
1H), 1.70 -
1.55 (m, 2H), 1.50 (s, 9H), 1.14- 1.10 (m, 3H).
A stereoisomeric mixture of VIII-3 (6.00 g, 90 % purity, 10.2 mmol) was
separated by
chiral Prep. SFC (Column: Chiralpak IG 5 i.tm 20 mm * 250 mm; Mobile Phase:
CO2:
MeOH: DEA = 75 : 25 : 0.3 at 50 g/min; Col. Temp: 40 C; Wavelength: 214 nm,
Back
pressure: 100 bar) to afford the title compounds VIII-3-A (2.70 g, 90 %
purity, 45 %
yield, 100 % stereopure) and WII-3-B (2.60 g, 90 % purity, 43 % yield, 99.2 %
stereopure) as yellow solids.
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VIII-3-A: Chiral analysis (Colum: Chiralpak IG 5 pm 4.6 mm * 250 mm; Mobile
Phase: CO2: MeOH: DEA = 75 : 25 : 0.2 at 3.00 g/min; Col. Temp: 40 C;
Wavelength:
214 nm, Back pressure: 100 bar, RT = 2.73 min). 11-1 NMR (400 MHz, CDC13) 6
8.05 (s,
0.7H), 7.80 - 7.79 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz,
0.7H), 7.32 -
7.28 (m, 0.3H), 7.18 - 7.15 (m, 0.7H), 7.00 (s, 0.3H), 6.90 - 6.76 (m, 2H),
5.96 (s, 0.7H),
5.87 (s, 0.3H), 4.35 - 4.16 (m, 2.7H), 4.09 - 3.99 (m, 2H), 3.84 - 3.79 (m,
0.3H), 2.92 -
2.83 (m, 2H), 2.63(s, 2H), 2.48 (s, 1H), 2.03 - 2.00 (m, 1H), 1.87 - 1.84 (m,
1H), 1.72 -
1.59 (m, 2H), 1.50 (s, 9H), 1.14- 1.09 (m, 3H).
VIII-3-B: Chiral analysis (Colum: Chiralpak IG 5 pm 4.6 mm * 250 mm; Mobile
Phase: CO2: MeOH: DEA = 75 : 25 : 0.2 at 3.00 g/min; Col. Temp: 40 C;
Wavelength:
214 nm, Back pressure: 100 bar, RT = 3.59 min). 11-1 NMR (400 MHz, CDC13) 6
8.05 (s,
0.7H), 7.79 (d, J= 2.8 Hz, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 2.8 Hz,
0.7H),
7.32 - 7.28 (m, 0.3H), 7.18 - 7.15 (m, 0.7H), 6.99 (s, 0.3H), 6.90 - 6.76 (m,
2H), 5.96 (s,
0.7H), 5.87 (d, J= 2.0 Hz, 0.3H), 4.36 - 4.16 (m, 2.7H), 4.09 - 3.99 (m, 2H),
3.84- 3.78
(m, 0.3H), 2.92 - 2.83 (m, 2H), 2.63 (s, 2H), 2.49 (s, 1H), 2.03 - 2.00 (m,
1H), 1.87 -
1.79 (m, 1H), 1.73 - 1.69 (m, 1H), 1.61 - 1.56 (m, 1H), 1.50 (s, 9H), 1.15 -
1.10 (m, 3H).
Compound 111II-4:
Methyl 6-(1-(tert-butoxycarbonyppiperidin-4-y1)-4-(3-fluoro-2-methylpheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.133 min, mass calcd. for C26H3iFN404S 514.6, m/z found
515.1
[M+1-11 . 11-1 NMR (400 MHz, CDC13) 6 8.10 (br s, 1H), 7.79 - 7.78 (m, 1H),
7.49 (d, J=
3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.17 - 7.00 (m, 2H), 6.95 - 6.88 (m,
1H), 6.01
(s, 0.7H), 5.91 (s, 0.3H), 4.40 - 4.17 (m, 2.7H), 3.88 - 3.80 (m, 0.3H), 3.59 -
3.58 (m,
3H), 2.99 - 2.79 (m, 2H), 2.54 (d, J= 2 Hz, 2.2H), 2.38 (d, J= 2 Hz, 0.8H),
2.04 - 1.59
(m, 4H), 1.50 (s, 9H).
A stereoisomeric mixture of methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-
(3-
fluoro-2 -
methylpheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate VIII-4 (5.0
g, 90 %
purity, 8.77 mmol) was separated by chiral Prep. HPLC (separation conditon:
Column: Chiralpak IG 5 pm 20 * 250 mm; Mobile Phase: CO2 : Me0H : DEA = 75:
25 : 0.3 at 50 g/ min; Temp: 30 C; Wavelength: 230 nm) to give the title
compounds
VIII-4-A (2.2 g, 90 % purity, 44 % yield, 99.1 % stereopure) and VIII-4-B (2.0
g, 90 %
purity, 40 % yield, 100 % stereopure) as yellow solids.
chiral analytical: (Column: Chiralpak IG 5 gm 4.6 * 250 mm; Mobile Phase:
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CO2: Me0H = 75: 25 at 3 g/ min; Col. Temp: 40 C; Wavelength: 214 nm, Back
pressure: 100 bar, RT = 3.38 min). 111 NMR (400 MHz, CDC13) 6 8.09 (s, 1H),
7.79 -
7.78 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.16 -
7.04 (m, 2H),
6.99 - 6.88 (m, 1H), 6.00 (s, 0.7H), 5.91 (s, 0.3H), 4.43 - 4.16 (m, 2.7H),
3.87 - 3.81 (m,
0.3H), 3.59 - 3.58 (m, 3H), 2.98 - 2.78 (m, 2H), 2.54 (d, J= 2 Hz, 2.2H), 2.37
(d, J=
2.4 Hz, 0.8H), 2.03 - 1.59 (m, 4H), 1.50 (s, 9H).
VIII-4-B: chiral analytical: (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
CO2: Me0H = 75: 25 at 3 g/ min; Col. Temp: 40 C; Wavelength: 214 nm, Back
pressure: 100 bar, RT = 2.91 min). 111 NMR (400 MHz, CDC13) 6 8.10 (s, 1H),
7.79 -
7.78 (m, 1H), 7.49 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 3.2 Hz, 0.7H), 7.17 -
7.12 (m, 2H),
7.00 - 6.88 (m, 1H), 6.01 (s, 0.7H), 5.91 (d, J= 3.2 Hz, 0.3H), 4.43 - 4.17
(m, 2.7H),
3.88 - 3.80 (m, 0.3H), 3.59 - 3.58 (m, 3H), 2.98 - 2.79 (m, 2H), 2.54 (d, J= 2
Hz, 2.2H),
2.39 (d, J= 2 Hz, 0.8H), 2.04 - 1.56 (m, 4H), 1.50 (s, 9H).
Compound VIII-5-B:
methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-(4-fluoro-2-methylpheny0-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single stereoisomer)
Intermediate VI11-5-2:
Methyl 6-(1-(tert-butoxycarbonyppiperidin-4-y1)-444-fluoro-2-methylpheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 1.79 min, mass calcd. for
C26H3iFN4O4S 514.2, m/z found 515.4 [M+111 . 111 NMR (400MHz, CDC13) 6 8.09
(s,
0.7H), 7.79 (d, J= 2.8 Hz, 1H), 7.49 (d, J= 3.2 Hz, 0.3H), 7.42 (d, J= 2.8 Hz,
0.7H),
7.32 - 7.28 (m, 0.3H), 7.17 - 7.13 (m, 0.7H), 7.07 (s, 0.3H), 6.90 - 6.76 (m,
2H), 5.95 (s,
0.7H), 5.85 (s, 0.3H), 4.40 - 4.20 (m, 2H), 3.59 (s, 2H), 3.58 (s, 1H), 2.97 -
2.79 (m, 2H),
2.63 (s, 2H), 2.47 (s, 1H), 2.02 - 1.97 (m, 1H), 1.90 - 1.81 (m, 1H), 1.72 -
1.59 (m, 3H),
1.50 (s, 9H).
A stereoisomeric mixture of methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-
(4-
fluoro-2-methylpheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
VIII-5-2
(2.00 g, 3.88 mmol) was separated by chiral Prep. SFC (Column: Chiralpak IG 5
pm
20 * 250 mm; Mobile Phase: CO2: Me0H : DEA= 75 : 25 : 0.3 at 50 g/min; Col.
Temp
C; Wavelength: 214 nm; Back pressure: 100 bar) to afford title compounds VIII-
5-2A (684 mg, 34 % yield, 99.3 % stereopure) as yellow solids and VIII-5-2B
(607 mg,
30 % yield, 100 % stereopure) as yellow solids.
35 VIII-5-2A: LC-MS (ESI): RT = 1.89 min, mass calcd. for C26H3iFN4O4S
514.2, m/z
found 515.1 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
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Mobile Phase: CO2 : Me0H : DEA = 75 : 25 : 0.2 at 3.0 g/min; Col. Temp: 40 C;
Wavelength: 280 nm, Back pressure: 100 bar; RT = 3.81 min).
VIII-5-2B: LC-MS (ESI): RT = 1.88 min, mass calcd. for C26H31FN404S 514.2, m/z
found 515.1 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H : DEA = 75 : 25 : 0.2 at 3.0 g/min; Col. Temp: 40 C;
Wavelength: 280 nm, Back pressure: 100 bar; RT = 2.93 min).
Compound VIII-6:
methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-(2-chloro-3-fluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 1.55 min, mass calcd. For C25H28C1FN404S 534.2 m/z found
535.5
[M+11] .111 NMR (400 MHz, DMSO-d6) 69.55 (d, J= 3.6 Hz, 0.8H), 9.14 (s, 0.2H),
8.00 - 7.98 (m, 1.7H), 7.93 (d, J= 3.2 Hz, 0.3H), 7.40 - 7.31 (m, 2H), 7.21 -
7.15 (m,
1H), 6.07 (s, 0.2H), 5.97 (d, J= 3.6 Hz, 0.8H), 4.15 - 3.98 (m, 2.2H), 3.84-
3.76 (m,
0.8H), 3.52 (s, 2.4H), 3.51 (s, 0.6H), 2.82 - 2.71 (m, 2H), 1.99 - 1.65 (m,
4H), 1.44 (s,
9H).
A stereoisomeric mixture of VIII-6 (1.95 g, 3.65 mmol) was separated by chiral
Prep.
SFC (Column: Chiralpak IG 5 pm 20 * 250 mm; Mobile Phase: CO2: Me0H = 70: 30
at 50 g/ min; Col. Temp 41.1 C; Wavelength: 214 nm; Back pressure: 100 bar)
to
afford the title compounds VIII-6-A (910 mg, 47 % yield, 100 % stereopure) and
VIII-
6-B (960 mg, 49 % yield, 99.1 % stereopure) as yellow solids.
VIII-6-A: LC-MS (ESI): RT = 1.96 min, mass calcd. for C25H28C1FN404S 534.2,
m/z
found 535.2 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 pm 4.6 * 250 mm;
Mobile Phase: CO2: Me0H = 70: 30 at 2.999 g/min; Temp: 40 C; Wavelength: 230
nm, RT = 2.74 min).
VIII-6-B: LC-MS (ESI): RT = 1.96 min, mass calcd. for C25H28C1FN404S 534.2,
m/z
found 535.3 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 pm 4.6 * 250 mm;
Mobile Phase: CO2: Me0H = 70: 30 at 2.999 g/min; Temp: 40.4 C; Wavelength:
230
nm, RT = 3.60 min).
Compound VIII-7:
methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-(2-chloro-4-fluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydro-pyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
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A stereoisomeric mixture of VIII-7 (7.00 g, 13.1 mmol) was further separated
by
chiral Prep. HPLC (Column: Chiralpak IA 5 gm 20 * 250 mm; Mobile Phase: Hex:
Et0H = 90 : 10 at 23 mL/ min; Temp: 30 C; Wavelength: 230 nm) to afford
stereoisomers VIII-7-A (2.44 g, 35% yield) and VIII-7-B (1.56 g, 22 % yield).
VIII-7-A: SFC (analytical condition: Column: Chiralpak IG; Mobile Phase:
CO2:Me0H=70:30 at 1.0 mL/min; Temp: 41 C; Wavelength: 230 nm, RT = 2.59 min).
1H NMR (400 MHz, CDC13) 6 8.12 (s, 0.5H), 7.81 (t, J= 3.2 Hz, 1H), 7.48 (d, J=
3.2
Hz, 0.6H), 7.44 (d, J= 3.6 Hz, 0.4H), 7.41 (br s, 0.5H), 7.30 - 7.27 (m, 1H),
7.15 - 7.11
(m, 1H), 6.96 - 6.88 (m, 1H), 6.19 (s, 0.4H), 6.06 (d, J= 2.8 Hz, 0.6H), 4.35 -
4.21 (m,
2H), 4.20 - 4.12 (m, 0.4H), 3.96 - 3.89 (m, 0.6H), 3.60 (s, 2.4H), 3.59 (s,
0.6H), 2.94 -
2.78 (m, 2H), 2.10 - 1.79 (m, 3H), 1.74- 1.63 (m, 1H), 1.50 (s, 9H).
VIII-7-B: LC-MS (ESI): RT = 2.191 min, mass calcd. For C25H28C1FN404S 534.2
m/z
found 534.9 [M+Hi . Chiral HPLC (Column: Chiralpak IA 5 gm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H = 85 :15 at 1.0 mL/min; Temp: 30 C; Wavelength: 230
nm, RT = 6.154 min). 1H NMR (400 MHz, CDC13) 68.12 (s, 0.5H), 7.82 (t, J= 3.2
Hz,
1H), 7.47 (dd, J= 20.4, 3.0 Hz, 1H), 7.41 (br s, 0.5H), 7.30 - 7.28 (m, 1H),
7.15 - 7.11
(m, 1H), 6.96 - 6.88 (m, 1H), 6.19 (s, 0.4H), 6.06 (d, J= 2.4 Hz, 0.6H), 4.36 -
4.22 (m,
2H), 4.20 - 4.12 (m, 0.4H), 3.96 - 3.88 (m, 0.6H), 3.60 (s, 2.4H), 3.59 (s,
0.6H), 2.95 -
2.79 (m, 2H), 2.09 - 1.74 (m, 3H), 1.63 - 1.58 (m, 1H), 1.50 (s, 9H).
Compound VIII-8:
Ethyl 6-(1-(tert-butoxycarbonyppiperidin-4-y1)-442-chloro-4-fluoropheny1)-2-
(thiazol-
2-y0-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.01 min, mass calcd. for C26H30C1FN404S 548.2, m/z found
549.5
[M+1-11 . 1H NMR (400 MHz, DMSO-d6) 6 9.47 (d, J= 2.4 Hz, 0.7H), 9.04 (s,
0.3H),
8.01 - 7.99 (m, 1.7H), 7.93 - 7.92 (m, 0.3H), 7.43 - 7.34 (m, 2H), 7.24 - 7.18
(m, 1H),
6.03 (s, 0.2H), 5.92 (d, J= 3.2 Hz, 0.8H), 4.11 - 4.01 (m, 2H), 3.99 - 3.94
(m, 2H), 3.83
- 3.75 (m, 1H), 2.84 - 2.69 (m, 2H), 1.91 - 1.66 (m, 3H), 1.57 - 1.49 (m, 1H),
1.43 (s,
9H) , 1.10- 1.02 (m, 3H).
A stereoisomeric mixture of ethyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-
(2-
chloro-4-fluoropheny0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
VIII-8
(2.50 g, 4.55 mmol) was separated by Chiral Prep. HPLC (separation condition:
Column: Chiralpak IG 5 gm 20 * 250 mm; Mobile Phase: CO2 : Me0H = 70: 30 at 50
.. g/min; Temp: 30 C; Wavelength: 214 nm; Back Pressure: 100 bar) to give
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thecompounds WII-8-A (1.00 g, 40 % yield, 100 % stereopure) and VIET-8-B (1.20
g,
48 % yield, 99.8 % stereopure) as yellow solids.
VIII-8-A: Chiral analysis (Column: Chiralpak IG 5 gm 4.6 * 250 mm; Mobile
Phase:
CO2: Me0H = 70 : 30 at 3 g/min; Temp: 30 C; Wavelength: 230 nm, Back
Pressure:
100 bar; RT = 2.5 min).
VIII-8-B: Chiral analysis (Column: Chiralpak IG 5 gm 4.6 * 250 mm; Mobile
Phase:
CO2 : Me0H = 70 : 30 at 3 g/min; Temp: 30 C; Wavelength: 230 nm, Back
Pressure:
100 bar; RT = 3.4 min).
Compound VIII-9:
Ethyl 6-(1-(tert-butoxyearbonyl)piperidin-4-y1)-442-chloro-3-fluoropheny1)-2-
(thiazol-
2-y1)- 1,4-dihydropyrimidine-5-earboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
11-1 NMR (400 MHz, CDC13) 6 8.11(br s, 0.4H), 7.82 (d, J= 3.2 Hz, 1H), 7.54 -
7.41 (m,
1H), 7.35 - 7.29 (m, 0.6H), 7.25 - 7.12 (m, 2H), 7.10 - 7.00 (m, 1H), 6.27 (s,
0.5H), 6.14
(s, 0.5H), 4.38 - 4.18 (m, 3H), 4.08 - 3.90 (m, 2H), 2.95 - 2.76 (m, 2H), 2.01
- 1.61 (m,
4H), 1.50 (s, 9H), 1.11 (t, J= 7.2 Hz, 3H).
A stereoisomeric mixture of ethyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-
(2-
chloro-3-fluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate
WII-9
(1.00 g, 1.82 mmol) was separated by chiral Prep. SFC (Column: Chiralpak IG 5
pm
20 * 250mm; Mobile Phase: CO2: Me0H = 75 : 25 at 50 g/min; Col. Temp: 39.8 C;
Wavelength: 214 nm; Back pressure: 100 bar) to afford the compounds WII-9-A
(410
mg, 41% yield, 100 % stereopure) and VIII-9-B (450 mg, 45 % yield, 100 %
sterepure)
as a yellow solids.
VIII-9-A: Chiral analysis (Column: Chiralpak IG 5 gm 4.6 * 250 mm; Mobile
Phase:
CO2 : Me0H = 80 : 20 at 3 g/min; Col. Temp: 40 C; Wavelength: 214 nm; Back
pressure: 100 bar; RT = 4.69 min).
VIII-9-B: Chiral analysis (Column: Chiralpak IG 5 gm 4.6 * 250 mm; Mobile
Phase:
CO2 : Me0H = 80 : 20 at 3 g/min; Col. Temp: 40 C; Wavelength: 214 nm; Back
pressure: 100 bar; RT = 5.92 min).
Compound VIII- 10:
Methyl 6-(1-(tert-butoxyearbonyl)piperidin-4-y1)-4-(2-chloro-3,4-
difluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
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111 NMR (400MHz, CDC13) 6 8.16 (br s, 0.5H), 7.82 (d, J= 3.2 Hz, 1H), 7.51 (d,
J=
2.8 Hz, 0.5H), 7.46 (d, J= 3.2 Hz, 1H), 7.10 - 6.98 (m, 2H), 6.18 (s, 0.5H),
6.06 (s,
0.5H), 4.41 - 4.16 (m, 2H), 3.97 - 3.91 (m, 0.4H), 3.74- 3.69 (m, 0.6H), 3.61
(s, 1.2H),
3.60 (s, 1.8H), 3.02 - 2.78 (m, 2H), 2.08 - 1.80 (m, 2H), 1.73 - 1.58 (m, 2H),
1.50 (s,
9H).
A stereoisomeric mixture of VIII-10 (18.0 g, 32.6 mmol) was separated by
chiral Prep.
SFC (Column: chiralpak IG 5 pm 20 * 250 mm; Mobile Phase: CO2: Me0H = 70: 30
at 50 g/min; Co-solvent: Me0H; Col. Temp 40 C; Wavelength: 230 nm; Back
pressure: 100 bar) to give the title compounds VI11-10-A (8.0 g, 40 % yield,
100 %
.. stereopure) and VIII-10-B (8.0 g, 40%, 100% stereopure).
VIII-10-A: Chiral SFC: (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
CO2: Me0H : DEA = 70 : 30 : 0.2 at 2.999 g/min; Col. Temp: 39.6 C;
Wavelength:
230 nm, Back pressure: 100 bar, RT = 2.37 mm). 'H NMR (400 MHz, DMSO-d6) 6
9.62 (br s, 0.7H), 9.20 (s, 0.3H), 8.01 - 7.99 (m, 1.7H), 7.94 (d, J= 3.6 Hz,
0.3H), 7.49
- 7.42 (m, 1H), 7.23 - 7.15 (m, 1H), 6.03 (s, 0.3H), 5.94 (s, 0.7H), 4.18 -
3.99 (m, 2.3H),
3.85 - 3.76 (m, 0.7H), 3.54 (s, 2H), 3.53 (s, 1H), 2.92 - 2.65 (m, 2H), 1.96 -
1.51 (m,
4H), 1.44 (s, 9H).
VIII-10-B: Chiral SFC: (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
CO2: Me0H : DEA = 70 : 30 : 0.2 at 2.999 g/min; Col. Temp: 40 C; Wavelength:
230
nm, Back pressure: 100 bar, RT = 3.44 mm). 'H NMR (400 MHz, DMSO-d6) 6 9.62
(br
s, 0.7H), 9.20 (s, 0.3H), 8.01 - 7.99 (m, 1.7H), 7.94 (d, J= 3.6 Hz, 0.3H),
7.49 - 7.42 (m,
1H), 7.23 - 7.15 (m, 1H), 6.03 (s, 0.3H), 5.94 (s, 0.7H), 4.18 - 3.99 (m,
2.3H), 3.85 -
3.76 (m, 0.7H), 3.54 (s, 1H), 3.53 (s, 2H), 2.92 - 2.65 (m, 2H), 1.96 - 1.51
(m, 4H), 1.44
(s, 9H).
Compound VIII-11-6:
ethyl 6-(1-(tert-butoxyearbony1)-2-methylpiperidin-4-y1)-442-chloro-3,4-
difluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-earboxylate (a
mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 2.13 min, mass calcd. For
C27H31C1F2N404S 580.2, m/z found 581.0 [M+111 . 1FINMR (400 MHz, DMSO-d6) 6
9.61 - 9.59(m, 1H), 8.00 - 7.98 (m, 1.7H), 7.94 (d, J= 3.2 Hz, 0.3H), 7.49 -
7.43 (m,
1H), 7.21 - 7.16 (m, 1H), 6.05 - 6.02 (m, 0.3H), 5.95 - 5.91 (m, 0.7H), 4.47 -
4.29 (m,
1H), 4.07 - 3.94 (m, 4H), 3.02 - 2.82 (m, 1H), 1.99 - 1.55 (m, 3H), 1.43 (s,
9H), 1.36 -
1.23 (m, 1H), 1.18 - 1.16 (m, 3H), 1.10 - 1.07 (m, 3H).
Compound VIII-12:
226
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Ethyl 6-(1-(tert-butoxycarbonyOpiperidin-4-0-442-chloro-3,4-difluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.05 min, mass calcd. for C26H29C1F2N404S 566.2, m/z found
567.7 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.36 (s, 0.5H), 7.82 (d, J= 3.2 Hz,
1H),
7.51 (d, J= 2.8 Hz, 0.5H), 7.46 (d, J= 3.2 Hz, 0.5H), 7.38 (s, 0.5H), 7.10 -
6.99 (m,
2H), 6.20 (s, 0.5H), 6.08 (s, 0.5H), 4.30 (hr s, 1.5H), 4.09 - 3.99 (m, 2H),
3.97 - 3.89 (m,
0.5H), 2.91 - 2.79 (m, 2H), 1.80 - 1.74 (m, 3H), 1.61 - 1.58 (m, 2H), 1.50 (s,
9H), 1.13
(t, J= 6.8 Hz, 3H).
A stereoisomeric mixture of VIII-12 (13.0 g, 22.9 mmol) was separated by
chiral Prep.
HPLC (Column: Chiralpak IA 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H = 95 :
5
at 25 mL/min, Temp: 30 C; Wavelength: 214 nm) to afford the compounds WII-12-
A
(5 g, 38 % yield, 99.7 % stereopure) and VIII 12B (5 g, 38 % yield, 98.4 %
stereopure).
VIII-12-A: LC-MS (ESI): RT = 2.05 min, mass calcd. for C26H29C1F2N404S 566.2,
m/z
found 567.6 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H = 95 : 5 at 1.0 mL/min; Temp: 30 C; Wavelength: 230
nm;
RT = 7.937 min). 11-1 NMR (400 MHz, CDC13) 6 8.12 (s, 0.5H), 7.83 - 7.82 (m,
1H),
7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 3.2 Hz, 0.6H), 7.34 (s, 0.5H), 7.10 -
6.99 (m,
2H), 6.20 (s, 0.6H), 6.08 (d, J= 2.4 Hz, 0.4H), 4.36 - 4.14 (m, 2.6H), 4.10 -
3.99 (m,
2H), 3.97- 3.89 (m, 0.4H), 2.91 - 2.78 (m, 2H), 2.10- 1.63 (m, 3.5H), 1.58-
1.56 (m,
0.5H), 1.50 (s, 9H), 1.14 (t, J= 7.2 Hz, 3H).
VIII-12-B: LC-MS (ESI): RT = 2.05 min, mass calcd. for C26H29C1F2N404S 566.2,
m/z
found 567.6 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H = 95 : 5 at 1.0 mL/min; Temp: 30 C; Wavelength: 230
nm;
RT = 8.930 min). 11-1 NMR (400 MHz, CDC13) 6 8.12 (s, 0.5H), 7.83- 7.82 (m,
1H),
7.51 (d, J= 3.2 Hz, 0.4H), 7.46 (d, J= 3.2 Hz, 0.6H), 7.34 (s, 0.5H), 7.10 -
6.99 (m,
2H), 6.20 (s, 0.6H), 6.08 (d, J= 2.4 Hz, 0.4H), 4.36 - 4.14 (m, 2.6H), 4.10 -
3.99 (m,
2H), 3.97- 3.89 (m, 0.4H), 2.91 - 2.78 (m, 2H), 2.10- 1.63 (m, 3.5H), 1.58-
1.56 (m,
0.5H), 1.50 (s, 9H), 1.14 (t, J= 7.2 Hz, 3H).
Compound VIII-13:
Methyl 444-bromo-2-chloropheny1)-6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
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LC-MS (ESI): RT = 2.13 min, mass calcd. for C25H28BrC1N4O4S 594.1, m/z found
594.8 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.13 (s, 0.4H), 7.82 (t, J= 2.8 Hz,
1H),
7.56 - 7.54 (m, 1H), 7.50 (d, J= 2.8 Hz, 0.6H), 7.46 - 7.42 (m, 1H), 7.36 -
7.31 (m, 1H),
7.19 - 7.16 (m, 1H), 6.18 (s, 0.5H), 6.04 (d, J= 2.4 Hz, 0.5H), 4.35 - 4.17
(m, 2.4H),
3.97 - 3.90 (m, 0.6H), 3.61 (s, 1.5H), 3.59 (s, 1.5H), 2.90 - 2.81 (m, 2H),
1.96 - 1.62 (m,
4H), 1.50 (s, 9H).
A stereoisomeric mixture of VIII-13 (1.30 g, 90 % purity, 1.96 mmol) was
separated
by chiral Prep-HPLC (Column: Chiralpak AD 5 pm 20 * 250 mm; Mobile Phase:
Hex : Et0H : DEA = 70: 30 : 0.3 at 15 mL/min; Col. Temp: 40 C; Wavelength:
214
nm) to afford the title compounds VIII-13-2a (460 mg, 35 % yield, 90 % purity
from
HNMR, 100 % stereopure) and VIII-13-2b (480 mg, 39 % yield, 95 % purity from
HNMR, 96.2 % stereopure) as yellow solids.
VIII-13-2a: LC-MS (ESI): RT = 2.18 min, mass calcd. for C25H28BrC1N4O4S 594.1,
m/z
found 594.8 [M411+. Chiral HPLC(Colum: Chiralpak AD 5 pm 4.6 * 250 mm; Mobile
Phase: Hex : Et0H : DEA = 70: 30 : 0.2 at 1 mL/min; Col. Temp: 40 C;
Wavelength:
230 nm, RT = 4.34 min). 11-1 NMR (400 MHz, CDC13) 6 8.13 (s, 0.5H), 7.82 (t,
J= 3.2
Hz, 1H), 7.56 (t, J= 2.4 Hz, 1H), 7.50 (d, J= 3.2 Hz, 0.5H), 7.45 (d, J= 3.2
Hz, 0.5H),
7.43 (d, J= 2.4 Hz, 0.5H), 7.36 - 7.30 (m, 1H), 7.19- 7.16 (m, 1H), 6.18 (s,
0.5H), 6.04
(d, J= 2.4 Hz, 0.5H), 4.34 - 4.13 (m, 2.5H), 3.96 - 3.90 (m, 0.5H), 3.61 (s,
1.5H), 3.59
(s, 1.5H), 2.91 - 2.82 (m, 2H), 1.96 - 1.67 (m, 3H), 1.62 - 1.57 (m, 1H), 1.50
(s, 9H).
VIII-13-2b: LC-MS (ESI): RT = 2.15 min, mass calcd. for C25H28BrC1N4O4S 594.1,
m/z
found 594.8 [M411+. Chiral HPLC(Colum: Chiralpak AD 5 pm 4.6 * 250 mm; Mobile
Phase: Hex : Et0H : DEA = 70: 30 : 0.2 at 1 mL/min; Col. Temp: 40 C;
Wavelength:
230 nm, RT = 5.60 min). 11-1 NMR (400 MHz, CDC13) 6 8.13 (s, 0.5H), 7.82 (t,
J= 3.6
Hz, 1H), 7.56 (t, J= 2.4 Hz, 1H), 7.50 (d, J= 3.2 Hz, 0.5H), 7.45 (d, J= 2.8
Hz, 0.5H),
7.42 (d, J= 2.4 Hz, 0.5H), 7.37 - 7.31 (m, 1H), 7.19- 7.16 (m, 1H), 6.18 (s,
0.5H), 6.04
(d, J= 2.4 Hz, 0.5H), 4.35 - 4.14 (m, 2.5H), 3.96 - 3.90 (m, 0.5H), 3.61 (s,
1.5H), 3.59
(s, 1.5H), 2.92 - 2.81 (m, 2H), 2.12 - 2.04 (m, 0.5H), 1.96 - 1.64 (m, 3.5H),
1.50 (s, 9H).
Compound VIII-14:
Methyl 442-bromo-3,4-difluoropheny1)-6-(1-(tert-butoxyearbonyDpiperidin-4-y1)-
2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 1.96 min, mass calcd. for C25H27BrF2N4O4S 596.1, m/z found
599.3 [M+111 .111 NMR (400 MHz, DMSO-d6) 69.58 (d, J= 3.2 Hz, 0.7H), 9.16 (s,
0.3H), 8.00 - 7.98 (m, 1.7H), 7.93 - 7.92 (m, 0.3H), 7.51 - 7.36 (m, 1H), 7.23
- 7.12 (m,
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1H), 6.00 (s, 0.3H), 5.92 (d, J= 3.6 Hz, 0.7H), 4.16 - 4.02 (m, 2.3H), 3.82 -
3.76 (m,
0.7H), 3.52 (s, 2.1H), 3.51 (s, 0.9H), 2.78 (hr s, 2H), 1.97 - 1.50 (m, 4H),
1.44 (s, 9H).
A stereoisomeric mixture of VIII-14 (950 mg, 1.59 mmol) was separated by
chainl
Prep. SFC (Column; Chiralpak IG 5 pm 20 * 250 mm; Mobile Phase; CO2: Me0H :
DEA= 70 : 30 : 0.2 at 50 g/ min; Col. Temp 41.1 C; Wavelength; 214 nm; Back
pressure; 100 bar) to afford the title compounds VIII-14-A (450 mg, 47 %
yield, 100 %
stereopure) and VIII-14-B (460 mg, 48 % yield, 100 % stereopure) as yellow
solids.
VIII-14-A: LC-MS (ESI); RT = 1.85 min, mass calcd. for C25H27BrF2N4O4S 596.1,
m/z
found 597.5 [M+Hi . Chiral analysis (Column; Chiralpak IG 5 pm 4.6 * 250 mm;
Mobile Phase; CO2: Me0H : DEA= 70: 30 : 0.2 at 2.999 g/min; Temp; 40 C;
Wavelength; 230 nm, RT = 2.72 min). 111 NMR (400 MHz, DMSO-d6) 6 9.52 (br s,
0.7H), 9.15 (s, 0.3H), 8.00 - 7.92 (m, 2H), 7.51 - 7.45 (m, 1H), 7.23 - 7.13
(m, 1H), 6.01
(s, 0.3H), 5.92 (s, 0.7H), 4.14- 3.99 (m, 2.3H), 3.82 - 3.76 (m, 0.7H), 3.52
(s, 3H), 2.86
- 2.71 (m, 2H), 1.96 - 1.50 (m, 4H), 1.44 (s, 9H).
VIII-14-B: LC-MS (ESI); RT = 1.85 min, mass calcd. for C25H27BrF2N4O4S 596.1,
m/z
found 597.5 [M+Hi . Chiral analysis (Column; Chiralpak IG 5 pm 4.6 * 250 mm;
Mobile Phase; CO2: Me0H ; DEA= 70: 30 ; 0.2 at 2.999 g/min; Temp; 40 C;
Wavelength; 230 nm, RT = 3.99 min). 111 NMR (400 MHz, DMSO-d6) 6 9.57 (d, J=
3.6 Hz, 0.7H), 9.15 (s, 0.3H), 8.00 - 7.92 (m, 2H), 7.51 - 7.44 (m, 1H), 7.23 -
7.12 (m,
1H), 6.01 (s, 0.3H), 5.92 (d, J= 3.2 Hz, 0.7H), 4.16 - 3.99 (m, 2.3H), 3.82 -
3.75 (m,
0.7H), 3.52 - 3.51 (m, 3H), 2.92 - 2.71 (m, 2H), 1.96 - 1.49 (m, 4H), 1.44 (s,
9H).
Compound WII-15:
Methyl 442-bromo-3-fluoropheny0-6-(1-(tert-butoxycarbonyOpiperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
111 NMR (400 MHz, CDC13) 6 8.13 (s, 0.5H), 7.85 - 7.80 (m, 1H), 7.52 - 7.47
(m, 1H),
7.47 - 7.43 (m, 0.5H), 7.25 - 7.18 (m, 1H), 7.14- 6.98 (m, 2H), 6.25 (s,
0.5H), 6.12 -
6.07 (m, 0.5H), 4.41 - 4.16 (m, 2.5H), 4.01 - 3.90 (m, 0.5H), 3.65 - 3.56 (m,
3H), 2.97 -
2.78 (m, 2H), 2.02 - 1.80 (m, 2H), 1.75 - 1.64 (m, 2H), 1.54 - 1.47 (m, 9H).
A stereoisomeric mixture of methyl 4-(2-bromo-3-fluoropheny1)-6-(1-(tert-
butoxycarbonyl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
WII-15 (6.40 g, 107 mmol) was separated by chiral Prep. SFC (Column; Chiralpak
IG 5 pm 20 * 250 mm; Mobile Phase; CO2 ; Me0H = 70: 30 at 50 g/min; Col. Temp;
30 C; Wavelength; 214 nm, Back pressure; 100 bar) to afford the title
compounds
VIII-15-A (2.60 g, 38 % yield, 100 % stereopure) and VIII-15-B (2.90 g, 38 %
yield,
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99.5 % stereopure) as yellow solids.
VIII-15-A: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; CO2 :
Me011
= 70 : 30 at 3.0 g/min; Col. Temp: 40 C; Wavelength: 254 nm, Back pressure:
100 bar,
RT = 3.25 min). 111 NMR (400 MHz, CDC13) 6 8.13 (s, 0.511), 7.83 - 7.81 (m,
111), 7.50
- 7.49 (m, 111), 7.45 - 7.44 (m, 0.511), 7.26 - 7.14 (m, 111), 7.10 - 6.98 (m,
211), 6.25 (s,
0.511), 6.10 (s, 0.511), 4.41 - 4.13 (m, 2.511), 4.00 - 3.92 (m, 0.511), 3.60 -
3.58 (m, 311),
2.97 - 2.77 (m, 211), 2.00 - 1.74 (m, 211), 1.64 - 1.55 (m, 211), 1.54 - 1.45
(m, 911).
VIII-15-B: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; CO2
Me011
= 70 :30 at 3.0 g/min; Temp: 40 C; Wavelength: 254 nm, RT = 4.31 min). 111
NMR
(400 MHz, CDC13) 6 8.13 (s, 0.511), 7.83 - 7.81 (m, 111), 7.52 - 7.48 (m,
111), 7.44 - 7.43
(m, 0.511), 7.26 - 7.17 (m, 111), 7.12 - 6.97 (m, 211), 6.25 (s, 0.511), 6.10
(s, 0.511), 4.37 -
4.09 (m, 2.511), 4.98 - 3.94 (m, 0.511), 3.63 - 3.59 (m, 311), 2.96 - 2.79 (m,
211), 2.01 -
1.81 (m, 211), 1.74 - 1.58 (m, 211), 1.51 - 1.45 (m, 911).
Compound VIII-16-2B:
methyl 442-bromo-4-fluoropheny1)-6-(1-(tert-butoxycarbonyppiperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single stereoisomer)
Intermediate VIII-16-1:
Methyl 442-bromo-4-fluoropheny0-6-(1-(tert-butoxycarbonyppiperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.207 min, mass calcd. for C25H28BrFN404S 578.1, m/z found
579.0 [M+111 . 1H NMR (400 MHz, CDC13) 68.12 (s, 0.411), 7.83 - 7.81 (m, 111),
7.51 -
7.45 (m, 1.611), 7.34 - 7.30 (m, 111), 7.01 - 6.94 (m, 111), 6.17 (s, 0.411),
6.02 (d, J= 2.8
Hz, 0.611), 4.32 - 4.17 (m, 211), 3.94- 3.93 (m, 0.311), 3.61 - 3.60 (m, 311),
3.50 - 3.49
(m, 0.711), 2.86 (br s, 211), 2.10 - 1.66 (m, 3.311), 1.51 (s, 911), 1.46 -
1.35 (m, 0.711).
A stereoisomeric mixture of methyl 4-(2-bromo-4-fluoropheny1)-6-(1-(tert-
butoxycarbonyl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
VIII-16-1 (5.00 g, 8.65 mmol) was seperated by chiral SFC (Column: Chiralpak
IG
5 i.tm 20 * 250 mm;, Mobile Phase: CO2 : Me0H = 70 : 30 at 50 g/min, Temp: 30
C;
Wavelength: 214 nm, Back pressure: 100 bar) to get VIII-16-2A (1.6 g, 32 %
yield,
100 % stereopure) as yellow solids and VIII-16-2B (1.8 g, 36 % yield, 100 %
stereopure) as yellow solids.
VIII-16-2A: Chiral HPLC analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
Mobile Phase:CO2 Me0H = 70 : 30, at 3.0 g/min; Temp: 40 C; Wavelength: 220
nm;
RT = 2.98 min). 1H NMR (400 MHz, CDC13) 68.12 (s, 0.411), 7.84- 7.81 (m, 111),
7.55
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- 7.45 (m, 1.6H), 7.33 - 7.31 (m, 1H), 7.01 - 6.93 (m, 1H), 6.17 (s, 0.4H),
6.02 (d, J=
2.8 Hz, 0.6H), 4.36 - 4.14 (m, 2.4H), 3.96 - 3.91 (m, 0.6H), 3.61 - 3.60 (m,
3H), 2.89
(hr s, 2H), 2.12 - 1.64 (m, 3.5H), 1.58 (s, 0.5H), 1.51 (s, 9H).
VIII-16-2B: Chiral HPLC analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 70: 30 at 3.0 g/min; Temp: 40 C; Wavelength: 230
nm;
RT = 4.46 min). 1H NMR (400 MHz, CDC13) 68.12 (s, 0.4H), 7.83 - 7.81 (m, 1H),
7.50
- 7.44 (m, 1.6H), 7.35 - 7.33 (m, 1H), 7.01 - 6.93 (m, 1H), 6.17 (s, 0.4H),
6.02 (d, J=
2.8 Hz, 0.6H), 4.37 - 4.14 (m, 2.4H), 3.96 - 3.91 (m, 0.6H), 3.61 - 3.60 (m,
3H), 2.96 -
2.77 (m, 2H), 2.11 - 1.63 (m, 3.5H), 1.58 (s, 0.5H), 1.51 (s, 9H).
Compound VIII-17:
Ethyl-6-(1-(tert-butoxycarbonyl)pyrrolidin-3-y1)-442-chloro-3,4-
difluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized.
LC-MS (ESI): RT = 2.144 min, mass calcd. for C25H27C1F2N404S 552.1, m/z found
553.1 [M+111 . 1H NMR (300 MHz, CDC13) 68.27 (s, 0.3H), 7.77 - 7.73 (m, 1H),
7.46 -
7.35 (m, 1.7H), 7.09 - 6.97 (m, 2H), 6.15 (s, 0.3H), 6.06 - 6.01 (m, 0.7H),
4.76 - 4.65 (m,
0.3H), 4.47 - 4.40 (m, 0.7H), 4.04 - 3.95 (m, 2H), 3.71 - 3.31 (m, 4H), 2.39 -
1.99 (m,
2H), 1.47- 1.42 (m, 9H), 1.10- 1.04(m, 3H).
Compound VIII-18-2:
Ethyl 6-(1-(tert-butoxycarbonypazetidin-3-y1)-442-chloro-3,4-difluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 1.657 min, mass calcd. for
C24H25C1F2N404S 538.1, m/z found 539.1 [M+111 . 1H NMR (400 MHz, CDC13) 6 8.57
(s, 0.1H), 7.85 - 7.83 (m, 1H), 7.54 (d, J= 2.8 Hz, 0.9H), 7.47 - 7.45 (m,
1H), 7.10 -
7.07 (m, 2H), 6.21 (s, 0.1H), 6.10 (d, J= 2.8 Hz, 0.9H), 4.89 - 4.85 (m,
0.1H), 4.64 -
4.56 (m, 0.9H), 4.40 - 4.25 (m, 3H), 4.17 - 4.13 (m, 1H), 4.06 (q, J= 7.2 Hz,
2H), 1.49
(s, 9H), 1.13 (t, J= 7.2 Hz, 3H).
Compound VIII-19-4:
Methyl 6-(1-(tert-butoxycarbonyl)azetidin-3-y1)-4- (2-chloro-4-fluoropheny1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 1.56 min, mass calcd. for
C23H24C1FN404S 506.1, m/z found 507.4 [M+111 .
A stereoisomeric mixture of VIII-19-4 (9.00 g, 17.8 mmol) was separated by
chiral
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Prep. HPLC (Column: Chiralpak IC 5um 20*250mm, Mobile Phase: Me0H Et0H =
70 : 30 at 20 mL/min, Temp: 30 C, Wavelength: 214 nm) to afford the compounds
VIII-19-4A (3.5 g, 39 % yield, 100 % ee) and VIII-19-4B (3.58 g, 40 % yield,
99.4 %
ee).
Compound VIII-19-4A: LC-MS (ESI): RT = 1.55 min, mass calcd. for
C23H24C1FN404S
506.1, m/z found 507.6 [M+1-11 . Chiral HPLC (Column: Chiralpak IC 5i.tm 4.6 *
250
mm; Mobile Phase: Hex: Et0H = 70 : 30 at 1.0 mL/min; Temp: 30 C; Wavelength:
230 nm, RT = 6.015 min); 1H NMR (400 MHz, DMSO-d6) 6 9.65 (d, J=3.6 Hz, 1H),
8.04 - 7.93 (m, 2H), 7.42 - 7.38 (m, 2H), 7.21(dt, J= 8.8, 3.2 Hz, Hz, 1H),
5.94 (d, J=
3.2 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.14 - 3.99 (m, 4H), 3.52 (s, 3H), 1.42 (s,
9H).
Compound VIII-19-4B: LC-MS (ESI): RT = 1.56 min, mass calcd. for
C23H24C1FN404S
506.1, m/z found 507.6 [M+1-11 . Chiral HPLC (Column: Chiralpak IC 5i.tm 4.6 *
250
mm; Mobile Phase: Hex: Et0H = 70 : 30 at 1.0 mL/min; Temp: 30 C; Wavelength:
230 nm, RT = 7.158 min); 1H NMR (400MHz, DMSO-d6) 69.66 - 9.65 (d, J= 2.8 Hz,
1H), 8.04 - 8.02 (m, 2H), 7.42 - 7.38 (m, 2H), 7.21 (dt, J= 8.8, 3.2 Hz, 1H),
5.94 (d, J
= 2.8 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.13 - 3.97 (m, 4H), 3.52 (s, 3H), 1.42
(s, 9H).
Compound VIII-20-6B:
methyl 442-chloro-4-fluoropheny1)-6-(1-(544-(ethoxycarbonyl)piperidin-1-
yl)pyrimidin-2-yppiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a single stereoisomer)
Intermediate VIII-20-6:
Methyl 442-chloro-4-fluoropheny1)-6-(1-(544-(ethoxycarbonyl)piperidin-1-
yl)pyrimidin-2-yppiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 1.933 min, mass calcd. for
C32H35C1FN704S 667.2, m/z found 668.1 [M+1-11-F. 1H NMR (400 MHz, CDC13) 8.15
(s,
1H), 8.14 (s, 1H), 7.80 (d, J = 3.2 Hz, 0.5H), 7.76 (d, J = 3.2 Hz, 0.5H),
7.46 (d, J = 3.2
Hz, 0.5H), 7.42 (d, J = 3.2 Hz, 0.5H), 7.33 - 7.29 (m, 1H), 7.14- 7.11 (m,
1H), 6.97 -
6.89 (m, 1H), 6.20 (s, 0.5H), 6.07 (d, J = 2.4 Hz, 0.5H), 4.91 - 4.75 (m, 2H),
4.30 - 4.24
(m, 0.5H), 4.17 (q, J = 7.2 Hz, 2H), 4.05 - 3.99 (m, 0.5H), 3.62 (s, 1.5H),
3.61 (s, 1.5H),
3.38 - 3.32 (m, 2H), 3.05 - 2.93 (m, 2H), 2.75 - 2.69 (m, 2H), 2.42 - 2.36 (m,
1H), 2.06 -
2.03 (m, 3H), 1.96 - 1.89 (m, 3H), 1.79 - 1.69 (m, 2H), 1.27 (t, J = 7.2 Hz,
3H).
A racemic mixture of methyl 4-(2-chloro-4-fluoropheny1)-6-(1-(5-(4-
(ethoxycarbonyl)
pip eridin- 1-yl)pyrimidin - 2 -yl)pip eridin- 4-y1) -2- (thiazol- 2 - yl) -1,
4- dihydropyrimidine -
5-carboxylate VIII-20-6 (200 mg, 90 % purity, 0.269 mmol) was separated by
chiral
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Prep. HPLC (separation condition: Column: Chiralpak IE 5 um 20 * 250 mm;
Mobile
Phase: Me0H : DCM : DEA = 80 : 20 : 0.3 at 14 mL/min; Temp: 30 C; Wavelength:
254 nm) to give VIII-20-6A (90 mg, 90 % purity from 1H NMR, 45 % yield, 100 %
stereopure) and VIII-20-6B (80 mg, 90 % purity from 1H NMR, 40 % yield, 99.7 %
stereopure) as yellow solids.
VIII-20-6A: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase: Me0H : DCM : DEA = 80 : 20 : 0.2 at 1 mL/ min; Temp: 30 C; Wavelength:
254 nm, RT = 8.560 min). 1H NMR (400 MHz, CDC13) 68.15 (s, 1H), 8.14 (s, 1H),
7.81 (d, J = 3.2 Hz, 0.5H), 7.76 (d, J = 3.2 Hz, 0.5H), 7.47 (d, J = 3.2 Hz,
0.5H), 7.43
(d, J = 3.2 Hz, 0.5H), 7.32 - 7.29 (m, 1H), 7.15 - 7.12 (m, 1H), 6.97 - 6.89
(m, 1H), 6.20
(s, 0.5H), 6.07 (d, J = 2.8 Hz, 0.5H), 4.90 - 4.75 (m, 2H), 4.31 - 4.25 (m,
0.5H), 4.17 (q,
J = 7.2 Hz, 2H), 4.05 - 3.99 (m, 0.5H), 3.63 (s, 1.5H), 3.61 (s, 1.5H), 3.39 -
3.33 (m,
2H), 2.98 - 2.94 (m, 2H), 2.76 - 2.69 (m, 2H) , 2.43 - 2.37 (m, 1H), 2.08 -
2.02 (m, 3H),
1.96 - 1.89 (m, 3H), 1.79 - 1.70 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).
VIII-20-6B: Chiral analysis (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm; Mobile
Phase: Me0H : DCM : DEA = 80 : 20 : 0.2 at 1 mL/ min; Temp: 30 C; Wavelength:
254 nm, RT = 12.299 min). 1H NMR (400 MHz, CDC13) 6 8.18 (s, 1H), 8.17 (s,
1H),
7.84 (d, J = 4.0 Hz, 0.5H), 7.78 (d, J = 4.0 Hz, 0.5H), 7.50 (d, J = 4.0 Hz,
0.5H), 7.46
(d, J = 4.0 Hz, 0.5H), 7.36 - 7.31 (m, 1H), 7.19 - 7.14 (m, 1H), 7.01 - 6.91
(m, 1H), 6.23
(s, 0.5H), 6.10 (d, J = 3.2 Hz, 0.5H), 4.93 - 4.82 (m, 2H), 4.34 - 4.26 (m,
0.5H), 4.20 (q,
J = 9.6 Hz, 2H), 4.08 - 4.02 (m, 0.5H), 3.65 (s, 1.5H), 3.64 (s, 1.5H), 3.41 -
3.29 (m,
2H), 3.00 - 2.95 (m, 2H), 2.84 - 2.72 (m, 2H) , 2.46 - 2.39 (m, 1H), 2.11 -
1.91 (m, 6H),
1.78 - 1.69 (m, 2H), 1.31 (t, J = 9.6 Hz, 3H).
Compound VIII-21-B:
ethyl 4-(2-bromo-3-fluoropheny1)-6-(1-(tert-butoxycarbonyl)piperidin-4-0-2-
(thiazol-
2-0-1,4-dihydropyrimidine-5-carboxylate (a single stereoisomer)
Intermediate VIII-21:
Ethyl 442-bromo-3-fluoropheny1)-6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 2.11 min, mass calcd. for
C26H3oBrFN404S 592.1, m/z found 594.9 [M+111 . 111 NMR (300 MHz, CDC13) 6 8.10
(s, 0.4H), 7.82 - 7.80 (m, 1H), 7.50 - 7.47 (m, 0.6H), 7.44 - 7.39 (m, 1H),
7.24 - 7.17 (m,
1H), 7.13 - 7.11 (m, 1H), 7.10 - 6.95 (m, 1H), 6.26 (s, 0.5H), 6.11 (d, J= 2.4
Hz, 0.5H),
4.36 - 4.14 (m, 2.4H), 4.08 - 3.90 (m, 2.6H), 2.94- 2.77 (m, 2H), 2.08 - 1.71
(m, 3H),
1.62 - 1.54 (m, 1H), 1.50 (s, 9H), 1.13 - 1.08 (m, 3H).
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A racemic mixture of WII-21 (7.60 g, 95 % purity, 12.2 mmol) was separated by
chiral Prep. SFC (separation condition: Column: Chiralpak IG 5 pm 20 * 250 mm;
Mobile Phase: CO2 : Me0H = 75 : 25 at 50 g/min; Col. Temp.: 40 C; Wavelength:
254
nm; Back Pressure: 100 Bar) to afford the title compounds VIII-21-A (3.20 g,
95 %
purity, 42 % yield, 100 % stereopure) as yellow solids and VIET-21-B (3.20 g,
95 %
purity, 42 % yield, 99.3 % stereopure) as yellow solids.
VIII-21-A: LC-MS (ESI): RT = 2.268 min, mass calcd. for C26H3oBrFN404S 592.1,
m/z
found 593.1 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 pm 20 * 250 mm;
Mobile Phase: CO2 : Me0H = 75 : 25 at 3.0 g/min; Col. Temp.: 40 C;
Wavelength:
254 nm; Back Pressure: 100 Bar, RT = 3.98 min). 111 NMR (300 MHz, CDC13) 6
8.09
(s, 0.4H), 7.82 - 7.80 (m, 1H), 7.49 - 7.40 (m, 1.6H), 7.24 - 7.17 (m, 1H),
7.17 - 7.11 (m,
1H), 7.07 - 6.98 (m, 1H), 6.26 (s, 0.5H), 6.12 (s, 0.511), 4.35 - 3.91 (m,
511), 2.93 - 2.78
(m, 211), 2.01 - 1.81 (m, 211), 1.71 - 1.56 (m, 211), 1.50 (s, 911), 1.10 (t,
J= 7.2 Hz, 311).
WII-21-B: LC-MS (ESI): RT = 2.249 min, mass calcd. for C26H3oBrFN404S 592.1,
m/z
found 593.0 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 pm 20 * 250 mm;
Mobile Phase: CO2 : Me0H = 75 : 25 at 3.0 g/min; Col. Temp.: 40 C;
Wavelength:
254 nm; Back Pressure: 100 Bar, RT = 4.84 min). 111 NMR (300 MHz, CDC13) 6
8.14 -
8.08 (m, 0.3H), 7.81 (d, J= 3.0 Hz, 1H), 7.51 - 7.34 (m, 1.7H), 7.24 - 7.20
(m, 1H),
7.07 - 7.00 (m, 1H), 6.27 - 6.10 (m, 1H), 4.39 - 3.90 (m, 511), 2.98 - 2.76
(m, 211), 2.06 -
1.77 (m, 2.511), 1.68 - 1.57 (m, 1.5H), 1.50 (s, 911), 1.10 (t, J= 7.2 Hz,
311).
Compound WII-22-2:
Ethyl 442-bromo-4-fluoropheny0-6-(1-(tert-butoxycarbonyOpiperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single stereoisomer)
Intermediate VIII-22:
Ethyl 442-bromo-4-fluoropheny1)-6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 2.06 min, mass calcd. for
C26H3oBrFN404S 592.1, m/z found 595.5 [M+111 . 111 NMR (300 MHz, CDC13) 68.10
(s, 0.4H), 7.86 - 7.80 (m, 1H), 7.53 - 7.49 (m, 0.6H), 7.47 - 7.44 (m, 0.4H),
7.42 - 7.38
(m, 0.6H), 7.35- 7.30 (m, 211), 7.05 - 6.92 (m, 1H), 6.20 (s, 0.4H), 6.06 (d,
J= 1.2 Hz,
0.6H), 4.39 - 4.16 (m, 2.411), 4.11 - 3.89 (m, 2.611), 2.97 - 2.76 (m, 211),
2.14- 1.70 (m,
3H), 1.61- 1.56 (m, 111), 1.52 (s, 9H), 1.18- 1.09 (m, 311).
A racemic mixture of ethyl 4-(2-bromo-4-fluoropheny1)-6-(1- (tert-
butoxycarbonyl)piperi
din-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate WII-22 (820 mg,
90 %
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purity, 1.24 mmol) was separated by Chiral Prep. HPLC (Column: Chiralpak IG 5
i.tm 30 mm * 250 mm; Mobile Phase: CO2 : Me0H = 70 : 30 at 55 g/min; Col.
Temp:
40 C; Wavelength: 214 nm, Back pressure: 100 bar) to afford the title
compound
VIII-22-1 (380 mg, 90 % purity from 111 NMR, 46 % yield, 100 % stereopure) and
VIII-22-2 (370 mg, 90 % purity from 111 NMR, 45 % yield, 99.8 % stereopure) as
yellow solids.
VIII-22-1: LC-MS (ESI): RT = 2.128 min, mass calcd. for C26H3oBrFN404S 592.1,
m/z
found 593.0 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 70: 30 at 3 g/min; Col. Temp: 40 C; Wavelength:
230
nm; Back pressure: 100 bar, RT = 3.09 min). 111 NMR (400 MHz, CDC13) 6 8.08
(br s,
0.4H), 7.82 - 7.80 (m, 1H), 7.49 (d, J= 2.8 Hz, 0.6H), 7.43 (d, J= 3.2 Hz,
0.4H), 7.38
(s, 0.6H), 7.33 - 7.28 (m, 2H), 7.01 - 6.93 (m, 1H), 6.18 (s, 0.4H), 6.05 (d,
J= 2.4 Hz,
0.6H), 4.37 - 4.14 (m, 2.4H), 4.08 - 4.00 (m, 2H), 3.95 - 3.89 (m, 0.6H), 2.91
- 2.79 (m,
2H), 2.07 - 1.81 (m, 2.6H), 1.74 - 1.68 (m, 0.4H), 1.64 - 1.58 (m, 1H), 1.50
(s, 9H), 1.15
- 1.10 (m, 3H).
VIII-22-2: LC-MS (ESI): RT = 2.128 min, mass calcd. for C26H3oBrFN404S 592.1,
m/z
found 593.0 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm;
Mobile Phase: CO2 : Me0H = 70: 30 at 3 g/min; Col. Temp: 40 C; Wavelength:
230
nm; Back pressure: 100 bar, RT = 4.32 min). 111 NMR (400 MHz, CDC13) 6 8.08
(br s,
0.4H), 7.82 - 7.80 (m, 1H), 7.49 (d, J= 3.2 Hz, 0.6H), 7.43 (d, J= 3.2 Hz,
0.4H), 7.38
(s, 0.6H), 7.33 - 7.28 (m, 2H), 7.01 - 6.93 (m, 1H), 6.18 (s, 0.4H), 6.05 (d,
J= 2.4 Hz,
0.6H), 4.36 - 4.14 (m, 2.4H), 4.08 - 4.00 (m, 2H), 3.95 - 3.89 (m, 0.6H), 2.91
- 2.79 (m,
2H), 2.07- 1.81 (m, 2.6H), 1.73- 1.68 (m, 0.4H), 1.64- 1.58 (m, 1H), 1.50 (s,
9H), 1.14
- 1.10 (m, 3H).
Compound VIII-23-B:
Methyl 6-(1-(5-(3-(tert-butoxy)-3-oxopropyl)PYridin-270piperidin-4-y1)-4-(2-
chloro-4-
fluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
Intermediate VIII-23:
Methyl 6-(1-(5-(3-(tert-butoxy)-3-oxopropyl)PYridin-270piperidin-4-y1)-442-
chloro-4-
fluorophenyl)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a mixture
of 2
stereoisomers)
By utilizing the analogous procedure of Method B, the title compound was
synthesized as yellow solids. LC-MS (ESI): RT = 1.99 min, mass calcd. for
C32H35C1FN504S 639.2, m/z found 640.1 [M+111 . 111 NMR (400 MHz, CDC13) 68.18
(s, 0.5H), 8.07 (s, 1H), 7.81 (d, J= 2.8 Hz, 0.5H), 7.77 (d, J= 3.2 Hz, 0.5H),
7.48 -
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7.29 (m, 3.5H), 7.15 - 7.12 (m, 1H), 6.98 - 6.89 (m, 1H), 6.70 - 6.66 (m, 1H),
6.20 (s,
0.5H), 6.07 (d, J=2.8 Hz, 0.5H), 4.49 - 4.20 (m, 2.5H), 4.03 - 3.95 (m, 0.5H),
3.62 (s,
1.5H), 3.61 (s, 1.5H), 3.00 - 2.89 (m, 2H), 2.82 - 2.77 (m, 2H), 2.52 - 2.47
(m, 2H), 2.30
- 2.20 (m, 0.5H), 2.12 - 2.06 (m, 1H), 2.00 - 1.94 (m, 1H), 1.88 - 1.72 (m,
1.5H), 1.44 (s,
9H).
A racemic mixture of methyl 6-(1-(5-(3-(tert-butoxy)-3-oxopropyl)pyridin-2-
yl)piperidin-4-y1)-4-(2-chloro-4-fluoropheny1)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate VIII-23 (220 mg, 95 % purity, 0.326 mmol) was separated by
chiral
Prep. HPLC (Column: Chiralpak IE 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H
:
DEA = 50 : 50 : 0.3 at 10 mL/min; Temp: 30 C; Wavelength: 254 nm) to give the
title
compound VIII-23-A (89 mg, 95 % purity from 1H NMR, 40 % yield, 100 %
stereopure) as yellow solids and WII-23-B (80 mg, 95 % purity from 1H NMR, 36
%
yield, 99.9 % stereopure) as yellow solids.
WII-23-A: LC-MS (ESI): RT = 1.86 min, mass calcd. for C32H35C1FN504S 639.2,
m/z
found 640.0 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 um 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/ min; Temp: 30 C;
Wavelength: 254 nm, RT = 7.100 min). 1H NMR (400 MHz, CDC13) 6 8.18 (s, 0.5H),
8.07 (s, 1H), 7.81 (d, J= 3.2 Hz, 0.5H), 7.77 (d, J= 2.8 Hz, 0.5H), 7.47 (d,
J= 3.2 Hz,
0.5H), 7.43 - 7.29 (m, 3H), 7.15 - 7.12 (m, 1H), 6.98 - 6.89 (m, 1H), 6.69 -
6.66 (m, 1H),
6.20 (s, 0.5H), 6.07 (d, J= 2.4 Hz, 0.5H), 4.49 - 4.33 (m, 2H), 4.27 - 4.21
(m, 0.5H),
4.02 - 3.95 (m, 0.5H), 3.62 (s, 1.5H), 3.61 (s, 1.5H), 2.99 - 2.88 (m, 2H),
2.82 - 2.77 (m,
2H), 2.52 - 2.47 (m, 2H), 2.30 - 2.20 (m, 0.5H), 2.12 - 1.72 (m, 3.5H), 1.44
(s, 9H).
VIII-23-B: LC-MS (ESI): RT = 1.85 min, mass calcd. for C32H35C1FN504S 639.2,
m/z found 640.0 [M+Hi . Chiral analysis (Column: Chiralpak IE 5 um 4.6 * 250
mm;
Mobile Phase: Hex : Et0H : DEA = 50 : 50 : 0.2 at 1 mL/ min; Temp: 30 C;
Wavelength: 254 nm, RT = 11.757 min). 1H NMR (400 MHz, CDC13) 6 8.18 (s,
0.5H),
8.07 (s, 1H), 7.81 (d, J= 3.2 Hz, 0.5H), 7.77 (d, J= 3.2 Hz, 0.5H), 7.47 (d,
J= 3.2 Hz,
0.5H), 7.43 - 7.29 (m, 3H), 7.15 - 7.12 (m, 1H), 6.98 - 6.89 (m, 1H), 6.69 -
6.66 (m, 1H),
6.20 (s, 0.5H), 6.07 (d, J=2.4 Hz, 0.5H), 4.49 - 4.33 (m, 2H), 4.27 - 4.21 (m,
0.5H),
4.03 - 3.95 (m, 0.5H), 3.62 (s, 1.5H), 3.61 (s, 1.5H), 2.99 - 2.88 (m, 2H),
2.82 - 2.77 (m,
2H), 2.52 - 2.47 (m, 2H), 2.30 - 2.20 (m, 0.5H), 2.13 - 1.72 (m, 3.5H), 1.44
(s, 9H).
Part VI: Preparation of free amine (FA) products of general formula IX
Free amine 1: (exemplified with Method D)
methyl 4-(3,4-difluoro-2-methylpheny1)-6-(piperidin-4-y0-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate (FA1, a single stereoisomer)
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To a solution of methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-y1)-4-(3,4-
difluoro-2-
methylpheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate VIII- 1-B
(270
mg, 0.510 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3
mL) at
room temperature. After stirred at room temperature for 0.5 hour, the mixture
was
concentrated under reduced pressure to give a residue, which was dissolved in
ethyl
acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution
(25 mL) for three times, water (25 mL) for three times, and brine (25 mL) for
three
times, dried over Na2SO4(s) and filtered. The filtrate was concentrated under
reduced
pressure to give the title compound (220 mg, 100 % yield) as yellow solids. LC-
MS
(ESI): RT = 1.896 min, mass calcd. for C211-122F2N402S 432.1, m/z found 432.9
[M+Hi .
Spectral analyses of free amines of general formula IX
Free amine 2:
ethyl 4-(3-flmoro-2-methylpheny0-6-(piperidin-4-y0-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate (FA2, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-2-B.
LC-MS (ESI): RT = 1.53 min, mass calcd. for C22H25FN402S 428.2, m/z found
429.0
[M+1-1] . 11-1 NMR (400 MHz, CDC13) 6 8.37 (s, 0.4H), 7.79 (d, J= 3.2 Hz, 1H),
7.52 (d,
J= 3.2 Hz, 0.6H), 7.40 (d, J= 3.2 Hz, 0.4H), 7.14- 7.01 (m, 2.6H), 6.97 - 6.88
(m,
1H), 6.01 (s, 0.3H), 5.93 (s, 0.7H), 4.35 - 4.29 (m, 0.4H), 4.06 - 3.93 (m,
2.6H), 3.59 -
3.42 (m, 2H), 3.10 - 2.93 (m, 2H), 2.53 (s, 1H), 2.39 (s, 2H), 2.37 - 2.26 (m,
1H), 2.15 -
2.08 (m, 1.3H), 2.01 - 1.82 (m, 1.7H), 1.13 - 1.08 (m, 3H).
Free amine 3: ethyl 4-(4-flmoro-2-methylpheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA3, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound WII-3-B.
LC-MS (ESI): RT = 1.536 min, mass calcd. for C22H25FN402S 428.2, m/z found
429.1
[M+1-11 . 11-1 NMR (400 MHz, CDC13) 6 8.49 (s, 0.3H), 7.81 - 7.79 (m, 1H),
7.53 (d, J=
3.2 Hz, 0.7H), 7.39 (d, J= 2.8 Hz, 0.3H), 7.30 - 7.28 (m, 0.7H), 7.17 - 7.13
(m, 0.3H),
7.09 (s, 0.7H), 6.90 - 6.84 (m, 1.7H), 6.81 - 6.76 (m, 0.3H), 5.95 (s, 0.3H),
5.88 (d, J=
1.6 Hz, 0.7H), 4.41 - 4.35 (m, 0.3H), 4.06 - 3.92 (m, 2.7H), 3.60 - 3.53 (m,
2H), 3.11 -
3.00 (m, 2H), 2.62 (s, 1H), 2.48 (s, 2H), 2.45 - 2.08 (m, 3H), 2.01 - 1.97 (m,
0.3H), 1.86
- 1.83 (m, 0.7H), 1.13 - 1.08 (m, 3H).
Free amine 4: methyl 4-(3-fluoro-2-methylpheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y0-
1,4-dihydropyrimidine-5-carboxylate (FA4, a single stereoisomer)
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By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-4-A.
LC-MS (ESI): RT = 1.481 min, mass calcd. for C211123FN402S 414.5, m/z found
415.1
[M411+. 11-1 NMR (400 MHz, CDC13) 6 8.26 (s, 1H), 7.76 (d, J= 2.8 Hz, 1H),
7.50 (d, J
= 2.8 Hz, 0.4H), 7.39 (d, J= 3.2 Hz, 0.6H), 7.26 - 7.06 (m, 2H), 7.00 - 6.87
(m, 1H),
5.99 (s, 0.6H), 5.90 (s, 0.4H), 4.25 - 4.17 (m, 0.6H), 3.97 - 3.88 (m, 0.4H),
3.58 (s, 3H),
3.52 - 3.44 (m, 0.7H), 3.32 - 3.25 (m, 1.3H), 3.04 - 2.82 (m, 2H), 2.53 (s,
2H), 2.38 (s,
1H), 2.35 - 2.19 (m, 1H), 2.00 - 1.73 (m, 3H).
Free amine 5: methyl 4-(4-fluoro-2-methylpheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA5, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-5-2B.
LC-MS (ESI): RT = 1.38 min, mass calcd. for C211123FN402S 414.2, m/z found
415.1
[M411+. 11-1 NMR (400MHz, CD30D) 6 7.80 (d, J= 3.2 Hz, 1H), 7.64 (d, J= 3.2
Hz,
1H), 7.22 - 7.19 (m, 1H), 6.83 - 6.73 (m, 2H), 5.78 (m, 1H), 4.00 - 3.80 (m,
1H), 3.50 (s,
3H), 3.19 - 3.13 (m, 2H), 2.78 - 2.69 (m, 2H), 2.46 (s, 3H), 2.12 - 1.81 (m,
3H), 1.65 -
1.62 (m, 1H).
Free amine 6: methyl 4-(2-chloro-3-fluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA6, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-6-B.
11-1 NMR (300 MHz, DMSO-d6) 8.01 (s, 2H), 7.38 - 7.18 (m, 3H), 6.00 (s, 0.8H),
5.76 -
5.74 (m, 0.2H), 3.83 - 3.74 (m, 1H), 3.53 - 3.48 (m, 3H), 3.29 - 3.18 (m, 2H),
2.86 -
2.71 (m, 2H), 2.06 - 1.59 (m, 4H).
Free amine 7: methyl 4-(2-chloro-4-fluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA7, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-7-B.
LC-MS (ESI): RT = 1.444 min, mass calcd. For C201121C12FN402S 470.1, m/z found
434.9 [M-HC1+111 .111 NMR (400 MHz, DMSO-d6) 6 9.00 (hr s, 1H), 8.60 (hr s,
1H),
8.02 (dd, J= 4.4, 3.2 Hz, 2H), 7.43 (dd, J= 8.8, 2.8 Hz, 1H), 7.36 (dd, J=
8.8, 6.0 Hz,
1H), 7.21 (td, J= 8.4, 2.8 Hz, 1H), 5.94 (s, 1H), 3.86 - 3.79 (m, 1H), 3.54
(s, 3H), 3.40
- 3.35 (m, 2H), 3.02 - 2.89 (m, 2H), 2.19 - 2.02 (m, 2H), 1.88 (d, J= 14.4 Hz,
1H), 1.72
(d, J= 14.4 Hz, 1H).
Free amine 8: ethyl 4-(2-chloro-4-fluoropheny1)-6-(piperidin-4-y0-2-(thiazol-2-
y0-1,4-
dihydropyrimidine-5-carboxylate (FA8, a single stereoisomer)
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By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-8-B.
LC-MS (ESI): RT = 1.897 min, mass calcd. for C211122C1FN402S 448.1, m/z found
449.1 [M+Hi .
Free amine 9: ethyl 4-(2-chloro-3-fluoropheny1)-6-(piperidin-4-y0-2-(thiazol-
270-1,4-
dihydropyrimidine-5-carboxylate (FA9, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-9-B.
1H NMR (300 MHz, CDC13) 6 8.33 (s, 0.511), 7.86 -7.78 (m, 111), 7.58 - 7.38
(m, 1.511),
7.20 - 6.96 (m, 311), 6.24 (s, 0.411), 6.10 (s, 0.611), 4.10 - 3.95 (m, 311),
3.56 - 3.39 (m,
211), 3.08 - 2.85 (m, 211), 2.38 - 2.15 ( m, 111), 2.15 - 2.08 (m, 111), 1.92 -
1.74 (m, 211),
1.16- 1.06 (m, 311).
Free amine 10: methyl 4-(2-chloro-3,4-difluoropheny1)-6-(piperidin-4-y1)-2-
(thiazol-2-
y1)-1,4-dihydropyrimidine-5-carboxylate (FA10, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-10-B.
1H NMR (400 MHz, CDC13) 6 8.40 (s, 0.411), 7.85 - 7.78 (m, 111), 7.53 (d, J=
2.8 Hz,
111), 7.44 (d, J= 3.2 Hz, 0.611), 7.12 - 6.96 (m, 211), 6.18 (s, 0.411), 6.07
(s, 0.611), 4.32
- 4.17 (m, 111), 4.07 - 3.92 (m, 211), 3.61 (s, 211), 3.60 (s, 111), 3.39 -
3.29 (m, 111), 3.11
- 2.85 (m, 211), 2.45 - 2.17 (m, 1.411), 2.04 - 1.81 (m, 2.611).
Free amine 11: ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(2-methylpiperidin-4-
y1)-2-
(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (FAll, a mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII 116.
LC-MS (ESI): RT = 1.774 min, mass calcd. for C221123C1F2N402S 480.1, m/z found
481.1 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 8.01 (d, J= 6.8 Hz, 211), 7.50 -
7.42
(m, 111), 7.24 - 7.18 (m, 111), 5.96 (d, J= 10.8 Hz, 1H), 4.13 - 4.04 (m,
111), 4.00 - 3.94
(m, 211), 3.67 - 3.53 (m, 111), 3.16 - 2.95 (m, 211), 2.12 - 1.92 (m, 211),
1.82 - 1.76 (m,
0.611), 1.66 - 1.61 (m, 111), 1.55 - 1.50 (m, 0.411), 1.25 - 1.23 (m, 311),
1.07 (t, J= 7.2
Hz, 311).
Free amine 12: ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(piperidin-4-0-2-
(thiazol-2-
y1)-1,4-dihydropyrimidine-5-carboxylate (FA12, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound WII-12-B.
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LC-MS (ESI): RT = 1.55 min, mass calcd. for C211121C1F2N402S 466.1, m/z found
467.1 [M+Hi .
Free amine 13: methyl 4-(4-bromo-2-chloropheny0-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA13, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-13-2b.
LC-MS (ESI): RT = 1.61 min, mass calcd. for C20112oBrC1N402S 494.0, m/z found
494.7 [M+111 . 1H NMR (400 MHz, CDC13) 6 8.26 (s, 0.6H), 7.83 - 7.79 (m, 1H),
7.56 -
7.55 (m, 1H), 7.50 (d, J= 3.2 Hz, 0.4H), 7.44 (d, J= 3.2 Hz, 0.8H), 7.37 (d,
J= 2.0 Hz,
0.2H), 7.35 - 7.30 (m, 1H), 7.21 - 7.17 (m, 1H), 6.17 (s, 0.6H), 6.04 (s,
0.4H), 4.18 -
4.12 (m, 0.6H), 3.97 - 3.91 (m, 0.4H), 3.61 (s, 1H), 3.59 (s, 2H), 3.30 - 3.20
(m, 2H),
2.90 - 2.79 (m, 2H), 2.19 - 2.13 (m, 0.5H), 1.98 - 1.86 (m, 2.5H), 1.83 - 1.62
(m, 2H).
Free amine 14: methyl 4-(2-bromo-3,4-difLuoropheny1)-6-(piperidin-4-y1)-2-
(thiazol-2-
y1)-1,4-dihydropyrimidine-5-carboxylate (FA14, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-14-B.
LC-MS (ESI): RT = 1.64 min, mass calcd. for C20HnBrF2N402S 496.0, m/z found
497.4 [M+1] .
Free amine 15: methyl 4-(2-bromo-3-fluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA15, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-15-B.
1H NMR (400 MHz, CDC13) 6 9.59 - 9.01 (m, 1H), 7.82 (s, 1H), 7.58 - 7.37(m,
2H),
7.30 - 7.27 (m, 0.5H), 7.25 - 7.23 (m, 0.5H), 7.11 - 7.02 (m, 2H), 6.24 (s,
0.2H), 6.14 -
6.09 (m, 0.8H), 4.09 - 4.01 (m, 0.8H), 3.74 (s, 0.2H), 3.67 - 3.51 (m, 5H),
3.17 - 3.02 (m,
2H), 2.53 - 2.38 (m, 1H), 2.34- 2.23 (m, 1H), 2.13 - 2.07 (m, 1H), 1.93 - 1.83
(m, 1H).
Free amine 16: methyl 4-(2-bromo-4-fluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-
1,4-dihydropyrimidine-5-carboxylate (FA16, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-16-2B.
LC-MS (ESI): RT = 1.903 min, mass calcd. for C2oH2oBrFN4O2S 478.1, m/z found
479.0 [M+111 .1H NMR (400 MHz, CDC13) 6 8.34 (s, 0.3H), 7.84 - 7.80 (m, 1H),
7.53 -
7.52 (m, 1H), 7.43 - 7.42 (m, 0.3H), 7.34 - 7.31 (m, 1.2H), 7.26 - 7.25 (m,
0.5H), 7.03 -
6.93 (m, 1H), 6.16 (s, 0.3H), 6.04 (s, 0.7H), 4.25 - 4.21 (m, 0.3H), 4.06 -
4.00 (m, 0.7H),
3.61 - 3.60 (m, 3H), 3.56 - 3.49 (m, 1H), 3.37 - 3.30 (m, 0.7H), 3.09 - 2.85
(m, 3H),
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2.48 - 2.39 (m, 1.211), 2.35 - 2.21 (m, 0.811), 2.02 - 1.99 (m, 0.611), 1.92 -
1.81 (m,
1.4H).
Free amine 17: ethyl 442-chloro-3,4-difluoropheny1)-6-(pyrrolidin-3-y1)-2-
(thiazol-2-
y1)-1,4-dihydropyrimidine-5-carboxylate (FA17, a mixture of 4 stereoisomers)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-17.
LC-MS (EST): RT = 1.531 min, mass calcd. for C20H19C1F2N402S 452.1, m/z found
453.0 [M+Hi . 11-1 NMR (300 MHz, CDC13) 6 10.45 - 10.33 (m, 111), 7.84 (s,
111), 7.41
(s, 111), 7.12 - 7.02 (m, 211), 6.17 - 6.15 (m, 111), 4.67 (hr s, 111), 4.15 -
4.01 (m, 211),
3.36 - 3.19 (m, 211), 3.01 - 2.94 (m, 211), 2.46 - 2.10 (m, 1.511), 1.99 -
1.77 (m, 1.511),
1.15- 1.10 (m, 311).
Free amine 18: ethyl 6-(azetidin-3-y1)-4-(2-chloro-3,4-difluoropheny1)-2-
(thiazol-2-y0-
1,4-dihydropyrimidine-5-carboxylate (FA18, a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-18-2.
LC-MS (EST): RT = 1.555 min, mass calcd. for Ci9Hi7C1F2N402S 438.1, m/z found
439.0 [M+Hi .
Free amine 19: methyl 6-(azetidin-3-y0-442-chloro-4-fluoropheny1)-2-(thiazol-2-
y0-
1,4-dihydropyrimidine-5-carboxylate (FA19, a mixture of 2 stereoisomers)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-19-4.
LC-MS (EST): RT = 1.32 min, mass calcd. for Ci811i6C1FN402S 406.1, m/z found
407.4
[M+11] . 11-1 NMR (400 MHz, DMSO-d6 + D20) 6 8.01 (d, J= 3.2 Hz, 111), 7.95
(s, 111),
7.44 - 7.40 (m, 211), 7.22 - 7.17 (m, 111), 5.98 (s, 111), 4.58 (s, 111), 3.96
- 3.88 (m, 411),
3.51 (s, 311).
Free amine 19-1B: Methyl 6-(azetidin-3-y1)-4-(2-chloro-4-fluoropheny1)-2-
(thiazol-2-
y1)-1,4-dihydropyrimidine-5-carboxylate hydrochloride (FA19-1B, a single
stereoisomer)
To a suspension of methyl 6-(1-(tert-butoxycarbonyl)azetidin-3-y1)-4-(2-chloro-
4-
fluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate VIII 194B
(3.58
g, 7.07 mmol) in methanol (35 mL) was added 4M hydrochloride in methanol (35
mL,
14 mmol), which was stirred at room temperature for 1.5 hours. The mixture was
concentrated to give a residue, which was purified by silica gel
chromatography
column (dichloromethane : methanol = 10:1) to give the title compound (2.76 g,
98 %
yield) as yellow solids. 11-1 NMR (400 MHz, DMSO-d6) 6 9.37 (hr s, 211), 8.08
(d, J=
2.8 Hz, 111), 8.04 (d, J= 2.8 Hz, 111), 7.49 - 7.46 (m, 211), 7.42 (dd, J=
8.8, 2.4 Hz,
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1H), 7.19 (td, J= 11.2, 2.4 Hz, 111), 5.95 (s, 1H), 4.58 - 4.49 (m, 1H), 4.33 -
4.04 (m,
4H), 3.52 (s, 3H).
Free amine 20: Ethyl 4-(2-bromo-3-fluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-1,4-
dihydropyrimidine-5-carboxylate (FA20, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound VIII-21-B.
LC-MS (ESI): RT = 1.58 min, mass calcd. for C211-122BrFN402S 492.1, in/z found
494.8 [M+H] .
1H NMR (300 MHz, CDC13) 6 8.25 (s, 0.5H), 7.83 (d, J= 3.0 Hz, 0.4H), 7.80 (d,
J= 2.7 Hz,
0.6H), 7.51 (d, J= 3.0 Hz, 0.4H), 7.44 (d, J= 3.0 Hz, 0.6H), 7.23 - 7.14 (m,
1.5H), 7.09 - 6.98 (m,
1H), 6.27 (s, 0.6H), 6.13 (s, 0.4H), 4.24 - 3.97 (m, 3H), 3.34 - 3.20 (m, 2H),
2.94 - 2.80 (m, 2H),
2.20 - 2.09 (m, 0.8H), 1.93 - 1.63 (m, 3.2H), 1.13 (t, J= 7.2 Hz, 3H).
Free amine 21: Ethyl 4-(2-bromo-4-fluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-
2-y1)-1,4-
dihydropyrimidine-5-carboxylate (FA21, a single stereoisomer)
By utilizing the analogous procedure of Method D, the title compound was
synthesized from compound WEI-22-2.
1H NMR (400 MHz, CDC13) 6 8.22 (br s, 0.5H), 7.82 (d, J = 3.2 Hz, 0.5H), 7.79
(d, J = 3.2 Hz,
0.5H), 7.49 (d, J= 2.8 Hz, 0.5H), 7.42 (d, J= 3.2 Hz, 0.5H), 7.38 (br s,
0.5H), 7.33 - 7.28 (m,
2H), 7.02 - 6.93 (m, 1H), 6.18 (s, 0.5H), 6.05 (s, 0.5H), 4.19 -4.13 (m,
0.5H), 4.08 -4.00 (m, 2H),
3.97 - 3.92 (m, 0.5H), 3.36 - 3.20 (m, 2H), 2.92 - 2.79 (m, 2H), 2.23 - 2.17
(m, 0.6H), 1.91 - 1.83
(m, 2H), 1.77- 1.66 (m, 1.4H), 1.15- 1.10 (m, 3H).
Part VII: Preparation of building blocks (BB) of general formula X for
coupling step
Building block 1: ethyl 2-(2-chloropyrimidin-5-yl)acetate (BB1)
Building block 2: methyl 2-chloro-5-methylpyrimidine-4-carboxylate (BB2)
SOCl2 (2 eq)
Me0H, 0 C-rt
0 OH 2h 0 0
BB2-1 BB2
To a solution of 2-chloro-5-methylpyrimidine-4-carboxylic acid BB2-1 (500 mg,
95 %
purity, 2.75 mmol) in methanol (10 mL) was added thionyl chloride (662 mg, 99
%
purity, 5.51 mmol) at 0 C under nitrogen atmosphere. After stirred at 0 C
for 30
minutes and at room temperature for 2 hours, the mixture was diluted with
ethyl
acetate (200 mL). The mixture was washed with saturated sodium bicarbonate
aqueous solution (40 ml) for three times. The organic layers were dried over
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Na2SO4(s) and filtered. The filtrate was concentrated under reduced pressure
to
give the title compound (415 mg, 99 % purity, 80 % yield) as yellow solid. LC-
MS
(ESI): RT = 0.837 min, mass calcd. for C7117C1N202 186.0, m/z found 187.0 [M+1-
11 .1H
NMR (300 MHz, DMSO-d6) 6 8.64 (s, 111), 3.89 (s, 311), 2.39 (s, 311).
Building block 3: methyl 2-bromothiazole-5-carboxylate (BB3)
Building block 4: Ethyl 2-chloro-5-methylpyrimidine-4-carboxylate (BB4)
)H,ro
a a
0
(3.0 eq)
N N N N
ftJ H202 (3.3 eq), H2SO4 (2.9 eq)
FeSO4 .7H20(3.0 eq), AcOH, II
water/toluene(v/v, 1/2), 0
BB4-1 BB4
- 10 C r.t., 1.5 h
A round bottom flask A was charged with ethyl 2-oxopropanoate (27.0 g, 232.6
mmol)
and the flask was cooled to - 10 C. Acetic acid (80 mL) was added while
maintaining
the temperature below - 5 C. 30 % hydrogen peroxide aqueous solution (26.4
mL,
258.4 mmol) was added dropwise as to maintaining the temperature at - 5 C.
Another flask B was charged with 2-chloro-5-methylpyrimidine BB4-1 (10.0 g,
77.8
mmol), toluene (80 mL) and water (40 mL). After the flask B was cooled to -10
C,
sulfic acid (12.4 mL, 228.2 mmol) was added followed by ferrous sulfate
heptahydrate (64.8 g, 233.1 mmol). To the flask B was added the peroxide
solution
over 1 hour while keeping the temperature at 0 C - 5 C. After the addition,
the
reaction mixture was further stirred for 30 minutes. Then it was poured into
ice
water (1 L). The mixture was extracted with ethyl acetate (500 mL) for three
times.
The combined organic layers were washed with 0.5 M solution bisulfate aqueous
solution (500 mL) and brine (500 mL), dried over Na2SO4(s) and filtered. The
filtrate
was concentrated in vacuo to give a residue, which was purified by C18 column
(acetonitrile water = 30 % to 90 %) to give the title compound (8.50 g, 95 %
purity,
52 % yield) as yellow solids. LC-MS (ESI): RT = 2.04 min, mass calcd. for
C8119C1N202 200.0, m/z found mass 200.9 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 6
8.63
(s, 111), 4.48 (q, J= 7.2 Hz, 211), 2.51 (s, 311), 1.44 (t, J= 7.2 Hz, 311).
Building block 5: 1-Methyl-1H-pyrazole-4-carboxylic acid (BB5)
0
.)
CH3I (2 eq.) 0)-.CN Na0H(1.6eq HON
NaH (1.75 eq.) N' Et0H, reflux
\ overnight
C r.t., 2h,
BB5-1 then 60 C, 6h BB5-2 BB5
Intermediate BB5-2:
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Ethyl 1-methyl- 1H-pyrazole-4-carboxylate
To a solution of ethyl 111-pyrazole-4-carboxylate BB5-1 (5.00 g, 35.7 mmol) in
tetrahydrofuran (20 mL) was added 60 % wt. sodium hydride in mineral oil (2.50
g,
62.5 mmol) at 0 C under nitrogen atmosphere. The reaction mixture was stirred
room temperature for 1 hour and then iodomethane (10.0 g, 70.5 mmol) was
added.
After stirred at 60 C for 6 hours, the reaction mixture was cooled down,
quenched
with water (40 mL) and extracted with ethyl acetate (60 mL) for three times.
The
combined organic layers were washed with brine (20 mL), dried over Na2SO4(s)
and
concentrated to afford the title compound (5.6 g, 80 % purity from 111 NMR, 83
%
.. yield) as colourless oil. 111 NMR (300 MHz, CDC13) 6 7.83 (s, 211), 4.26 -
4.19 (m, 211),
3.87 (s, 311), 1.36 - 1.26 (m, 311).
Building block 5:
1-Methyl- 1H-pyrazole-4-carboxylic acid
To a solution of ethyl 1-methy1-11-1-pyrazole-4-carboxylate BB5-2 (3.0 g, 80 %
purity,
.. 15.6 mmol) in ethanol (10 mL) was added sodium hydroxide (1.0 g, 25 mmol)
in
water (30 mL) at room temperature. After refluxed overnight, the reaction
mixture
was cooled down, acidified with 1 M hydrochloride aqueous solution (20 mL)
till PH
3 and extracted with ethyl acetate (40 mL) for three times. The combined
organic
layers were washed with water (20 mL) for three times, dried over Na2SO4(s)
and
concentrated to afford the title compound (1.8 g, 92 % yield) as white solids.
LC-MS
(ESI): RT = 0.24 min, mass calcd. for C5116N202 126.1, m/z found 127.3 [M+111
.111
NMR (300 MHz, DMSO-d6) 6 12.2 (br s, 111), 8.20 (s, 111), 7.77 (s, 111), 3.86
(s, 311).
Building block 6: ethyl 2-chlorooxazole-4-carboxylate (BB6)
Building block 7: 2-chloropyrimidine-5-carboxylic acid (BB7)
Building block 8: Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (BB8)
Building block 9: Ethyl 2-(2-chloropyrimidin-4-yl)acetate (BB9)
o 0
),A(1.2 eq)
CI N CI
0 ,
ONCI
NaH (2.4eq) I I
0
THF 0 - 70 C 4h
BB9-1 BB9
At a temperature between 0 and 5 C, sodium hydride (1.22 g, 60 % wt. in
mineral
oil, 30.5 mmol) was added portionwise to a solution of ethyl 3-oxobutanoate
(1.96 g,
98 % purity, 14.8 mmol) in tetrahydrofuran (100 mL). The reaction mixture was
stirred allowing the temperature to rise to room temperature slowly. Then 2,4-
dichloropyrimidine BB9-1 (2.00 g, 95 % purity, 12.7 mmol) was added
portionwise
and the reaction was stirred at 70 C for 4 hours. After cooling to room
temperature,
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the reaction mixture was poured onto ice-water (80 mL) and extracted with
ethyl
acetate (100 mL) twice. The combined organic layers were dried over Na2SO4(s),
filtered and concentrated to afford a residue, which was purified by silica
gel column
chromatography (petroleum ether ethyl acetate = 4:1) to give the title
compound
BB9 (700 mg, 90 % purity, 25 % yield) as colorless oil. 111 NMR (400 MHz,
CDC13) 6
8.59 - 8.57 (m, 111), 7.33 - 7.32 (m, 0.711), 7.27 - 7.26 (m, 0.311), 4.23 -
4.16 (m, 211),
3.99 (s, 0.511), 3.82 - 3.81 (m, 1.511), 1.30 - 1.23 (m, 311).
Building block 10: ethyl 2-chlorooxazole-5-carboxylate (BB10)
Building block 11: ethyl 2-bromothiazole-4-carboxylate (BB 11)
Building block 12: Ethyl 2-(2-chloro-4-methylpyrimidin-5-yl)acetate (BB12)
0
)1-NH BP0 (2.0 eq.)
HN)-H-rOH conc. H2SO4 (0.9 eq.) HN)H(
L
1\1c) AcOH, 80 C, 0/fl ON 0 Et0H, 90 C, o/n 1\lj 0
BB12-1 BB12-2 BB12-3
13' B
(2.1 eq.)
POCI3
_________________ N)r
110 C, 3h CI N 0 Pd(PPh3)4(0=1 eq.) CIN
K2CO3 (3.0 eq.)
BB12-4 Dioxane, 90 C, o/n BB12
Intermediate BB12-2:
2-(2,4-Dioxo-1,2,3,4-tetrahydropyriraidin-5-ypacetic acid
To the solution of uracil BB12-1 (23.0 g, 205 mmol) in acetic acid glacial
(800 mL)
was added benzoyl peroxide (100 g, 413 mmol) at room temperature. After
stirred at
80 C overnight and cooled down to room temperature, the mixture was
concentrated under reduced pressure to remove the volatile, then the residue
was
washed with ethyl acetate (200 mL) to give the title compound (22 g, 35 %
purity
from 11-1 NMR (including un-reacted BB12-1), 22 % yield) as white solids. LC-
MS
(ESI): RT = 0.22 min, mass calcd. for C6116N204 170.0, miz found 168.9 [M-111-
. 11-1
NMR (400 MHz, DMSO-de) 6 12.28 (br s, 111), 11.12 (s, 111), 10.76 (s, 111),
7.36 (s,
111), 3.14 (s, 211).
Intermediate BB12-3:
Ethyl 2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetate
To the solution of 2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetic acid
BB12-2
(22.0 g, 35 % purity, 45.3 mmol) in ethanol (220 mL) was added sulfuric acid
(conc.,
4.0 g, 40.8 mmol) at room temperature. After stirred at 90 C overnight and
cooled
down to room temperature, the mixture was concentrated under reduced pressure
to
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remove the volatile, then the residue was washed with ethyl acetate (150 mL)
to
give the title compound (19 g, 35 % purity from 11I NMR,74 % yield) as white
solids.
11I NMR (400 MHz, DMSO-de) 6 11.14 (s, 1H), 10.78 (s, 1H), 7.38 (s, 1H), 4.04
(q, J=
7.2Hz, 2H), 3.21 (s, 2H), 1.17 (t, J= 7.2Hz, 3H).
Intermediate BB12-4:
Ethyl 2-(2,4-dichloropyrimidin-5-yl)acetate
The mixture of ethyl 2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetate
BB12-3
(19.0 g, 35 % purity, 33.6 mmol) in phosphorus oxychloride (300 mL) was
stirred at
110 C for 3 hours. It was cooled down to room temperature and concentrated
under
reduced pressure to remove the volatile, and the residue was dissolved in
ethyl
acetate (500 mL). Ice water (200 mL) was added, followed by extraction with
ethyl
acetate (200 mL) three times. The combined organic layers were washed with
brine
(100 mL) and dried over Na2SO4(s) and filtered. The filtrate was concentrated
under
reduced pressure to give a crude product, which was purified by C18 column
(acetonitrile : water = 40 % to 80 %) to give the title compound (4.40 g, 90 %
purity
from 11I NMR, 51 % yield) as yellow oil. LC-MS (ESI): RT = 1.50 min, mass
calcd. for
C8118C12N202 234.0, m/z found 232.9 [M-11]-. 11I NMR (300 MHz, CDC13) 6 8.81
(s,
1H), 4.13(q, J= 7.2 Hz, 2H), 3.90 (s, 2H), 1.19 (t, J= 7.2 Hz, 3H).
Building block 12:
Ethyl 2-(2-chloro-4-methylpyrimidin-5-yOacetate
To the solution of ethyl 2-(2,4-dichloropyrimidin-5-yl)acetate BB12-4 (100 mg,
90 %
purity, 0.383 mmol) in 1,4-dioxane (2 mL) was added 2,4,6-trimethy1-
1,3,5,2,4,6-
trioxatriborinane (98.0 mg, 0.781 mmol), potassium carbonate (159 mg, 1.15
mmol)
and tetrakis(triphenylphosphine)pallad- ium (44 mg, 0.038 mmol) under nitrogen
atmosphere at room temperature. After stirred at 90 C under nitrogen
atmosphere
overnight and cooled down to room temperature, the reaction mixture was poured
into water (10 mL) and extracted with ethyl acetate (20 mL) for three times.
The
combined organic layers were washed with brine (20 mL) and dried over
Na2SO4(s)
and filtered. The filtrate was concentrated under reduced pressure to give a
crude
product, which was purified by C18 column (acetonitrile : water = 40 % to 90
%) to
give the title compound (27.0 mg, 95 % purity, 31 % yield) as brown oil. LC-MS
(ESI):
RT = 0.89 min, mass calcd. for C91InC1N202 214.1, m/z found 214.9 [M+Hi . 111
NMR
(300 MHz, DMSO-d6) 6 8.53 (s, 1H), 4.11 (q, J= 7.2 Hz, 2H), 3.84 (s, 2H), 2.41
(s, 3H),
1.19 (t, J= 7.2 Hz, 3H).
Building block 13: Ethyl 2,5-dichloropyrimidine-4-carboxylate (BB13)
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0
CI CI
)-Hr0
N N 0 PM ecl') N N
H202 (3.2 eq.), FeSO4(3.1 eq.), H2SO4(3.1 eq.)
CI toluene/H20/AcOH(v/v/v=2/1/2), -10 C, 1.5h 0 CI
BB13-1 BB13
Around bottom flask A was charged with ethyl 2-oxopropanoate (4.70 g, 40.5
mmol)
and the flask was cooled to -10 C, acetic acid (13 mL) was added while
maintaining
the temperature below -5 C. 33 % hydrogen peroxide aqueous solution (1.3 mL,
42.4
mmol) was added dropwise as to maintain the temperature below -5 C. Another
flask B was charged with 2,5-dichloropyrimidine BB13-1 (2.00 g, 13.2 mmol),
toluene (13 mL) and water (7 mL). After the flask was cooled to -15 C,
sulfuric acid
(2.2 mL, 41.3 mmol) was added followed by ferrous sulfate heptahydrate (11.2
g,
40.3 mmol). To the flask of B was added the peroxide solution which had been
prepared in flask A over 1 hour while keeping the temperature below -10 C,
the
resulting mixture was stirred at the same temperature for 30 minutes. The
reaction
mixture was poured into ice water (200 mL) and neutralized to pH ¨ 7 with 1 M
sodium hydroixde aqueous solution and filtered. The cake was washed with
dicloridemethane (200 mL) twice. The filtrate was combined and the aqueous
layer
was separated and extrated with dicloridemethane (200 mL) twice. The combined
organic layers were washed with water (200 mL), brine (200 mL), dried over
Na2SO4(s) and filtered. The filtrate was concentrated under reduced preesure
to give
a residue, which was purified by silica gel chromatography column (petroleum
ether:
ethyl acetate = 100 1 to 50 :1) to afford the title compound (300 mg, 96 %
purity,
10 % yield) as colorless oil. LC-MS (ESI): RT = 1.682 min, mass calcd. for
C7H6C12N202 220.0, m/z found 221.0 [M+111 . 11-1 NMR (300 MHz, CDC13) 6 8.73
(s,
1H), 4.49 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 311).
Building block 14: (cis)-tert-Butyl 3-(2-chloropyrimidin-5-y1)-3-
hydroxycyclobutanecarboxylate (BB14)
_N
Br /)¨CI
CI
0
BB14-2(1 0 eq) HO I
n-BuLi(1 eq), -78 C, 1h õ
0 I cis
0
BB14-1 BB14
To a solution of tert-butyl 3-oxocyclobutanecarboxylate BB14-1 (2.00 g, 98 %
purity,
11.5 mmol) and 5-bromo-2-chloropyrimidine BB14-2 (2.27 g, 98 % purity, 1.50
mmol)
in dry tetrahydrofuran (120 mL) was added 2.5 M n-butyllithium in hexane (4.8
mL,
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12.0 mmol) dropwise over 25 minutes at - 78 C under nitrogen atmosphere.
After
stirred at - 78 C for 1 hour, the reaction mixture was quenched with
saturated
ammonium chloride aqueous solution (30 mL). The resulting mixture was warmed
to room temperature, diluted with water (80 mL) and extracted with ethyl
acetate
(80 mL) twice. The combined organic layers were washed with brine (100 mL),
dried
over Na2SO4(s) and filtered. The filtrate was concentrated to give a residue,
which
was purified by silica gel column chromatography (petroleum ether ethyl
acetate =
1 to 5:1) to give the title compound (1.40 g, 90 % purity, 38 % yield) as
light
yellow solids. LC-MS (ESI): RT = 1.51 min, mass calcd. for C131117C1N203
284.1, m/z
10 found 284.8 [M+111 . 111 NMR (400 MHz, CDC13) 6 8.76 (s, 211), 4.37 (br
s, 111), 3.01 -
2.94 (m, 111), 2.87 - 2.81 (m, 211), 2.60 - 2.55 (m, 214), 1.50 (s, 911).
Building block 15: ethyl 2-chloro-4-(trifluoromethyl)thiazole-5-carboxylate
(BB15)
Building block 16: ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (BB16)
Building block 18: Methyl 2-fluoroisonicotinate (BB18)
F\ F\
OH
N?/ _________ CH2N2 (1.05eq ) NI)/
\¨ 0 DCM/Me0H=3/1 \_/
0
BB18-1 r t , 2h
BB18
To a solution of 2-fluoroisonicotinic acid BB18-1 (400 mg, 2.84 mmol) in
methanol (3
mL) and dichloromethane (9 mL) was added dropwise 2 M diazomethane in
tetrahydrofuran (1.5 mL, 3.00 mmol) at 0 C. After stirred at room temperature
for 2
hours, the mixture was poured into water (10 mL) and the resulting mixture was
extracted with dichloromethane (10 mL) for three times. The combined organic
layers were concentrated under reduced pressure to give a residue, which was
purified by silica gel column chromatography (petroleum ether ethyl acetate =
10
1) to give the title compound (140 mg, 26 % yield) as yellow oil. 1H NMR (400
MHz,
DMSO-d6) 6 8.47 (d, J= 5.2 Hz, 111), 7.82 - 7.79 (m, 111), 7.60 - 7.59 (m,
111), 3.92 (s,
M.
Building block 19: methyl 6-fluoronicotinate (BB19)
Building block 20: methyl 6-fluoropicolinate (BB20)
Building block 21: methyl 6-chloropyrimidine-4-carboxylate (BB21)
Building block 22: 5-chloropyrazine-2-carboxylic acid (BB22)
Building block 23: 2-chloropyrimidine-4-carboxylic acid (BB23)
Building block 24: ethyl 2-bromo-5-methyloxazole-4-carboxylate (BB24)
Building block 25: ethyl 2-chlorooxazole-5-carboxylate (BB25)
Building block 26: 2-(2-Ethoxy-2-oxoacetamido)acetic acid (BB26)
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0
ocI
0
H2NThr (:) (1 2 eq) DCM/TFA(v/v=3/1)
_rOx __________________________________________________________
HCI 0 TEA (2.5 eq) 0 0 r t , overnight
DCM, 0 C- r t , 3h
BB26-1 BB26-2
0
HON)yo,
I H
0 0
BB26
Intermediate BB26-2:
Ethyl 2-02-(tert-butoxy)-2-oxoethyl)amino)-2-oxoacetate
To the solution of tert-butyl 2-aminoacetate hydrochloride BB26-1 (2.00 g,
11.7 mmol)
and triethylamine (3.02 g, 29.2 mmol) in dichloromethane (30 mL) was added
ethyl
oxalyl monochloride (1.6 mL, 14.0 mmol) dropwise at 0 C. After the addition,
the
mixture was stirred at room temperature for 3 hours. Then it was diluted with
dichloromethane (50 mL) and washed with 1 M hydrochloride aqueous solution (40
mL) twice, saturated sodium bicarbonate aqueous solution (40 mL) and brine (40
mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated to give
the title
compound (2.10 g, 95 % purity from 11-1 NMR, 74 % yield) as light yellowish
oil. LC-
MS (ESI): RT = 1.49 min, mass calcd. for Ci0Hi7N05 231.1, m/z found 176.0 [M+H-
56] . 11-1 NMR (400 MHz, CDC13) 6 7.52 (br s, 1H), 4.37 (q, J= 7.2 Hz, 2H),
4.02 (d, J
= 5.6 Hz, 2H), 1.49 (s, 9H), 1.39 (t, J= 7.2 Hz, 3H).
Building block 26:
2-(2-Ethoxy-2-oxoacetaraido)acetic acid
To a solution of ethyl 2-((2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoacetate BB26-
2
(2.10 g, 95 % purity, 8.63 mmol) in dichloromethane (21 mL) was added
trifluoroacetic acid (7 mL). After stirred at room temperature overnight, the
mixture
was concentrated to give the title compound (2.10 g, 70 % purity from 11-1
NMR, 97 %
yield) as brown oil. LC-MS (ESI): RT = 0.32 min, mass calcd. for C6H9N05
175.0, m/z
found 176.1 [M411+. 11-1 NMR (400 MHz, CDC13) 6 7.72 (s, 1H), 4.38 (q, J= 7.2
Hz,
2H), 4.20 (d, J= 5.6 Hz, 2H), 1.39 (t, J= 7.2 Hz, 3H).
Building block 27: Methyl 6-chloro-4-methylpyridazine-3-carboxylate (BB27)
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OH
,
CI 13 OH CI
Ag20 (2.45 eq),
0 N=N 0 N'N 0 N=N
Pd(PPh3)4 (0.05 eq),
K2CO3 (3.0 eq)
BB27-1 THF, 80 C, overnight BB27 BB27-2
A mixture of methyl 4,6-dichloropyridazine-3-carboxylate BB27-1 (400 mg, 95 %
purity, 1.84 mmol), methylboronic acid (135 mg, 98 % purity, 2.21 mmol) and
potassium carbonate (768 mg, 99 % purity, 5.50 mmol) in tetrahydrofuran (10
mL)
was degassed for 10 minutes with nitrogen. Then tetrakis(triphenylphosphine)
palladium(0) (112 mg, 95 % purity, 0.092 mmol) and silver oxide (1.10 g, 95 %
purity,
4.51 mmol) were added, and the solution was further degassed with nitrogen for
an
additional 5 minutes. The vial was sealed and the reaction was heated at 80 .0
overnight under nitrogen atmosphere. Then the mixture was cooled down to room
temperature and concentrated. The obtained residue was purified by silica gel
column chromatography (petroleum ether ethyl acetate = 3 1) to give the title
compound BB27 (30 mg, 74 % purity, 6 % yield) and methyl 4-chloro-6-
methylpyridazine-3-carboxylate BB27-2 (53 mg, 53 % purity, 8 % yield) as
yellow oil.
BB27: 111 NMR (400 MHz, CDC13) 6 7.46 (s, 111), 4.04 (s, 311), 2.59 (s, 311).
BB27-2: 11-1 NMR (400 MHz, CDC13) 6 7.48 (s, 111), 4.04 (s, 311), 2.77 (s,
311).
Building block 28: Methyl 6-chloro-2-methylpyrimidine-4-carboxylate (BB28)
ci CI CI OH
H2SO4(13 M), I Pd(01302Cl2(0.05eq), DIEA(1.6eq)
N N N N >
NaOH (6 M)
CO(5 M Pa), 100 C,Me0H/DMF,16h
0 - rt,16h
BB28-1 BB28-2
0 0
(:))"OH POCI3
>
N N 110 C, 30 min N N
BB28-3 BB28
Intermediate BB28-2:
6-Chloro-2-methylpyrimidin-4-ol
To 13 M sulfuric acid aqueous solution (25 mL, 32.5 mmol) was added portion-
wise
4,6-dichloro-2-methylpyrimidine BB28-1 (4.00 g, 97 % purity, 23.8 mmol) at 0
.0
over 20 minutes. After stirred at 0 .0 for 1.5 hours and at room temperature
overnight, the reaction mixture was poured into 6 M sodium hydroxide aqueous
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solution (80 mL) in an ice bath. The resulting solids were then collected by
filtration,
washed with warm water (100 mL) and dried under high vacuum to provide the
desired product (3.00 g, 95 % purity from 111 NMR, 83 % yield) as white
solids. 111
NMR (400 MHz, DMSO-de) 6 12.87 (br s, 1 II), 6.34 (s, 1 H), 2.30 (s, 3 11).
Intermediate BB28-3:
Methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate
A suspension of 6-chloro-2-methylpyrimidin-4-ol BB28-2 (2.50 g, 95 % purity,
16.4
mmol), /V,/V-diisopropylethylamine (3.30 g, 25.5 mmol) and [1,1'-
bis(diphenylphosphino)ferroceneidichloropalladium(II) (605 mg, 0.827 mmol) in
methanol (10 mL) and /V,/V-dimethylformamide (10 mL) was heated at 100 C
under
carbon monoxide atmosphere (5 MPa) for 16 hours. The resulting solids were
then
collected by filtration, washed with methanol (30 mL), followed by diethyl
ether (60
mL) and dried under vacuum to give the title compound (2.10 g, 95 % purity
from 11-1
NMR, 72 % yield) as brown solids. 11-1 NMR (400 MHz, DMSO-de) 6 12.85 (br s,
111),
6.72 (s, 111), 3.82 (s, 311), 2.33 (s, 311).
Building block 28:
Methyl 6-chloro-2-methylpyrimidine-4-carboxylate
A mixture of methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate BB28-3 (300 mg,
95 % purity, 1.70 mmol) in phosphoryl trichloride (10 mL) was stirred at 110
0C for
30 minutes. Then the mixture was cooled down to room temperature and
concentrated to give a residue, which was purified by prep. TLC (petroleum
ether
ethyl acetate = 8:1) to give the title compound (60 mg, 96 % purity from 11-1
NMR,
18 % yield) as colorless oil. 11-1 NMR (400 MHz, DMSO-de) 6 7.96 (s, 111),
3.92 (s, 311),
2.70 (s, 311).
Building block 29 and Building block 30:
Methyl 5-chloro-3-methylpyrazine-2-carboxylate (BB29) and methyl 6-chloro-3-
methylpyrazine-2-carboxylate (BB30)
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Me0H I mCPBA (1.5 ecl)
Ther0H
HCI (conc. 0.85 eg), 1\1-(C)i CHCI3, 70 C, 3 h
0 85 C, overnight 0
BB29-1 BB29-2
6
POCI3 chiral separation >
NJ( N (ON DMF, 100 C, 1 h
1- 1
0 0 _
BB29-3
CIN
I ,
CINn-r()
0
0
BB29 BB30
Intermediate BB29-2:
Methyl 3-methylpyrazine-2-carboxylate
To a solution of 3-methylpyrazine-2-carboxylic acid BB29-1 (1.0 g, 7.10 mmol)
in
methanol (30 mL) was added concentrated hydrochride aqueous solution (0.5 mL,
6
mmol) at room temperature. After stirred at 85 C overnight, the mixture was
concentrated under reduced pressure to give a residue, which was dissolved in
ethyl
acetate (5 mL) and washed with saturated sodium bicarbonate aqueous solution
(15
mL) twice. Then the combined aqueous layers were extracted with ethyl acetate
(60
mL) twice. The combined organic layers were washed with water (30 mL) twice
and
brine (30 mL), dried over anhydrous Na2SO4(s) and filtered. The filtrate was
concentrated under reduced pressure to give the title compound (850 mg, 85 %
purity, 67 % yield) as white solids. LC-MS (ESI): RT = 0.738 min, mass calcd.
for
C7118N202 152.1, m/z found 153.0 [M411+. 111 NMR (300 MHz, CDC13) 6 8.64 -
8.61
(m, 111), 8.55 - 8.51 (m, 111), 4.05 - 4.00 (m, 311), 2.90 - 2.85 (m, 311).
Intermediate BB29-3:
Mixture of 3-(methoxycarbony0-2-methylpyrazine 1-oxide and 2-(methoxycarbony1)-
3-methylpyrazine 1-oxide
To a solution of methyl 3-methylpyrazine-2-carboxylate BB29-2 (100 mg, 85 %
purity, 0.560 mmol) in chloroform (4 mL) was added meta-chloroperoxybenzoic
acid
(168 mg, 85 % purity, 0.83 mmol) at room temperature. After 70 C for 3 hours,
the
mixture was diluted with waster (10 mL), then basified with saturated
bicarbonate
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aqueous sodium to pH 8 ¨ 9 and extracted with dichloromethane (30 mL) twice.
The
combined organic layers were washed with water (10 mL) twice and brine (10
mL),
dried over Na2SO4(s) and filtered. The filtrate was concentrated under reduced
pressure to leave a residue, which was purified by column chromatography on
silica
gel (dichloromethane : methanol = 10 :1) to give the title compound (90 mg, 90
%
purity, 87 % yield) as white solids. LC-MS (EST): RT = 0.541 min, mass calcd.
for
C7118N203 168.1, m/z found 169.0 [M+Hi .
Building block 29 and Building block 30:
Methyl 5-chloro-3-methylpyrazine-2-carboxylate (BB29) and methyl 6-chloro-3-
.. methylpyrazine-2-carboxylate (BB30)
To a solution of mixture of 3-(methoxycarbony1)-2-methylpyrazine 1-oxide and 2-
(methoxycarbony1)-3-methylpyrazine 1-oxide BB29-3 (680 mg, 90 % purity,3.64
mmol) in N,N-dimethylformamide (10 mL) was added phosphoryl trichloride (1 mL)
at room temperature. After stirred at 100 C for 1 hour, the reaction mixture
was
.. cooled down and added 1 M sodium carbonate aqueous solution (10 mL) slowly
at 0
C, then extracted with ethyl acetate (50 mL) twice. The combine organic layers
were washed with water (30 mL) twice and brine (30 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated under reduced pressure to leave a
residue,
which was purified by column chromatography on silica gel (ethyl acetate :
methanol
.. = 10 : 1) to give the white solids, which was separated by Chiral Prep.
HPLC
(Column: Chiralpak ID 5 i.tm 20 mm * 250 mm; Mobile Phase: CO2 : Me0H = 70 :
30
at 50 g/ min; Temp: 40 C; Wavelength: 230 nm) to afford the title compounds
BB29
(250 mg, 95 % purity, 39 % yield, 100 % stereopure) and BB30 (300 mg, 95 %
purity,
46 % yield, 98.9 % stereopure ) as yellow solids.
.. BB29: Chiral HPLC (Column: Chiralpak ID 5 i.tm 4.6 * 250 mm; Mobile Phase:
CO2:
Me0H = 70 : 30 at 3 g/ min; Temp: 40 C; Wavelength: 280 nm, RT = 3.17 min).
111
NMR (400 MHz, CDC13) 6 8.74 (s, 1H), 3.91 (s, 3H), 2.71 (s, 3H).
BB30: Chiral HPLC (Column: Chiralpak ID 5 i.tm 4.6 * 250 mm; Mobile Phase:
CO2:
Me0H = 70 : 30 at 3 g/ min; Temp: 40 C; Wavelength: 280 nm, RT = 4.31 min).
111
NMR (400 MHz, CDC13) 6 8.91 (s, 1H), 3.92 (s, 3H), 2.73 (s, 3H).
Building block 31: Ethyl 2-chloro-6-methylpyrimidine-4-carboxylate (BB31)
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0
H2NANH2 (to eq) NOH Nycl
II 0
BB31-2 POCI3
conc.HCI, Et0H 115 C, 1 hour
0 0
90 C, 16 hours 0 OEt 0 OEt
BB31-1 BB31-3 BB31
Intermediate BB31-3:
Ethyl 2-hydroxy-6-methylpyrimidine-4-carboxylate:
To a solution of ethyl 2,4-dioxopentanoate BB31-1 (5.00 g, 31.6 mmol) and urea
BB31-2 (1.90 g, 31.6 mmol) in ethanol (40 mL) was added concentrated
hydrochloride aqueous solution (4.3 mL) at room temperature. After stirring at
90
C for 16 hours, the reaction mixture was cooled down to room temperature,
adjusted to PH 7 - 8 with 10 M saturated sodium hydroxide aqueous solution and
concentrated to give a residue, which was purified by C18 column (acetonitrile
water = 1 % to 25 %) to give the title compound BB31-3 (650 mg, 11 % yield) as
yellow solids. 11-1 NMR (400 MHz, DMSO-d6) 6 6.47 (s, 1H), 4.31 (q, J= 7.2 Hz,
2H),
2.26 (s, 3H), 1.30 (t, J= 7.2 Hz, 3H).
Building block 31:
Ethyl 2-chloro-6-methylpyrimidine-4-carboxylate:
A mixture of ethyl 2-hydroxy-6-methylpyrimidine-4-carboxylate BB31-3 (550 mg,
3.02 mmol) in phosphorus oxychloride (10 mL) was stirred at 115 0C for 1 hour.
Then it was allowed to cool down to room temperature and the solvent was
removed
under reduced pressure to give a residue, which was basified to pH 8 - 9 with
saturated sodium bicarbonate aqueous solution (20 mL, and extracted with ethyl
acetate (10 mL) for three times. The combined organic layers were washed with
brine (10 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under
reduced pressure to give a residue, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 10 1 to 1 3) to give the title
compound (85 mg, 14 % yield) as yellow solids. 11-1 NMR (400 MHz, CDC13) 6
7.80 (s,
1H), 4.49 (q, J= 7.2 Hz, 2H), 2.65 (s, 3H), 1.44 (t, J= 7.2 Hz, 3H).
Building block 32: tert-Butyl 6-chloro-4-((4-methoxybenzyl)oxy)nicotinate
(BB32)
ci (1.0 eq.) PMBO CI
1 DMAP (0.2 eq.) N OH
ON
HON ________________________
THF, 70 C, 3 h. *0 NaH (1.2 eq.)
0 DMF, 0 C to r. t ,
3h
BB32-1 BB32-2 BB32
Intermediate BB32-2:
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tert-Butyl 4,6-dichloronicotinate
To a solution of 4,6-dichloronicotinic acid BB32-1 (10.0 g, 0.05 mol) in
tetrahydrofuran (100 mL) was added di- tert-butyl dicarbonate (22.7 g, 0.10
mol) and
4-dimethylaminopyridine (1.20 g, 0.01 mol) at room temperature. After stirred
at 70
0C for 3 hours, the mixture was cooled down to room temperature and
concentrated
under reduced pressure to give a residue, which was purified by silica gel
column
chromatography (petroleum ether : ethyl acetate = 30 : 1 to 20 :1) to afford
the title
compound (11.0 g, 89 % yield) as colorless oil. LC-MS (ESI): RT = 1.84 min,
mass
calcd. for C1oHl1Ci2NO2 247.0, m/z found 247.9 [M+Hi . 1H NMR (300 MHz, CDC13)
6
8.76 (s, 111), 7.44 (s, 111), 1.61 (s, 91I).
Building block 32:
tert-Butyl 6-chloro-4-((4-methoxybenzyl)oxy)nicotinate
To a solution of (4-methoxyphenyl)methanol (2.80 g, 20.3 mmol) in /V,/V-
dimethylformamide (35 mL) was added 60 % wt. sodium hydride in mineral oil
(970
mg, 24.3 mmol) portionwise at 0 0C under nitrogen atmosphere. After stirring
for 1
hours at 0 C, tert-butyl 4,6-dichloronicotinate BB32-2 (5.00 g, 20.2 mmol)
was
added. The resulting mixture was stirred at room temperature for 3 hours. Then
it
was quenched with ice (50 g) and extracted with ethyl acetate (100 mL) twice.
The
combined organic layers were washed with brine (100 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated under reduced pressure to give a
residue,
which was purified by silica gel column chromatography (petroleum ether :
ethyl
acetate = 20 : 1 to 10 :1) the afford the crude product, which was further
purified by
C18 column (acetonitrile : water = 30 % to 70 %) to give the title compound
(2.50 g,
35 % yield) as white solids. LC-MS (ESI): RT = 1.83 min, mass calcd. for
C181120C1N04 349.1, m/z found 349.9 [M411+. 1H NMR (400 MHz, CDC13) 6 8.62 (s,
111), 7.38 - 7.36 (m, 211), 6.95 - 6.91 (m, 311), 5.11 (s, 211), 3.83 (s,
311), 1.50 (s, 911).
Building block 33: tert-Butyl 6-chloro-5-fluoronicotinate (BB33)
NCI 1\1 CI (Boc)20 (2eq) N CI
KMn04 (2 eq) I
I DMAP (0.3 eq)
/F pyridine/water HO F t-BuOH, 80 C 0
0
BB33-1 BB33-2 BB33
Intermediate BB33-2:
6-Chloro-5-fluoronicotinic acid
To a solution of 2-chloro-3-fluoro-5-methylpyridine BB33-1 (1.00 g, 6.86 mmol)
in
water (5 mL) and pyridine (5 mL) was added potassium permanganate (2.20 g,
13.7
mmol) at room temperature. After stirring at 100 C under nitrogen atmosphere
for
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4 hours, the reaction mixture was cool down to room temperature and filtered.
The
filtrate was concentrated under reduced pressure to give the title compound
(700 mg,
58 % yield) as white solids. LC-MS (ESI): RT = 0.30 min, mass calcd. for
C6H3C1FN02 175.0, m/z found 174.0 [M-Ht. 11-1 NMR (400 MHz, CD30D) 6 8.70 (d,
J
= 1.2 Hz, 1H), 8.06 (dd, J= 8.8, 1.6 Hz, 1H).
Building block 33:
tert-Butyl 6-chloro-5-fluoronicotinate
To a solution of 6-chloro-5-fluoronicotinic acid BB33-2 (600 mg, 3.43 mmol) in
tert-
butanol (20 mL) was added 4-dimethylaminopyridine (126 mg, 1.03 mmol) and di-
tert-butyl dicarbonate (1.50 g, 6.86 mmol) at room temperature. After stirring
at 80
C overnight, the reaction mixture was cool down to room temperature and
filtered.
The filtrate was concentrated under reduced pressure to give a residue, which
was
purified by silica gel column chromatography (petroleum ether ethyl acetate =
50
1) to give the title compound (300 mg, 38 % yield) as white solids. LC-MS
(ESI): RT =
1.80 min, mass calcd. for Ci0HliC1FN02 231.1, m/z found 232.1 [M+111 . 11-1
NMR
(400 MHz, DMSO-d6) 6 8.73 (d, J= 1.6 Hz, 1H), 8.27 (dd, J= 8.4, 2.0 Hz, 1H),
1.57 (s,
9H).
Building block 34: Methyl 2-chloro-3-fluoroisonicotinate (BB34)
CI J\I CI
TMSCHN2 (0.3 eq)
DCM, Me0H, AcOH,
0 OH 0 C, 1 h 0 0
BB34-1 BB34
To a solution of 2-chloro-3-fluoroisonicotinic acid BB34-1 (200 mg, 95 %
purity, 1.08
mmol) in dichloromethane (3 mL) at 0 C was added dropwise methanol (1 mL) and
0.6 M (diazomethyl)trimethylsilane in dichloromethane (0.6 mL, 0.360 mmol).
After
stirred at 0 C for 1 hour, the mixture was quenched with acetic acid (0.5 mL)
and
concentrated in vacuo. Then the residue was partitioned between water (10 mL)
and
dichloromethane (1BB34-1. The combined organic layers were washed with brine
(10 mL), dried over anhydrous Na2SO4(s), filtered and concentrated to give the
title
compound (205 mg, 90 % purity from 11-1 NMR, yield 90 %) as pale solids. 11-1
NMR
(300 MHz, CDC13) 6 8.30 (d, J= 4.8 Hz, 1H), 7.70 (t, J= 4.8 Hz, 1H), 4.00 -
3.97 (m,
3H).
Building block 35: Ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (BB35)
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NCI
I I Na104 (1.5 eq), I I
iJ3 OSnB FN KMn04 (0.4 eq) FN
FN BB35-2 (1.0 eq)
dioxane/water = 5 : 3, rt,4h
CI Pd(PPh3)4 (0.1 eq),
0 0
DMF, 90 C, 2h
BB35-1 BB35-3 BB35
Intermediate BB35-3:
2-Chloro-4-(1-ethoxyviny1)-5-fluoropyrimidine
To a solution of 2,4-dichloro-5-fluoropyrimidine BB35-1 (500 mg, 3.00 mmol)
and
tributyl (1-ethoxyvinyl) tin BB35-2 (1.08 g, 3.00 mmol) in /V,/V-
dimethylformamide
(5 mL) was added tetrakis(triphenylphosphine) palladium (347 mg, 0.300 mmol)
at
room temperature under nitrogen atmosphere. The mixture was sitrred at 90 C
for
2 hours. Another batch (500 mg) was combined to work-up. The mixutre was
cooled
down to room temperature and poured into water (30 mL). It was extracted with
ethyl acetate (20 mL) twice. The combined organic layers were washed with
water
(20 mL), brine (20 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under reduced pressure to give a residue, which was purified by
silica
gel column chromatography (petroleum ether: ethyl acetate = 50 : 1 to 10 :1)
to give
the title compound (1.7 g, 60 % purity from 111 NMR, 86 % yield, 0.3 eq
SnBu3C1 by
11-1 NMR) as colorless oil. 111 NMR (400 MHz, CDC13) 6 8.47 (d, J= 2.8 Hz,
1H), 5.31
(d, J= 2.8 Hz, 1H), 4.73 (d, J= 2.8 Hz, 1H), 3.97 (q, J= 7.2 Hz, 2H), 1.43 (t,
J= 7.2
Hz, 3H).
Building block 35:
Ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate
To a solution of 2-chloro-4-(1-ethoxyetheny1)-5-fluoropyrimidine BB35-3 (1.70
g, 60 %
purity, 5.03 mmol) in dioxane (50 mL) and water (30 mL) was added sodium
periodate (1.61 g, 7.53 mmol) and potassium permanganate (0.32 g, 2.03 mmol)
at
room temperature. The mixture was stirred at room temperature for 4 hours.
Then
insoluble solids from the mixture were filtered off and the filtrate was
extracted
with ethyl acetate (30 mL) for three times. The combined organic layers were
washed with brine (30 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under reduced pressure to give a residue, which was purified by
silica
gel column chromatography (petroleum ether: ethyl acetate = 30: 1 to 8: 1) to
give
the title compound (700 mg, 94.5 % purity, 64 % yield) as colorless oil. LC-MS
(ESI):
RT = 1.521 min, mass calcd. for C7H6C1FN202204.0, m/z found 205.0 [M+111 . 111
NMR (400 MHz, CDC13) 6 8.70 (d, J= 1.6 Hz, 1H), 4.51 (q, J= 7.2 Hz, 2H), 1.44
(t, J
= 7.2 Hz, 3H).
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Building block 36: Ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate (BB36)
acetaldehyde (1.2 eq) N OH
urea (1.2 eq) y õOH
0 0 T
),u, acetic acid (cat.) ONH con.HNO3:H20=5:2, 0 N
Et0H, 95 C,
N2, overnight 10
BB36-1 BB36-2 BB36-3
NCI
II NaOH (1.2 eq) õCI
POCI3 ___________ (DN T
90 C, 2d THF:H20 = 1:4, ON
r.t., 16h
OH
BB36-4 BB36
Intermediate BB36-2:
Ethyl 2-hydroxy-4,6-dimethy1-1,2-dihydropyrimidine-5-carboxylate
5 .. To a solution of ethyl acetoacetate BB36-1 (20.0 g, 0.154 mol),
acetaldehyde (7.50 g,
0.170 mol) and urea (10.2 g, 0.170 mol) in anhydrous ethanol (50 mL) was added
acetic acid (30 drops) at room temperature. After stirred at 95 C under
nitrogen
atmosphere overnight, the mixture was allowed to cool down to room temperature
and diluted with water (200 mL). The appeared precipitate was collected by
10 filtration and washed with water (200 mL), followed by a mixed solvent
of petroleum
ether (167 mL) and ethyl acetate (33 mL) to give the desired product (11.4 g,
36 %
yield) as white solids. LC-MS (ESI): RT = 1.65 min, mass calcd. for C9Hi4N203
198.1,
m/z found 199.0 [M+111 . 111 NMR (400 MHz, DMS0- d6) 6 8.98 (s, 1H), 7.21 (s,
1H),
4.13 - 4.03 (m, 3H), 2.16 (s, 3H), 1.19 (t, J= 7.6 Hz, 3H), 1.10 (d, J= 6.0
Hz, 3H).
Intermediate BB36-3:
Ethyl 2-hydroxy-4,6-dimethylpyrimidine-5-carboxylate
To a solution of concentrated nitric acid (20 mL) and water (8 mL) was added
ethyl
2-hydroxy-4,6-dimethy1-1,2-dihydropyrimidine-5-carboxylate BB36-2 (5.00 g,
25.3
mmol) portionwise at 0 C. After stirred at 0 C for 1 hour, the reaction
mixture was
basified by sodium bicarbonate (-15 g, 17.9 mmol) to pH - 6. The aqueous
solution
was extracted with a mixed solvent dichloromethane and methanol (v/v = 20/1,
50
mL) for four times. The combined organic layers were concentrated to give the
desired product (3.00 g, 61 % yield) as yellow solids. LC-MS (ESI): RT = 1.22
min,
mass calcd. for C9Hi2N203 196.1, m/z found 197.0 [M411+. 1H NMR (400 MHz,
DMSO-d6) 6 12.13 (br s, 1H), 4.26 (q, J= 6.8 Hz, 2H), 2.35 (s, 6H), 1.29 (t,
J= 6.8 Hz,
3H).
Intermediate BB36-4:
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Ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate
A mixture of ethyl 2-hydroxy-4,6-dimethylpyrimidine-5-carboxylate BB36-3 (3.00
g,
15.3 mmol) in phosphorus oxychloride was stirred at 90 .0 under nitrogen
atmosphere for 2 days. After cooled down to room temperature, the mixture was
concentrated to give a residue, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 15 1) to give the desired
product
(1.60 g, 49 % yield) as pale yellow oil. LC-MS (EST): RT = 2.12 min, mass
calcd. for
C911iiC1N202 214.1, m/z found 214.9 [M+111 . 111 NMR (400 MHz, CDC13) 64.47 -
4.44 (m, 211), 2.56 (s, 611), 1.44 - 1.40 (m, 311).
Building block 36:
2-Chloro-4,6-dimethylpyrimidine-5-carboxylic acid
To a solution of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate BB36-4
(100 mg,
0.443 mmol) in water (4 mL) and tetrahydrofuran (1 mL) was added sodium
hydroxide (22 mg, 0.550 mmol) at room temperature. After stirred at room
temperature for 16 hours, the mixture was concentrated under reduced pressure
to
give the crude title compound (110 mg, 60 % purity, 80 % yield) as white
solids,
which was used for the next step without further purification. LC-MS (EST): RT
=
0.27 min, mass calcd. for C7117C1N202 186.0, m/z found 186.9 [M+111 .
Building block 37: Ethyl 2-chloro-5,6-dimethylpyrimidine-4-carboxylate (BB37)
Na104 (2 eq.)
CI N CI (1 CI N CI
eq.) KMn04 (0.4 eq.)
I ________________________________ > ___________________________ >
[(C61-15)3P]2PdC12 (0.2 eq-)
dioxane,H20
CI DMF,100 C.8h r.t.,2h
BB37-1 BB37-2
,13'OH
CI N CI H0 q') CI
I (1 e
'
Pd[P(06H5)3]4 (0.1 eq.)
00\ K2CO3(3 eq.),dioxane ()(3
110 oC,overnight
BB37-3 BB37
Intermediate BB37-2:
2,4-Dichloro-6-(1-ethoxyviny1)-5-methylpyrimidine
To the solution of 2,4,6-trichloro-5-methylpyrimidine BB37-1 (5.50 g, 27.9
mmol) in
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/V,/V-dimethylformamide (30 mL) was added tributy1(1-ethoxyvinyNtannane (10.0
g,
27.7 mmol) and bis(triphenylphosphinOpalladium(II) chloride (410 mg, 5.61
mmol)
under nitrogen atmosphere. After stirred at 100 C under nitrogen atmosphere
for 8
hours, the reaction mixture was cooled to room temperature, dilluted with
water (30
mL) and extracted with ethyl acetate (30 mL) twice. The combined organic
layers
were washed with brine (30 mL), dried over Na2SO4(s), filtered and
concentrated to
give a residue, which was purified by silica gel column chromatography
(petroleum
ether : ethyl acetate = 20 :1) to give the desired compound (4.00 g, 90 %
purity from
11-1 NMR, 55 % yield) as white solids. 11-1 NMR (400 MHz, CDC13) 6 4.78 (d, J=
3.2
Hz, 1H), 4.57 (d, J= 3.2 Hz, 1H), 3.93 (q, J= 6.8 Hz, 2H), 2.40 (s, 3H), 1.39
(t, J= 6.8
Hz, 3H).
Intermediate BB37-3:
Ethyl 2,6-dichloro-5-methylpyrimidine-4-carboxylate
The suspension of sodium periodate (1.34 g, 8.49 mmol) in water (5 mL) was
sonicated until a clear solution was obtained. Then a solution of 2,4-dichloro-
6-(1-
ethoxyviny0-5-methylpyrimidine BB37-2 (5.50 g, 90 % purity, 21.2 mmol) in 1,4-
dioxane (25 mL) and potassium permanganate (9.28 g, 43.4 mmol) was added at
room temperature. After stirred at room temperature under nitrogen atmosphere
for
2 hours, the reaction mixture was diluted with water (60 mL) and extracted
with
ethyl acetate (60 mL) twice. The combined organic layers were washed with
brine
(60 mL), dried over Na2SO4(s), filtered and concentrated to give a residue,
which was
purified by silica gel column chromatography (petroleum ether : ethyl acetate
= 20 :
1) to give the title compound (4.00 g, 90 % purity from 11-1 NMR, 72 % yield)
as white
solids. 11-1 NMR (400 MHz, CDC13) 6 4.46 (q, J= 6.8 Hz, 2H), 2.47 (s, 3H),
1.41 (t, J =
6.8 Hz, 3H).
Building block 37:
Ethyl 2-chloro-5,6-dimethylpyrimidine-4-carboxylate
To a solution of ethyl 2,6-dichloro-5-methylpyrimidine-4-carboxylate BB37-3
(2.00 g,
90 % purity, 7.66 mmol) and methylboronic acid (460 mg, 7.69 mmol) in 1,4-
dioxane
(10 mL) was added tetrakis(triphenylphosphinOpalladium (890 mg, 0.770 mmol)
and potassium carbonate anhydrous (3.20 g, 23.2 mmol) at room temperature.
After
stirred at 110 C under nitrogen atmosphere overnight, the reaction mixture
was
cooled to room temperature, diluted with water (20 mL) and extracted with
ethyl
acetate (20 mL) twice. The combined organic layers were washed with brine (20
mL),
dried over Na2SO4(s), filtered and concentrated to give a residue, which was
purified
by C18 column (acetonitrile : water = 40 % to 70 %) to give the title compound
(600
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mg, 90 % purity from 11-1 NMR, 33 % yield) as white solids. 11-1 NMR (400 MHz,
CDC13) 6 4.45 (q, J= 7.2 Hz, 2H), 2.58 (s, 3H), 2.38 (s, 3H), 1.43 (t, J= 7.2
Hz, 3H).
Building block 38: Ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate (BB38)
o 0õ0
CI CI B
0
N 1\1
N N 0 (3 eq) Oy (1 0 eq)
y .
H202 (3 eq), H2SO4 (3 eq) 0 Br Pd(OAc)2 (0.1 eq), Cy3P (0.2 eq),
Br FeSO4 .7H20(3 eq) AcOH, r K3PO4 (3.0 eq), toluene/water(v/v
water/toluene(v/v, 1/2), 3/1), 85 C, 16 h
BB38-1 - 10 C ¨ r.t., 1.5 h BB38-2
CI
CI
N 1\1
0 I Pt02, H2 balloon
Et0H, 20 C, 1 h'-. 0 N N '
I /
01
OI
BB38-3 BB38
Intermediate BB38-2:
Ethyl 5-bromo-2-chloropyrimidine-4-carboxylate
Around bottom flask A was charged with ethyl 2-oxopropanoate (5.40 g, 98 %
purity,
45.6 mmol) and the flask was cooled to - 10 C. Acetic acid (20 mL) was added
while
maintaining the temperature below - 5 C. 30 % hydrogen peroxide aqueous
solution
(4.7 mL, 46.0 mmol) was added dropwise as to maintain the temperature at - 5
Another flask B was charged with 5-bromo-2-chloropyrimidine (3.0 g, 98 %
purity,
15.2 mmol), toluene (20 mL) and water (10 mL). After the flask was cooled to -
10 C,
sulfuric acid (2.5 mL, 46.0 mmol) was added followed by ferrous sulfate
heptahydrate (13.2 g, 98 % purity, 46.5 mmol). To the flask B was added the
peroxide solution which had been prepared in flask A over 1 hour while keeping
the
temperature at - 10 C. After the addition, the reaction mixture was further
stirred
for 30 minutes. Then it was poured into ice water (100 mL), neutralized to pH
¨ 7
with 1 N sodium hydroxide aqueous solution and filtered over celite. The
celite was
washed with dichloromethane (200 mL). The organic layer was separated and the
aqueous layer was extracted with dichloromethane (200 mL). The combined
organic
layers were washed with 0.5 M sodium bisulfite aqueous solution (200 mL) and
brine (200 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated to
give a residue, which was purified by silica gel chromatography (petroleum
ether :
ethyl acetate = 100: 1 to 50 :1) to give the title compound (850 mg, 90 %
purity, 19 %
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yield) as colorless oil and recover 5-bromo-2-chloropyrimidine (1.5 g, 90 %
purity, 46 %
yield) as white solids. LC-MS (EST): RT = 1.39 min, mass calcd. for
C7H6BrC1N202
263.9, 265.9, m/z found 265.0, 267.0 [M+111 . 1H NMR (400 MHz, CDC13) 6 8.85
(s,
1H), 4.50 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 311).
.. Intermediate BB38-3:
Ethyl 2-chloro-5-vinylpyrimidine-4-carboxylate
To a mixture of ethyl 5-bromo-2-chloropyrimidine-4-carboxylate BB38-2 (300 mg,
90 %
purity, 1.02 mmol), 4,4,5,5-tetramethy1-2-viny1-1,3,2-dioxaborolane (160 mg,
98 %
purity, 1.02 mmol) and potassium phosphate (661 mg, 98 % purity, 3.05 mmol) in
toluene (9 mL) and water (3 mL) was added palladium acetate (24 mg, 99 %
purity,
0.106 mmol) and tricyclohexyl phosphine (61 mg, 95 % purity, 0.207 mmol) under
nitrogen atmosphere. After stirred at 85 C under nitrogen atmosphere for 16
hours,
the mixture was diluted with water (20 mL). The organic phase was separated
and
the aqueous layer was extracted with ethyl acetate (10 mL) for three times.
The
combined organic layers were washed with brine (10 mL), dried over Na2SO4(s)
and
filtered. The filtrate was concentrated to give a residue, which was purified
by silica
gel column chromatography (petroleum ether: ethyl acetate = 100 : 1 to 10 :1)
to
give the title compound (100 mg, 90 % purity, 41.6 % yield) as white solids.
LC-MS
(EST): RT = 1.67 min, mass calcd. for C9H9C1N202 212.0, m/z found 212.9 [M+111
. 1H
NMR (400 MHz, CDC13) 6 8.89 (s, 111), 7.17 - 7.10 (m, 111), 5.84 (d, J= 17.6
Hz, 111),
5.61 (d, J= 11.2 Hz, 111), 4.48 (q, J= 7.2 Hz, 211), 1.44 (t, J= 7.2 Hz, 311).
Building block 38:
Ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate
To a solution of ethyl 2-chloro-5-vinylpyrimidine-4-carboxylate BB38-3 (100
mg, 90 %
purity, 0.423 mmol) in ethanol (5 mL) was added platinum dioxide (25 mg, 99 %
purity, 0.109 mmol) under nitrogen atmosphere. After stirred at 20 C under
hydrogen atmosphere of balloon for 1 hour, the reaction mixture was filtered
and the
filtrate was concentrated to give the title compound (90 mg, 90 % purity, 89.1
%
yield) as black solids. LC-MS (EST): RT = 1.677 min, mass calcd. for
C9HiiC1N202
214.1, m/z found 215.0 [M+111 .
Building block 39: Methyl 3-(2-chloropyrimidin-5-yl)propanoate (BB39)
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CI CI
a N N
N
N 1\1 0 (1.2 eq) Pd/C(10%wt), H2
Pd(0Ac)2(4 mmol%), TEA(2.2 eq)
Et0Ac/DCM = 10/1
Br tri-m-tolylphosphine(8 mmol%) r t.,overnight
DMF, 130 C, 4h 0 0 0 0
BB39-1 BB39-2 BB39
Intermediate BB39-2:
Methyl 3-(2-chloropyrimidin-5-yl)acrylate
A suspension of 5-bromo-2-chloropyrimidine BB39-1 (5.0 g, 26 mmol), methyl
acrylate (2.6 g, 31 mmol), triethylamine (5.7 g, 57 mmol), wt. palladium
acetate (4
mmol%, 243 mg) and tri-m-tolylphosphine (8 mmol %, 630 mg,) in /V,/V-
dimethylformamide (30 mL) was stirred at 130 C for 4 hours. After cooling
down to
room temperature, the mixture was quenched with water (300 mL), extracted with
ethyl acetate (100 mL) twice. The combined organic layers were concentrated
under
reduced pressure to give a crude product, which was purified by silica gel
column
chromatography (petroleum ether ethyl acetate = 12 1 to 10 1) to give the
title
compound (600 mg, 12 % yield) as yellow solids. 111 NMR (300 MHz, CDC13) 6
8.76 (s,
2H), 7.59 (d, J= 15.9 Hz, 1H), 6.58 (d, J= 16.2 Hz, 1H), 3.84 (s, 3H).
Building block 39:
Methyl 3-(2-chloropyrimidin-5-yl)propanoate
To a solution ofmethyl 3-(2-chloropyrimidin-5-yl)acrylate BB39-2 (150 mg,
0.758
mmol) in ethyl acetate (20 mL) and dichloromethane (2 ml) was added 10 %
palladium on charcoal wt. (100mg) at room temperature. After stirred at room
temperature under hydrogen atmosphere overnight, the reaction mixture was
.. filtered and the filtrate was concentrated under reduced pressure to give
the title
compound (15 mg, 10 % yield) as yellow solids. 11-1 NMR (300 MHz, CDC13) 6
8.63 (s,
0.5H), 8.52 (s, 1.5H), 3.68 (s, 3H), 2.95 (d, J= 7.2 Hz, 2H), 2.67 (d, J= 7.2
Hz, 2H).
Building block 40: methyl 6-chloro-2-methoxypyrimidine-4-carboxylate (BB40)
Building block 41: methyl 6-fluoro-3-methoxypyrazine-2-carboxylate (BB41)
NF NF
)N Me0Na (1 eq)
______________________ >
Me0H, 0 C
0 0 0 0
1 h
BB41-1 BB41
To a solution of methyl 3,6-difluoropyrazine-2-carboxylate BB41-1 (400 mg,
2.30
mmol) in methanol (4 mL) was added sodium methoxide (122 mg, 2.26 mmol) at -20
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.C, then the reaction was stirred at 0 .0 for 1 hours. The mixture was
quenched with
saturated ammonium chloride aqueous solution (30 ml) at 0 .0 and then
extracted
with ethyl acetate (30 mL) twice. The combined organic layers were washed with
brine (20 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated under
reduced pressure and purified by silica gel column chromatography (petroleum
ether : ethyl acetate = 10 :1 to 5 :1) to give the title compound (80 mg, 18 %
yield, 96 %
purity) as white solids. LC-MS (ESI): RT = 1.34 min, mass calcd. for C7H7FN203
186.0, m/z found 186.9 [M+1-1] . 11-1 NMR (400 MHz, CDC13) 6 8.10 (d, J= 8.4
Hz, 1H),
4.09 (s, 3H), 3.99 (s, 3H).
Building block 42: methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (BB42)
CI, _NI CI 0 N CI
I I K2CO3(1 eq)
Me0H
r.t , overnight
0 0
BB42-1 BB42
To a solution of methyl 2,6-dichloropyrimidine-4-carboxylate BB42-1 (1.00 g,
4.83
mmol) in methanol (20 mL) was added potassium carbonate (669 mg, 4.84 mmol) at
room temperature. After stirred at room temperature overnight, the mixture was
concentrated under reduced pressure to give a residue. The residue was diluted
with
water (20 mL) and extracted with ethyl acetate (20 mL) twice. The combined
organic
layers were washed with brine (20 mL), dried over Na2SO4(s) and filtered. The
filtrate was concentrated under reduced pressure to give the title compound
(200 mg,
21% yield) as white soilds. LC-MS (ESI): RT = 1.53 min, mass calcd. for
C7H7C1N203
202.0, m/z found 203.0 [M+1-11 . 11-1 NMR (400 MHz, DMSO-d6) 6 7.45 (s, 1H),
4.02 (s,
3H), 3.90 (s, 3H).
Building block 43: Mixture of ethyl 2-chloro-4-methoxypyriraidine-5-
carboxylate and
ethyl 4-chloro-2-methoxypyrimidine-5-carboxylate (BB43)
CINCI Me0Na(1.6 eq) 0 N CIo N
N
Me0H, r.t , 2 h
0 0
BB43-1 BB43
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate BB43- 1 (1.00 g,
99 %
purity, 5.52 mmol) in methanol (10 mL) was added sodium methoxide (488 mg, 96
%
purity, 8.67 mmol) at room temperature. After stirred at this temperature for
2
hours, the mixture was concentrated under reduced pressure to give a residue,
which was partitioned between ethyl acetate (15 mL) and water (15 mL). The
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aqueous layer was separated and extracted with ethyl acetate (15 mL) twice.
The
combined organic layers were dried over Na2SO4(s), filtered and concentrated
under
reduced pressure to give a residue, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 100 1 to 10 1) to give the
title
compound (640 mg, 65 % yield, 1 1 by 111 NMR) as white solids. 111 NMR (400
MHz,
CDC13) 6 9.01 (s, 111), 8.86 (s, 111), 4.44 - 4.36 (m, 411), 4.14 (s, 311),
4.10 (s, 311), 1.43
- 1.37 (m, 611).
Building block 44: Methyl tert-butyl 6-chloro-5-fluoropicolinate (BB44)
0
HO)
INCI (Boc)20 (2 eq.)
DMAP (1 1 eq ), t-BuOH
BB44-1 50 C, overnight BB44
To the solution of 6-chloro-5-fluoropicolinic acid BB44-1 (200 mg, 1.09 mmol,
96 %
purity) in tert-butanol (4 mL) was added 4-dimethylaminopyridine (500 mg, 2.25
mmol, 98 % purity) and di- tert-butyl dicarbonate (150 mg, 1.20 mmol, 98 %
purity)
at room temperature. After stirred at 50 C under nitrogen atmosphere
overnight,
the mixture was washed with water (10 mL) and extracted with ethyl acetate (20
mL) twice. The combined organic layers were dried over Na2SO4(s) and filtered.
The
filtrate was and concentrated to give a residue, which was purified by silica
gel
column chromatography (petroleum ether ethyl acetate = 25 1 to 20 1) to give
the
title compound (180 mg, 90 % purity, 64 % yield) as white solids. 111 NMR (300
MHz,
CDC13) 6 8.03 - 7.99 (m, 111), 7.58 - 7.53 (m, 111), 1.63 (s, 911).
Building block 45: Ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate (BB45)
a oõo
CI CI
NN I
I (1.0 eq) N N Pt02, H2 balloon N N
0)
Oy
Pd(OAc)2 (0.1 eq), CY3P (0.2 eq), Et0H, 20 C, 1 h
Br
K3PO4 (3.0 eq), toluene/water, \(D \o
85 C, 16 h
BB38-2 BB45-1 BB45
Intermediate BB45-1:
Ethyl 2-chloro-5-(prop-1-en-2-yl)pyrimidine-4-carboxylate
To a mixture of ethyl 5-bromo-2-chloropyrimidine-4-carboxylate BB38-2 (300 mg,
90 %
purity, 1.02 mmol), 4,4,5,5-tetramethy1-2-(prop-1-en-2-y1)-1,3,2-dioxaborolane
(175
mg, 98 % purity, 1.02 mmol) and potassium phosphate (661 mg, 98 % purity, 3.05
mmol) in toluene (9 mL) and water (3 mL) was added palladium acetate (23 mg,
99 %
purity, 0.101 mmol) and tricyclohexyl phosphine (60 mg, 95 % purity, 0.203
mmol)
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under nitrogen atmosphere. After stirred at 85 C under nitrogen atmosphere
for 16
hours, the reaction mixture was diluted with water (20 mL) and extracted with
ethyl
acetate (10 mL) for three times. The combined organic layers were washed with
brine (10 mL), dried over Na2SO4(s) and filtered. The filtrate was
concentrated to
give a residue, which was purified by silica gel column chromatography
(petroleum
ether ethyl acetate = 100 1 to 20 1) to give the title compound (90 mg, 90 %
purity, 35 % yield) as white solids. LC-MS (ESI): RT = 1.63 min, mass calcd.
for
Ci0HliC1N202 226.1, m/z found 226.9 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.62
(s,
1H), 5.33 (s, 1H), 5.07 (s, 1H), 4.43 (q, J= 7.2 Hz, 2H), 2.11 (s, 3H), 1.39
(t, J= 7.2 Hz,
3H).
Building block 45:
Ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate
To a solution of ethyl 2-chloro-5-(prop-1-en-2-yl)pyrimidine-4-carboxylate
BB45-1 (90
mgõ 90 % purity, 0.357 mmol) in ethanol (5 mL) was added platinum dioxide (20
mg,
99 % purity, 0.087 mmol) under nitrogen atmosphere. After stirred at 20 C
under
hydrogen atmosphere of balloon for 1 hour, the reaction mixture was filtered
and the
filtrate was concentrated to give the title compound (75 mg, 95 % purity, 87 %
yield)
as black solids. LC-MS (ESI): RT = 1.65 min, mass calcd. for
Ci0Hi3C1N202228.1, m/z
found 229.1 [M+Hi .
Building block 46: Ethyl 2-(2-chloropyrimidin-5-y1)-2-methylpropanoate (BB46)
NCI
N7C1
NaH (2.5 eq.)
Mel (2.2 eq.),
DMF, 0 C, 3h
BB46-1 BB46
To a mixture of 60 % wt. sodium hydride in mineral oil (50 mg, 1.25 mmol) in
/V,/V-
dimethylformamide (3 mL) was added slowly the solution of iodomethane (156 mg,
1.10 mmol) and ethyl 2-(2-chloropyrimidin-5-yl)acetate BB46-1 (100 mg, 0.498
mmol)
in /V,/V-dimethylformamide (3 mL) under nitrogen atmosphere at 0 C. After
stirring
at 0 C for 3 hours, the reaction mixture was quenched with water (10 mL),
then
extracted with ethyl acetate (20 mL) for three times. The combined organic
layers
were washed with water (5 mL), brine (5 mL), dried over Na2SO4(s) and
filtered. The
filtrate was concentrated under reduced pressure to give a crude product,
which was
purified by C18 column (acetonitrile water = 40 % to 80 %) to give the title
compound (65 mg, 90 % purity from 11-1 NMR, 51 % yield) as yellow oil. LC-MS
(ESI):
RT = 1.18 min, mass calcd. for Ci0Hi3C1N202 228.1, m/z found 229.1 [M+111 . 11-
1
NMR (400 MHz, CDC13) 6 8.63 (s, 2H), 4.16 (q, J= 7.2 Hz, 2H), 1.64 (s, 6H),
1.23 (t, J
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= 7.2 Hz, 3H).
Building block 47: Methyl 2-chloro-4-(methoxymethyl)thiazole-5-carboxylate
(BB47)
0 0 o o
H2N NH2
SO2C12 0 (1.0 eq)
0
DCM, r.t., overnight CI Et0H, 80 C, overnight
BB47-1 BB47-2
CI
s (1 5 eq)
0 CuCI (1.2 eq), MeCN, 0
0¨ r.t., 2 h, 70 C, 1 h 0¨
BB47-3 BB47
Intermediate BB47-2:
Methyl 2-chloro-4-methoxy-3-oxobutanoate
To a solution of methyl 4-methoxy-3-oxobutanoate BB47-1 (2.0 g, 98 % purity,
13.4
mmol) in dichloromethane (20 mL) was added sulfuryl chloride (1.2 mL). After
stirred at room temperature under nitrogen atmosphere overnight, the mixture
was
concentrated under reduced pressure to give a residue, which was dissolved in
ethyl
acetate (100mL). The solution was washed with water (50 mL) and brine (50 mL),
dried over Na2SO4(s), filtered and concentrated to give a residue, which was
purified
by silica gel column chromatography (petroleum ether ethyl acetate = 5 1) to
give
the title compound (1.6 g, 98.5 % purity, 65 % yield) as yellow oil. LC-MS
(ESI): RT =
1.11 min, mass calcd. for C6119C104 180.6, m/z found 181.1 [M+111 . 11-1 NMR
(300
MHz, CDC13) 6 5.03 (s, 111), 4.24 (s, 2H), 3.80 (s, 311), 3.39 (s, 3H).
Intermediate BB47-3:
Methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate
The mixture of methyl 2-chloro-4-methoxy-3-oxobutanoate BB47-2 (1.6 g, 98.5 %
purity, 8.73 mmol) and thiourea (671 mg, 99 % purity, 8.73 mmol) in ethanol
(15 mL)
was stirred at 80 C under nitrogen atmosphere overnight. Then the mixture was
cooled down to room temperature and concentrated under reduced pressure to
give a
residue, which was diluted with saturated aqueous sodium bicarbonate aqueous
solution (20 mL). The resulting solids were collected by filtration and
recrystallized
from water (5 mL) and ethanol (5 mL) to give the title compound (1.18 g, 91.9
%
purity, 61.4 % yield). LC-MS (ESI): RT = 0.35 min, mass calcd. for C7Hi0N203S
202.2,
m/z found 203.2 [M+11] . 11-1 NMR (300 MHz, CD30D) 6 4.64 (s, 211), 3.78 (s,
311),
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3.38 (s, 311).
Building block 47:
Methyl 2-chloro-4-(methoxymethyl)thiazole-5-carboxylate
To a suspension of tert-butyl nitrite (74 mg, 95 % purity, 0.628 mmol),
cuprous
chloride (57 mg, 97 % purity, 0.554 mmol) and in acetonitrile (1 mL) was added
methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate BB47-3 (100 mg, 91.9 %
purity, 0.454 mmol). After stirred at room temperature under nitrogen
atmosphere
for 2 hours and at 70 C for 1 hour, the mixture was cooled to room
temperature and
filtered. The filtrate was poured into 6 N hydrochloride aqueous solution (10
mL)
and extracted with ethyl acetate (20 mL). The organic layer was dried with
MgSO4(s)
and concentrated to give a residue, which was purified by silica gel column
chromatography (petroleum ether ethyl acetate = 5 1) to give the title
compound
(78 mg, 99 % purity, 77 % yield) as yellow oil. LC-MS (ESI): RT = 1.54 min,
mass
calcd. for C7118C1NO3S 221.7, m/z found 222.0 [M+Hi . 11-1 NMR (300 MHz,
CDC13) 6
4.85 (s, 211), 3.90 (s, 311), 3.49 (s, 311).
Building block 48: methyl 2-chloro-5-(trifluoromethyOisonicotinate (BB48)
Building block 49: 6-chloro-4-(trifluoromethyl)nicotinic acid (BB49)
Building block 50: tert-butyl 2-chloro-6-(trifluoromethypisonicotinate (BB50)
F3CNCI F3C N CI
Boc20 (1.5 eq), DMAP(1.1 eq),
0 OH
t-BuOH, 50 C, overnight
0 0
BB50-1 BB50
A mixture of 2-chloro-6-(trifluoromethyOisonicotinic acid BB50 1 (300 mg, 1.26
mmol, 95 % purity), di- tert-butyl dicarbonate (410 mg, 1.88 mmol) and N,N-
dimethylpyridin-4-amine (170 mg, 1.39 mmol) in 2-methylpropan-2-ol (9 mL) was
stirred at 50 C overnight. The solvent was removed and the residue was
purified by
silica gel column chromatography (petroleum ether ethyl acetate = 100 1 to 30
1)
.. to give title product (120 mg, 33 % yield, 99 % purity) as white solids. 11-
1 NMR (400
MHz, CDC13) 6 8.08 (s, 111), 8.01 (s, 111), 1.62 (s, 911).
Building block 51: benzoyl chloride (BB51)
Building block 52: 5-methylisoxazole-4-carbonyl chloride (BB52)
Building block 53: 1Hpyrazole-4-carbonyl chloride (BB53)
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0 0
HO
SOCl2
I N __________________ N
-----N 85 C, overnight
BB53-1 BB53
A mixture of 1H-pyrazole-4-carboxylic acid BB51-1 (641 mg, 5.72 mmol) in
thionyl
chloride (5 mL) was stirred at 85 .0 under nitrogen atmosphere overnight. Then
the
mixture was concentrated to give the title compound (680 mg, 91 % yield) as
white
solids which was directly used in next step.
Building block 54: 2-chloro-5-methylpyrimidine-4-carboxylic acid (BB54)
Building block 55: (trans)-3-(2-chloropyrimidin-5-y1)-3-
hydroxycydobutanecarboxylic
acid (BB55)
CI Et3SiH (9.2 eq)
0 DCM/TFA (v/v=10/3)
IT
CI
OH r.t., 2h; __ ' 0
) 0 30 C 4h; HO OH
BB14 50 C, overnight; BB55
40 C, 6h;
To a mixture of (trans)- tert-butyl 3-(2-chloropyrimidin-5-y1)-3-
hydroxycyclobutanecarboxylate BB14 (150 mg, 0.530 mmol) in anhydrous
dichloromethane (15 mL) was added trifluoroacetic acid (0.5 mL) and
triethylsilane
(565 mg, 4.86 mmol) at room temperature. After stirring at room temperature
for 2
hours, 30 .0 for 4 hours and 50 .0 overnight under nitrogen atmosphere,
trifluoroacetic acid (4 mL) was added. The obtained mixture was stirred at 40
.0 for
another 6 hours. Then it was cooled down to room temperature and concentrated
to
give a residue, which was dissolved in saturated sodium bicarbonate aqueous
solution (0.5 mL). The aqueous solution was extracted with ethyl acetate (3
mL) for
three times. The combined organic layers were concentrated to give the title
compound (100 mg, 83 % yield) as yellow solids. LC-MS (EST): RT = 0.554 min,
mass
calcd. for C9119C1N203228.0, m/z found 229.0 [M+Hl .
Building block 56: methyl 2-fluoro-5-methylisonicotinate (BB56)
Building block 57: Ethyl 2-chloro-5-(dimethylamino)pyrimidine-4-carboxylate
(BB57)
0
CI
)-Hr C) N CI N
CI
N N 0 (4.0 eq.)
F (1.1 eq.) NNH202 (3.0 eq.), FeSO4 7H20 (3.0 eq.), Et0Ac, 0 C, 1
h.,
H 0 0 r. t 1 h.
2SO4 (3.0 eq.), AcOH/PhMe/H20, 0 0
BB57-1 - 10 C, 0.5 h., then r. t., overnight
BB57-2 BB57
Intermediate BB57-2:
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Ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate
To a round bottom flask was added ethyl 2-oxopropanoate (7.01 g, 60.4 mmol)
and
the mixture was cooled to - 10 C. To the same flask, acetic acid (10 mL) was
added
while the internal temperature below - 5 C. 30 % wt. hydrogen peroxide
aqueous
solution (5.17 g, 45.6 mmol) was added dropwise maintaining the internal
temperature below - 5 C. To another round bottom flask with toluene (25 mL)
and
cooled to - 10 C was added 2-chloro-5-fluoropyrimidine BB57-1 (2 g, 15.1
mmol),
concentrated sulfuric acid (2.5 mL, 46.0 mmol) and ferrous sulfate
heptahydrate
(15.12 g, 45.3 mmol) while the internal temperature below - 5 C. To this
mixture,
the peroxide solution was added over 0.5 hour under nitrogen atmosphere at -10
C.
The mixture was stirred at -10 C for 0.5 hour and warmed up to room
temperature.
After stirred at room temperature overnight, the mixture was quenched with
water
(25 mL) at 0 C, poured into saturated sodium bicarbonate solution (300 mL)
and
extracted with ethyl acetate (60 mL) for three times. The combined organic
layers
were washed with saturated sodium bicarbonate solution (50 mL) and brine (50
mL),
dried over Na2SO4(s) and filtered. The filtrate was concertrated and purified
by silica
gel column chromatography (petroleum ether: ethyl acetate = 50 : 1 to 20 :1)
to give
the title compound (997 mg, 90 % purity from 11-1 NMR, 29 % yield) as yellow
oil. LC
MS (ESI): RT = 1.41 min, mass calcd. for C7H6C1FN202 204.0, m/z found 204.9
[M+111+. 11-1 NMR (400 MHz, DMSO-d6) 69.16 (d, J= 2.4 Hz, 1H), 4.42 (q, J= 6.8
Hz,
2H), 1.31 (t, J= 7.2 Hz, 3H).
Building block 57:
Ethyl 2-chloro-5-(dimethylamino)pyrimidine-4-carboxylate
To a solution of ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate BB57-2 (200
mg, 90 %
purity, 0.88 mmol) in ethyl acetate (1 mL) was added 33 % wt. dimethylamine
aqueous solution (0.2 mL, 0.996 mmol). The mixture was stirred at 0 0C for 1
hour
and then warmed up to room temperature. After stirred at room temperature for
1
hour, the mixture was concentrated to give the residue, which was purified by
Prep.
TLC (petroleum ether : ethyl acetate = 8 : 1) to afford the title compound
(180 mg,
95 % purity from 11-1 NMR, 85 % yield) as yellow oil. LC-MS (ESI): RT = 1.45
min,
mass calcd. for C9Hi2C1N302 229.1, m/z found 230.0 [M+111-F. 11-1 NMR (400
MHz,
DMSO-d6) 6 8.55 (s, 1H), 4.37 (q, J= 7.2 Hz, 2H), 2.91 (s, 6H), 1.32 (t, J=
7.2 Hz, 3H).
Building block 58: Ethyl 5-(bis(2,4-dimethoxybenzyl)amino)-2-chloropyrimidine-
4-
carboxylate (BB58)
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N CI
FN
DMBN
- DMB(O.95ecl) 0DMB
N
NaH (2.8 eq)
0 0'
THF, 0 C, 3 h CI N
BB57-2 BB58
Sodium hydride (528 mg, 60 % wt. in miniral oil, 13.2 mmol) was added into
tetrahydrofuran (50 mL) at 0 C and stirred for 3 minutes, then bis(2,4-
dimethoxybenzyl)amine (1.47 g, 95 % purity, 4.4 mmol) was added and stirring
continued for 15 minutes, followed by addition of ethyl 2-chloro-5-
fluoropyrimidine-
4-carboxylate BB57-2 (1.0 g, 95 % purity, 4.6 mmol) and the resulting mixture
was
stirred at 0 C for 3 hours. The mixture was quenched with ice water (40 mL)
at 0 C
and then it was extracted with ethyl acetate (50 mL) twice, the organic phase
was
combined and washed with water (50 mL) and brine (50 mL), dried over Na2SO4(s)
and filtered. The filtrate was concentrated and purified by silica gel column
chromatography (petroleum ether ethyl acetate = 10 1) to afford the title
compound (900 mg, 95 % purity from 11-1 NMR, 37 % yield) as yellow oil. LC-MS
(EST): RT = 1.971 min, mass calcd. for C25H28C1N306501.2, m/z found 502.2
[M+111 .
11-1 NMR (400 MHz, DMSO-d6) 6 8.32 (s, 1H), 7.10 (d, J= 8.4 Hz, 2H), 6.51 (d,
J= 2.0
Hz, 2H), 6.47 (dd, J= 8.0 Hz, 2.0 Hz, 2H), 4.27 (q, J= 7.2 Hz, 2H), 4.23 (s,
4H), 3.75 -
3.72 (m, 6H), 3.62 (s, 6H), 1.25 (t, J= 7.2 Hz, 3H).
Building block 59: Methyl 2-bromo-5-nitroisonicotinate (BB59)
N Br Mel (3.0 eq.)
NBr
Na2CO3 (3.0 eq.)
DMF, 0 C, 2 h 02N
0 OH 0
BB59-1 BB59
To the solution of 2-bromo-5-nitroisonicotinic acid BB59-1 (100 mg, 0.405
mmol) and
sodium carbonate (130 mg, 1.23 mmol) in N,N-dimethylformamide (2 mL) was
added iodomethane (173 mg, 1.22 mmol) at 0 C. After stirred at 0 C for 2
hours, the
mixture was poured into ethyl acetate (20 mL) and water (10 mL). Then the
aqueous
layer was extrected with ethyl acetate (20 mL) twice. The combined organic
layers
were washed with brine (120 mL), dried over Na2SO4(s) and filtered. The
filtrate
was concentrated and purified by silica gel column chromatography (petroleum
ether ethyl acetate = 10 1 to 5 1) give the tile compound (85 mg, 95 % purity
from
11-1 NMR, 76 % yield) as white solids. 11-1 NMR (400 MHz, DMSO-d6) 69.19 (s,
1H),
8.24 (s, 1H), 3.92 (s, 3H).
Building block 60: ethyl 2-chloro-5-methoxypyrimidine-4-carboxylate (BB60)
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Part VIII: Coupling of dihydropyrimidines of general formula XI
Compound XI-1-B: (exemplified with Method E)
Methyl 4-(3,4-difluoro-2-methylpheny0-6-(1-(542-ethoxy-2-oxoethyl)pyriraidin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
To a solution of ethyl 2-(2-chloropyrimidin-5-yl)acetate BB1 (45 mg, 0.213
mmol)
and methyl 4-(3,4-difluoro-2-methylpheny0-6-(piperidin-4-y1)-2-(thiazol-2-y1)-
1,4-
dihydropyrimidine-5-carboxylate FA1 (100 mg, 93 % purity, 0.220 mmol) in 1,4-
dioxane (3 mL) was added triethylamine (112 mg, 1.11 mmol) at room
temperature.
After stirred at 100 C under nitrogen atmosphere for 5 hours and cooled down
to
room temperature, the mixture was diluted with water (20 mL) and extracted
with
ethyl acetate (20 mL) twice. The combined organic layers were washed with
brine
(20 mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated
under
reduced pressure to give a residue, which was purified by C18 column
(acetonitrile
water = 75 % to 85 %) to give the title compound (78 mg, 56 % yield) as yellow
soilds.
LC-MS (EST): RT = 1.98 min, mass calcd. for C29H30F2N604S 596.2, m/z found
597.0
[M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.26 (d, J= 2.4 Hz, 2H), 8.11 (s, 0.8H),
7.79 -
7.75 (m, 1H), 7.48 (d, J= 3.2 Hz, 0.2H), 7.41 (d, J= 3.2 Hz, 0.8H), 7.13 -
7.05 (m,
0.2H), 6.96 - 6.86 (m, 2H), 5.95 (s, 0.8H), 5.86 (d, J= 2.0 Hz, 0.2H), 5.04 -
4.86 (m,
2H), 4.38 - 4.30 (m, 0.8H), 4.20 - 4.17 (m, 2H), 3.98 - 3.92 (m, 0.2H), 3.62
(s, 3H), 3.45
(s, 1.6H), 3.43 (s, 0.4H), 3.09 - 2.97 (m, 2H), 2.58 (d, J= 2.4 Hz, 2.4H),
2.43 (d, J= 2.0
Hz, 0.6H), 2.14 - 2.09 (m, 1H), 1.98 - 1.89 (m, 1H), 1.81 - 1.68 (m, 2H), 1.26
(q, J= 7.2
Hz, 3H).
Spectral analyses of dihydropyrimidine of general formula XI
Compound XI-3-S:
Ethyl 6-(1-(542-ethoxy-2-oxoethyl)pyrimidin-2-yOpiperidin-4-y1)-443-fluoro-2-
methylpheny0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA2.
LC-MS (ESI): RT = 2.00 min, mass calcd. for C301133FN604S 592.2, m/z found
593.0
[M411+. 11-1 NMR (400 MHz, CDC13) 6 8.27 - 8.26 (m, 2H), 8.07 (s, 0.7H), 7.78 -
7.74
(m, 1H), 7.46 (d, J= 3.2 Hz, 0.3H), 7.39 (d, J= 3.2 Hz, 0.7H), 7.19 - 7.03 (m,
2.3H),
6.95 - 6.88 (m, 1H), 6.03 (s, 0.8H), 5.93 (d, J= 2.0 Hz, 0.2H), 5.03 - 4.86
(m, 2H), 4.37
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- 4.32 (m, 0.8H), 4.20 - 4.11 (m, 2.2H), 4.09 - 4.01 (m, 2H), 3.44 (s, 1.5H),
3.43 (s,
0.5H), 3.08 - 2.97 (m, 2H), 2.54 (s, 2.3H), 2.40 (s, 0.7H), 2.15 - 2.09 (m,
1H), 2.01 -
1.95 (m, 1H), 1.82 - 1.66 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.15 - 1.10 (m,
3H).
Compound XI-4-B:
Methyl 244-(5-(ethoxycarbony0-644-fluoro-2-methylpheny1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-Opiperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB2 and FA3.
LC-MS (EST): RT = 2.137 min, mass calcd. for C29H3iFN604S 578.2, m/z found
579.1
[M+11] . 11-1 NMR (400 MHz, DMSO-d6) 6 9.50 (d, J= 3.6 Hz, 0.8H), 9.09 (s,
0.2H),
8.45 (s, 0.2H), 8.43 (s, 0.8H), 8.01 - 7.88 (m, 2H), 7.29 - 7.25 (m, 0.8H),
7.17 - 7.14 (m,
0.2H), 7.06 - 6.96 (m, 2H), 5.81 (s, 0.2H), 5.69 (d, J= 3.2 Hz, 0.8H), 4.88 -
4.73 (m,
2H), 4.00 - 3.98 (m, 2.1H), 3.93 - 3.88 (m, 3.9H), 2.95 - 2.85 (m, 2H), 2.67 -
2.55 (m,
3H), 2.18 (s, 3H), 1.99 - 1.77(m, 3H), 1.63 - 1.60 (m, 1H), 1.10 - 1.06 (m,
3H).
Compound XI-5-B:
Methyl 244-(643-fluoro-2-methylpheny0-5-(methoxycarbony0-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yppiperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB2 and FA4.
11-1 NMR (400 MHz, DMSO - d6) 6 9.57 (d, J= 3.6 Hz, 0.8H), 9.24 (s, 0.2H),
8.45 (s,
0.2H), 8.44 (s, 0.8H), 7.98 (d, J= 3.2 Hz, 0.8H), 7.95 (d, J= 3.2 Hz, 0.8H),
7.93 (d, J=
3.2 Hz, 0.2H), 7.90 (d, J= 2.8 Hz, 0.2H), 7.23 - 7.14 (m, 2H), 7.07 - 6.99 (m,
1H), 5.86
(s, 0.2H), 5.74 (d, J= 3.2 Hz, 0.8H), 4.89 - 4.74 (m, 2H), 4.27 - 4.20 (m,
0.2H), 3.94 -
3.91 (m, 0.8H), 3.88 (s, 0.8H), 3.87(s, 2.2H), 3.54 (s, 0.8H), 3.53 (s, 2.2H),
2.99 - 2.86
(m, 2H), 2.45 (d, J= 1.2 Hz, 0.8H), 2.39 (d, J= 1.6 Hz, 2.2H) 2.18 (s, 3H),
1.95 -
1.77(m, 3H), 1.64 - 1.60 (m, 1H).
Compound XI-6-B:
Methyl 6-(1-(542-ethoxy-2-oxoethyl)pyrimidin-2-yDpiperidin-4-y1)-4-(3-fluoro-2-
methylpheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA4.
LC-MS (EST): RT = 1.65 min, mass calcd. for C29H3iFN604S 578.2, m/z found
578.9
[M+111 . 11-1 NMR (400 MHz, DMSO-d6) 69.54 (d, J= 3.6 Hz, 0.8H), 9.18 (s,
0.2H),
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8.29 - 8.27 (m, 2H), 7.97 - 7.88 (m, 2H), 7.23 - 7.13 (m, 2H), 7.07 - 7.00 (m,
1H), 5.87
(s, 0.2H), 5.74 (d, J= 3.2 Hz, 0.8H), 4.92 - 4.77 (m, 2H), 4.24 - 4.19 (m,
0.2H), 4.10 (q,
J= 7.2 Hz, 2H), 3.93 - 3.88 (m, 0.8H), 3.54 (s, 2H), 3.53 (s, 3H), 2.94 - 2.85
(m, 2H),
2.46 (s, 0.7H), 2.39 (s, 2.3H), 1.92 - 1.58 (m, 4H), 1.20 (t, J= 7.2 Hz, 3H).
Compound XI-9-B:
Methyl 442-chloro-3-11uoropheny1)-6-(1-(542-ethoxy-2-oxoethyl)pyrimidin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
.. synthesized from compound BB1 and FA6.
1H NMR (400 MHz, DMSO-d6) 6 9.58 (d, J= 3.2 Hz, 0.7H), 9.22 (s, 0.3H), 8.29
(s,
0.8H), 8.28 (s, 1.2H), 7.99 - 7.90 (m, 2H), 7.41 - 7.29 (m, 2H), 7.32 - 7.17
(m, 1H), 6.08
(s, 0.3H), 5.99 (d, J= 3.6 Hz, 0.7H), 4.90 - 4.77 (m, 2H), 4.22 - 4.18 (m,
0.3H), 4.13 -
4.07 (m, 2H), 3.95 - 3.89 (m, 0.7H), 3.55 (s, 3H), 3.53 (s, 2H), 2.97 - 2.86
(m, 2H), 2.04
.. - 1.06 (m, 4H), 1.20 (t, J= 7.2 Hz, 3H).
Compound XI-10-1:
Methyl 244-(642-chloro-3-fluoropheny1)-5-(methoxycarbony0-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yppiperidin-1-ypthiazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
.. synthesized from compound BB3 and FAG.
1H NMR (400 MHz, DMSO-d6) 6 9.64 (d, J= 4.0 Hz, 0.8H), 9.38 (s, 0.2H), 8.00 -
7.96
(m, 1.7H), 7.92 (d, J= 2.8 Hz, 0.3H), 7.90 (s, 1H), 7.41 - 7.30 (m, 2H), 7.23 -
7.21 (m,
0.7H), 7.18 - 7.16 (m, 0.3H), 6.07 (s, 0.2H), 5.99 (d, J= 3.6 Hz, 0.8H), 4.19 -
4.08 (m,
2.2H), 3.93 - 3.87 (m, 0.8H), 3.76 (s, 3H), 3.54 (s, 2.2H) , 3.53 (s, 0.8H),
3.27 - 3.19 (m,
.. 2H), 2.24 - 1.99 (m, 1H), 1.94 - 1.90 (m, 1H), 1.87 - 1.67 (m, 2H).
Compound XI-13-S:
Methyl 442-chloro-4-fluoropheny1)-6-(1-442-ethoxy-2-oxoethyl)pyrimidin-2-
yDpiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB9 and FA7.
1H NMR (400 MHz, DMSO-d6) 6 9.50 (d, J= 3.6 Hz, 0.7H), 9.21 (s, 0.3H), 8.33 -
8.31
(m, 1H), 7.98 (d, J= 3.2 Hz, 0.7H), 7.95 - 7.93 (m, 1H), 7.90 (d, J= 3.2 Hz,
0.3H),
7.44 - 7.31 (m, 2H), 7.24 - 7.19 (m, 1H), 6.59 - 6.57 (m, 1H), 6.02 (s, 0.3H),
5.93 (d, J=
.. 4.0 Hz, 0.7H), 4.93 - 4.79 (m, 2H), 4.20 - 4.09 (m, 2.3H), 3.93 - 3.88 (m,
0.7H), 3.66 (s,
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2H), 3.54 (s, 211), 3.53 (s, 111), 2.93 - 2.83 (m, 211), 2.06 - 1.99 (m,
0.311), 1.91 - 1.70
(m, 311), 1.62 - 1.58 (m, 0.711), 1.22 - 1.18 (m, 311).
Compound XE-14-A:
Ethyl 244-(642-chloro-4-fluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB4 and FA7.
LC-MS (ESI): RT = 2.00 min, mass calcd. for C281128C1FN604S 598.2, m/z found
599.0
[M+11] . 11-1 NMR (400 MHz, CDC13) 6 8.28 (d, J= 4.0 Hz, 111), 8.13 (s,
0.511), 7.81 (d,
J= 3.2 Hz, 0.511), 7.77 (d, J= 3.2 Hz, 0.511), 7.47 (d, J= 3.2 Hz, 0.511),
7.42 - 7.41 (m,
111), 7.32 - 7.29 (m, 111), 7.15 - 7.12 (m, 111), 6.97 - 6.89 (m, 111), 6.20
(s, 0.511), 6.07
(d, J= 2.8 Hz, 0.511), 5.03 - 4.87 (m, 211), 4.43 (q, J= 7.2 Hz, 211), 4.33 -
4.27 (m,
0.511), 4.07 - 4.01 (m, 0.511), 3.63 (s, 1.611), 3.61 (s, 1.411), 3.06 - 2.95
(m, 211), 2.28 (s,
1.511), 2.26 (s, 1.511), 2.17 - 2.13 (m, 0.811), 2.01 - 1.92 (m, 1.611), 1.80 -
1.68 (m, 1.611),
1.42 (t, J= 7.2 Hz, 311).
Compound XI-15-S:
Methyl 442-chloro-4-fluoropheny1)-6-(1-(542-ethoxy-2-oxoethyppyrimidin-2-
yDpiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA7.
LC-MS (EST): RT = 2.01 min, mass calcd. for C281128C1FN604S 598.2, m/z found
598.8
[M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.27 (s, 111), 8.26 (s, 111), 8.13 (hr s,
0.511),
7.81 (d, J= 3.2 Hz, 0.511), 7.77 (hr s, 0.511), 7.47 (d, J= 3.2 Hz, 0.511),
7.42 (s, 111),
7.32 - 7.29 (m, 111), 7.15 - 7.12 (m, 111), 6.97 - 6.89 (m, 111), 6.21 (s,
0.511), 6.07 (d, J=
3.2 Hz, 0.511), 5.03 - 4.85 (m, 211), 4.35 - 4.28 (m, 0.511), 4.20 - 4.03 (m,
2.511), 3.63 (s,
1.511), 3.61 (s, 1.511), 3.45 (s, 111), 3.43 (s, 111), 3.08 - 2.96 (m, 211),
2.20 - 2.09 (m, 111),
2.01 - 1.94 (m, 1.511), 1.81 - 1.67 (m, 1.511), 1.28 (t, J= 8.8 Hz, 311).
Compound XI-16-B:
Ethyl 244-(642-chloro-4-fluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-Opiperidin-1-y1)-4-methylpyrimidine-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB8 and FA7.
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LC-MS (EST): RT = 4.252 min, mass calcd. for C281-128C1FN604S 598.2, m/z found
598.9 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.53 (d, J= 3.6 Hz, 0.7H), 9.29 (s,
0.3H), 8.77 (s, 0.3H), 8.76 (s, 0.7H), 7.98 (d, J= 2.8 Hz, 0.7H), 7.95 - 7.93
(m, 1H),
7.90 (d, J= 3.2 Hz, 0.3H), 7.45 - 7.41 (m, 1H), 7.38 - 7.30 (m, 1H), 7.24 -
7.19 (m, 1H),
6.02 (s, 0.3H), 5.93 (d, J= 3.6 Hz, 0.7H), 5.06 - 4.91 (m, 2H), 4.25 (q, J=
7.2 Hz,
2.2H), 4.00 - 3.91 (m, 0.8H), 3.55 (s, 2H), 3.53 (s, 1H), 3.05 - 2.96 (m, 2H),
2.60 (s, 1H),
2.59 (s, 2H), 1.99 - 1.64 (m, 4H), 1.30 (t, J= 7.2 Hz, 3H).
Compound XI-18-S:
Ethyl 244-(642-chloro-4-fluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yl)piperidin-1-yl)oxazole-4-earboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB6 and FA7.
LC-MS (EST): RT = 3.051 min, mass calcd. for C26H25C1FN505S 573.1, m/z found
573.9 [M+111 . 1H NMR (400 MHz, CDC13) 68.13 (s, 0.3H), 7.83 - 7.79 (m, 2H),
7.49
(d, J= 3.2 Hz, 0.7H), 7.44 (s, 1H), 7.30 - 7.28 (m, 111), 7.14 (d, J= 8.0 Hz,
1H), 6.98 -
6.89 (m, 1H), 6.20 (s, 0.3H), 6.07 (s, 0.7H), 4.40 - 4.31 (m, 4H), 4.28 - 4.25
(m, 0.4H),
4.02 - 3.96 (m, 0.6H), 3.61 (s, 3H), 3.19 - 3.08 (m, 2H), 2.26 - 1.69 (m, 4H),
1.37 (t, J=
6.8 Hz, 3H).
Compound XI-19-2:
Methyl 244-(642-chloro-4-fluoropheny1)-5-(methoxycarbony0-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yOpiperidin-1-yOthiazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB3 and FA7.
LC-MS (EST): RT = 1.63 min, mass calcd. for C25H23C1FN504S2 575.1, m/z found
575.8 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.57 (d, J= 3.6 Hz, 0.8H), 9.35 (s,
0.2H), 8.00 - 7.96 (m, 2H), 7.92 - 7.90 (m, 1H), 7.45 - 7.42 (m, 1H), 7.39 -
7.31 (m, 1H),
7.24 - 7.20 (m, 1H), 6.02 (s, 0.2H), 5.93 (d, J= 3.6 Hz, 0.8H), 4.19 - 4.08
(m, 2.2H),
3.93 - 3.87 (m, 0.8H), 3.76 (s, 3H), 3.54 (s, 2.4H), 3.53 (s, 0.6H), 3.27 -
3.18 (m, 2H),
2.08 - 1.67 (m, 4H).
.. Compound XI-21-B:
Ethyl 442-chloro-4-fluoropheny1)-6-(1-(542-ethoxy-2-oxoethyl)pyriraidin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA8.
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LC-MS (ESI): RT = 2.10 min, mass calcd. for C29H30C1FN604S 612.2, m/z found
613.1
[M41]+. 11-1 NMR (400 MHz, CDC13) 6 8.52 (hr s, 211), 7.93 (hr s, 111), 7.69
(hr s, 111),
7.41 - 7.34 (m, 111), 7.17 - 7.16 (m, 111), 7.05 - 6.97 (m, 111), 6.25 (hr s,
111), 5.23 -
5.09 (m, 211), 4.38 - 4.29 (m, 111), 4.22 (q, J= 7.2 Hz, 211), 4.14 - 4.05 (m,
211), 3.57
(hr s, 2H), 3.42 - 3.28 (m, 2H), 2.17 - 2.07 (m, 2H), 2.01 - 1.95 (m, 2H),
1.31 (t, J= 7.2
Hz, 3H), 1.17- 1.14 (m, 3H).
Compound XI-23-B:
Ethyl 442-chloro-3-fluoropheny1)-6-(1-(542-ethoxy-2-oxoethyl)pyriraidin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA9.
LC-MS (ESI): RT = 2.02 min, mass calcd. for C29H30C1FN604S 612.2, m/z found
613.0
[M41]+. 11-1 NMR (400 MHz, CDC13) 6 8.52 (hr s, 211), 8.01 (hr s, 111), 7.87
(hr s, 111),
.. 7.32 - 7.27 (m, 0.7H), 7.24- 7.15 (m, 2.311), 6.39 (hr s, 111), 5.25 - 5.13
(m, 211), 4.46 -
4.36 (m, 111), 4.21 (q, J= 6.4 Hz, 211), 4.11 - 4.07 (m, 211), 3.59 (s, 211),
3.37 - 3.24 (m,
211), 2.47 - 2.25 (m, 2H), 2.19 - 2.09 (m, 1H), 1.99 - 1.96 (m, 1H), 1.29 (t,
J= 7.2 Hz,
3H), 1.16 (t, J= 7.2 Hz, 3H).
Compound XI-24-B:
(cis)-Methyl 6-(145-(3-(tert-butoxycarbony1)-1-hydroxycydobutyl)pyrimidin-2-
y1)piperidin-4-y1)-442-chloro-3,4-difluoropheny1)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB14 and FA10.
LC-MS (ESI): RT = 1.73 min, mass calcd. for C33H35C1F2N605S 700.2, m/z found
701.0 [M+1-11 . 11-1 NMR (400 MHz, DMSO-d6) 6 9.64 (d, J= 3.6 Hz, 0.7H), 9.24
(s,
0.3H), 8.50 (s, 0.6H), 8.48 (s, 1.4H), 7.99 - 7.91 (m, 2H), 7.50 - 7.43 (m,
1H), 7.22 -
7.16 (m, 1H), 6.03 (s, 0.3H), 5.94 (d, J= 3.2 Hz, 0.7H), 5.77 (s, 0.5H), 5.75
(s, 0.5H),
4.91 - 4.80 (m, 2H), 4.22 - 4.16 (m, 0.3H), 3.95 - 3.89 (m, 0.7H), 3.55 (s,
2H), 3.54 (s,
1H), 2.95 - 2.87 (m, 2H), 2.67 - 2.59 (m, 3H), 2.45 - 2.41 (m, 2H), 2.06 -
1.60 (m, 4H),
1.41 (s, 9H).
Compound XI-25-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-Opiperidin-1-yDoxazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB10 and FA10.
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LC-MS (ESI): RT = 1.86 min, mass calcd. for C26H24C1F2N505S 591.1, m/z found
591.9 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.15 (s, 0.4H), 7.83 - 7.80 (m,
1H), 7.58
(s, 0.6H), 7.56 (s, 0.4H), 7.51 (d, J= 3.2 Hz, 0.6H), 7.46 (d, J= 3.2 Hz,
0.6H), 7.43 (s,
0.4H), 7.09 - 7.05 (m, 2H), 6.19 (s, 0.3H), 6.08 (d, J= 2.4 Hz, 0.7H), 4.48 -
4.30 (m,
4.4H), 4.07 - 4.01 (m, 0.6H), 3.62 (s, 2H), 3.61 (s, 1H), 3.25 - 3.14 (m, 2H),
2.25 - 2.10
(m, 1H), 2.02 - 1.72 (m, 3H), 1.36 (t, J= 6.4 Hz, 3H).
Compound XI-26-B:
Ethyl 5-ehloro-2-4-(642-ehloro-3,4-difluoropheny1)-5-(methoxyearbony1)-2-
(thiazol-2-
y1)-3,6-dihydropyrimidin-4-yppiperidin-1-y1)pyriraidine-4-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB13 and FA10.
LC-MS (EST): RT = 2.237 min, mass calcd. for C27H24C12F2N604S 636.1, m/z found
639.0 [M+Hi .
Compound XI-28-6:
Methyl 4-(2-chloro-3,4-difluoropheny0-6-(1-(5-(2-ethoxy-2-oxoethyl)-4-
methylpyrimidin-2-Opiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-
carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB12 and FA10.
LC-MS (EST): RT = 1.79 min, mass calcd. for C29H29C1F2N604S 630.2, m/z found
630.8 [M+11] . 11-1 NMR (400 MHz, DMSO-de) 6 9.63 (d, J= 4.0 Hz, 0.7H), 9.28
(s,
0.3H), 8.11 - 8.10 (m, 1H), 8.01 - 7.91 (m, 2H), 7.50 - 7.42 (m, 1H), 7.24-
7.14 (m, 1H),
6.02 (s, 0.3H), 5.94 (d, J= 3.6 Hz, 0.7H), 4.94- 4.79 (m, 2H), 4.22 - 4.15 (m,
0.3H),
4.09 (q, J= 6.8 Hz, 2H), 3.94 - 3.87 (m, 0.7H), 3.57 (s, 2H), 3.55 (s, 2.1H),
3.53 (s,
0.9H), 2.94 - 2.81 (m, 2H), 2.26 (s, 0.9H), 2.25 (s, 2.1H), 2.10 - 2.01 (m,
0.3H), 1.96 -
1.69 (m, 3H), 1.63 - 1.59 (m, 0.7H), 1.20 (t, J= 6.8 Hz, 3H).
Compound XI-29-S:
Methyl 442-chloro-3,4-difluoropheny1)-6-(1-(5-(2-ethoxy-2-oxoethyl)pyrimidin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA10.
11-1 NMR (400 MHz, CDC13) 6 8.27 - 8.26 (m, 2H), 8.16 (s, 1H), 7.82 - 7.81 (m,
0.4H),
7.78 - 7.77 (m, 0.6H), 7.48 - 7.47 (m, 0.4H), 7.44 - 7.43 (m, 0.6H), 7.10 -
6.99 (m, 2H),
6.20 (s, 0.6H), 6.07 - 6.06 (m, 0.4H), 5.04 - 4.86 (m, 2H), 4.35 - 4.28 (m,
0.6H), 4.20 -
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4.04 (m, 2.411), 3.63 (s, 1.311), 3.61 (s, 1.711), 3.45 (s, 1.211), 3.43 (s,
0.811), 3.07 - 2.96
(m, 211), 2.20 - 2.08 (m, 0.711), 2.05 - 1.91 (m, 1.311), 1.79 - 1.67 (m,
211), 1.29- 1.26 (m,
311).
Compound XI-30-B:
Methyl 442-chloro-3,4-difluoropheny0-6-(piperidin-4-y1)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-5-carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB3 and FA10.
11-1 NMR (400 MHz, DMSO-d6) 6 9.68 (d, J= 3.2 Hz, 0.811), 9.41 (s, 0.211),
8.01 - 7.96
(m, 1.7 H), 7.92 (d, J= 3.2 Hz, 0.311), 7.90 (s, 111), 7.49 - 7.43 (m, 111),
7.24 - 7.20 (m,
0.711), 7.17 - 7.14 (m, 0.311), 6.02 (s, 0.211), 5.94 (d, J= 3.6 Hz, 0.811),
4.18 - 4.08 (m,
2.111), 3.94- 3.87 (m, 0.911), 3.76 (s, 311), 3.54 (s, 2.211), 3.53 (s,
0.811), 3.28 - 3.19 (m,
211), 2.27 - 2.04 (m, 111), 1.99 - 1.89 (m, 111), 1.86 - 1.68 (m, 211).
Compound XI-31-B:
244-(642-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yppiperidin-1-y1)-4-(trifLuoromethypthiazole-5-carboxylate
(a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB15 and FA10.
LC-MS (EST): RT = 2.824 min, mass calcd. for C27H23C1F5N504S2 675.1, m/z found
675.8 [M+11] . 11-1 NMR (400 MHz, DMSO-d6) 6 9.67 (d, J= 3.6 Hz, 0.711), 9.42
(s,
0.311), 8.01 - 7.92 (m, 211), 7.49 - 7.42 (m, 111), 7.24- 7.14 (m, 111), 6.03
(s, 0.311), 5.95
(d, J= 4.0 Hz, 0.711), 4.25 (q, J= 7.2 Hz, 211), 4.20 - 4.02 (m, 2.311), 3.94 -
3.86 (m,
0.711), 3.54 (s, 2.111), 3.53 (s, 0.911), 3.29 - 3.21 (m, 211), 2.29 - 1.83
(m, 311), 1.76 -
1.69 (m, 111), 1.26 (t, J= 7.2 Hz, 311).
Compound XI-32-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-Opiperidin-1-y1)thiazole-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB11 and FA10.
LC-MS (EST): RT = 1.86 min, mass calcd. for C261124C1F2N504S2 607.1, m/z found
608.3 [M+11] . 111 NMR (400 MHz, DMSO-d6) 6 9.64 (d, J= 3.2 Hz, 0.711), 9.30
(s,
0.311), 8.00 - 7.96 (m, 1.711), 7.92 (d, J= 3.2 Hz, 0.311), 7.70 (s, 111),
7.49 - 7.42 (m,
111), 7.24 - 7.15 (m, 111), 6.03 (s, 0.311), 5.94 (d, J= 3.6 Hz, 0.711), 4.24
(q, J= 7.2 Hz,
211), 4.16 - 3.98 (m, 2.311), 3.90 - 3.83 (m, 0.711), 3.54 (s, 211), 3.53 (s,
111), 3.20 - 3.06
(m, 211), 2.10 - 1.65 (m, 411), 1.28 (t, J= 7.2 Hz, 311).
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Compound XI-33-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yppiperidin-1-ypoxazole-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB6 and FA10.
LC-MS (ESI): RT = 2.077 min, mass calcd. for C26H24C1F2N505S 591.1, m/z found
592.0 [M+111 .
Compound XI-34-10F:
ethyl 2-(44642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-y1)-2-methylpiperidin-1-yl)pyrimidine-5-carboxylate (a
mixture
of 2 stereoisomers)
Intermediate XI-34-10:
ethyl 2-(44642-chloro-3,4-difluoropheny0-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-y1)-2-methylpiperidin-1-yl)pyrimidine-5-carboxylate (a
mixture
of 4 stereoisomers)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB7 and FAll.
LC-MS (ESI): RT = 2.18 min, mass calcd. for C291129C1F2N604S 630.2, m/z found
630.8 [M+11] . 111 NMR (300 MHz, DMSO-d6) 6 9.65 - 9.61 (m, 0.811), 9.28 -
9.07 (m,
0.211), 8.81 (s, 21I), 7.97 - 7.95 (m, 21I), 7.51 - 7.41 (m, 111), 7.26 - 7.15
(m, 111), 6.05 -
5.92 (m, 11I), 5.37 - 5.18 (m, 11I), 4.91 - 4.76 (m, 11), 4.27 - 4.25 (m, 31),
4.03 - 3.98
(m, 21), 3.19 - 3.07 (m, 11), 1.95 - 1.62 (m, 41), 1.28 - 1.24 (m, 61), 1.10 -
1.06 (m,
31).
A stereoisomeric mixture of XI-34-10 (550 mg, 0.87 mmol) was separated by
Prep.
HPLC (separation condition: Column: Chiralpak IA 20 mm * 250mm 5 um Mobile
phase: Hex-Et0H-DEA-40-60-0.3 Flow rate: 22 mL/ min; Wavelength: 230 nm) to
give compounds Group 1 XI-34-10A & XI-34-10B (240 mg, 43 % yield, 100 % de) as
yellow solids and Group 2 XI-34-10F (140 mg, 25 % yield, 98.8 % de) as yellow
solids.
The Group 1 was separated by Prep. HPLC (separation condition: Column:
Chiralpak IE 4.6mm*250mm Sum; Mobile Phase: Hex:Et011:DEA=70:30:0.3 at 12
ml/min; Wavelength: 230 nm) to give the title compounds XI-34-10A (100 mg, 41%
yield, 100 % de) as yellow solids and XI-34-10B (100mg, 41 % yield, 99.8 %
de).
XI-34-10A: LC-MS (ESI): RT = 2.28 min, mass calcd. for C291129C1F2N604S 630.2,
m/z found 630.9 [M+111 . Chiral HPLC (Column: Chiralpak IE 4.6 mm * 250 mm 5
um; Mobile Phase: Hex-Et011-DEA-70-30-0.2 at 1.0 mL/ min; Wavelength: 230 nm,
RT = 10.865 min). 111 NMR (400 MHz, CD30D) 6 8.82 (s, 0.81), 8.81 (s, 1.21),
7.86 (s,
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0.411), 7.85 (s, 0.411), 7.70 (s, 0.611), 7.69 (s, 0.411), 7.27 - 7.21 (m,
211), 6.18 (s, 0.411),
6.11 (s, 0.611), 5.44- 5.33 (m, 111), 5.01 - 4.90 (m, 111), 4.68 - 4.60 (m,
0.411), 4.36 -
4.30 (m, 2.61I), 4.10 - 4.04 (m, 211), 3.25 - 3.13 (m, 111), 2.21 - 1.83 (m,
3.41I), 1.71 -
1.68 (m, 0.611), 1.38 - 1.35 (m, 611), 1.17 - 1.12 (m, 311).
XI-34-10B: LC-MS (ESI): RT = 2.31 min, mass calcd. for C291129C1F2N604S 630.2,
m/z
found 630.9 [M+111 . Chiral HPLC (Column: Chiralpak IE 4.6 mm * 250 mm 5 um;
Mobile Phase: Hex-Et0H-DEA-70-30-0.2 at 1.0 mL/ min; Wavelength: 230 nm, RT =
14.122 min). 1H NMR (400 MHz, CD30D) 68.82 (s, 0.811), 8.81 (s, 1.21I), 7.86 -
7.85
(m, 111), 7.69 - 7.68 (m, 111), 7.25 - 7.22 (m, 211), 6.16 (s, 0.411), 6.09
(s, 0.611), 5.42 -
5.28 (m, 111), 5.02 - 4.90 (m, 111), 4.67 - 4.60 (m, 0.411), 4.35 - 4.30 (m,
2.61I), 4.11 -
4.04 (m, 211), 3.27 - 3.16 (m, 111), 2.11 - 1.81 (m, 3.41I), 1.65 - 1.60 (m,
0.611), 1.37 -
1.31 (m, 611), 1.17 - 1.12 (m, 311).
XI-34-10F: LC-MS (ESI): RT = 2.18 min, mass calcd. for C291129C1F2N604S 630.2,
m/z
found 630.8 [M+111 . Chiral HPLC (Column: Chiralpak IA 4.6mm*250mm Sum;
Mobile Phase: Hex-Et0H-DEA-40-60-0.2 at 1.0 mL/ min;; Wavelength: 230 nm, RT =
10.549 and 11.719 min). 1H NMR (400 MHz, CD30D) 6 8.81 (s, 211), 7.85 (d, J=
3.2
Hz, 111), 7.69 (d, J= 3.2 Hz, 111), 7.25 - 7.21 (m, 211), 6.12 (d, J= 7.6 Hz,
111), 5.41 -
5.31 (m, 111), 5.00 - 4.91 (m, 111), 4.60 - 4.45 (m, 111), 4.33 (d, J= 7.2 Hz,
211), 4.10 -
4.05 (m, 211), 3.25 - 3.14 (m, 111), 2.20 - 1.72 (m, 411), 1.38 - 1.32 (m,
611), 1.16 - 1.13
(m, 311).
Compound XI-35-5R and XI-35-5S:
Ethyl 6-(1-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-y1)-442-chloro-3,4-
difluoropheny0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a single
stereoisomer) and ethyl 6-(144-(tert-butoxycarbonyl)phenyl)piperidin-4-y1)-442-
chloro-3,4-difluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a
single stereoisomer)
By utilizing the analogous procedure of Method B to give the racemic product
(180
mg) as yellow solids, which was separated by chiral Prep. HPLC (separation
condition: Column: Chiralpak IA 5 i.tm 20 * 250 mm; Mobile Phase: Hex : IPA:
DEA
= 70 : 30 : 0.3 at 22 mL/min; Col. Temp: 30 C; Wavelength: 214 nm) to afford
the
title compounds XI-35-5R (58 mg, 31 % yield, 100 % ee) and XI-35-5S (48 mg, 26
%
yield, 100 % ee) as yellow solids.
XI-35-5R: Chiral analysis (Column:Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA = 60 : 40 : 0.2 at 1.0 mL/ min; Temp: 30 C; Wavelength: 230
nm,
RT = 10.261 min). 1H NMR (400 MHz, DMSO-d6) 6 9.61 (d, J= 3.6 Hz, 0.811), 9.02
(s,
0.211), 8.00 - 7.93 (m, 211), 7.76 - 7.73 (m, 211), 7.50 - 7.43 (m, 111), 7.25
- 7.18 (m, 111),
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7.02 - 6.99 (m, 2H), 6.05 (s, 0.3H), 5.95 (d, J= 3.2 Hz, 0.7H), 4.12 - 3.97
(m, 4H), 3.88
- 3.82 (m, 1H), 2.92 - 2.82 (m, 2H), 2.06 - 1.89 (m, 2H), 1.82 - 1.77 (m, 1H),
1.68 - 1.63
(m, 1H), 1.52 (s, 9H), 1.11 - 1.04 (m, 3H).
XI-35-5S: Chiral analysis (Column: Chiralpak IG 5 i.tm 4.6 * 250 mm; Mobile
Phase:
Hex : Et0H : DEA= 60 : 40 : 0.2 at 1.0 mL/ min; Temp: 30 C; Wavelength: 230
nm,
RT = 16.394 min). 1H NMR (400 MHz, DMSO-d6) 6 9.61 (d, J= 3.6 Hz, 0.7H), 9.02
(s,
0.3H), 8.00 - 7.93 (m, 2H), 7.76 - 7.73 (m, 2H), 7.50 - 7.44 (m, 1H), 7.25 -
7.18 (m, 1H),
7.02 - 6.99 (m, 2H), 6.05 (s, 0.3H), 5.95 (d, J= 3.6 Hz, 0.7H), 4.12 - 3.97
(m, 4H), 3.88
- 3.81 (m, 1H), 2.94 - 2.82 (m, 2H), 2.06 - 1.88 (m, 2.2H), 1.82 - 1.79 (m,
1H), 1.66 -
1.63 (m, 0.8H), 1.52 (s, 9H), 1.11 - 1.04 (m, 3H).
Compound XI-36-S:
ethyl-6-(1-(5-(tert-butoxycarbony1)-4-((4-methoxybenzyl)oxy)pyridin-2-
yppiperidin-4-
y1)-442-chloro-3,4-difLuoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB32 and FA12.
LC-MS (ESI): RT = 2.11 min, mass calcd. for C39H40C1F2N506S 779.2, m/z found
779.8 [M+111+ . 1H NMR (400 MHz, CDC13) 69.62 (d, J= 3.6 Hz, 0.8H), 9.12 (d,
J=
4.0 Hz, 0.2H), 8.40 (s, 0.3H), 8.39 (s, 0.7H), 8.00 - 7.93 (m, 2H), 7.45 -
7.43 (m, 3H),
7.25 - 7.20 (m, 1H), 6.99 - 6.96 (m, 2H), 6.48 (s, 0.3H), 6.45 (s, 0.7H), 6.04
(s, 0.3H),
5.95 (d, J= 3.2 Hz, 0.7H), 5.15 (s, 2H), 4.73 - 4.57 (m, 2H), 4.03 - 3.92 (m,
3H), 3.75 (s,
3H), 2.98 - 2.88 (m, 2H), 1.94 - 1.76 (m, 3.2H), 1.67 - 1.60 (m, 0.8H), 1.41
(s, 9H), 1.10
(t, J= 7.2 Hz, 3H).
Compound XI-37-2:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(146-(methoxycarbonyl)pyridin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB20 and FA12.
LC-MS (ESI): RT = 3.676 min, mass calcd. for C281126C1F2N504S 601.1, m/z found
601.9 [M+111 . 1H NMR (400 MHz, DMSO-d6) 69.62 (d, J= 3.6 Hz, 0.7H), 9.15 (s,
0.3H), 7.99 - 7.91 (m, 2H), 7.71 - 7.67 (m, 1H), 7.51 - 7.43 (m, 1H), 7.30 -
7.28 (m, 1H),
7.25 - 7.18 (m, 1H), 7.13 (d, J= 8.8 Hz, 1H), 6.04 (s, 0.3H), 5.95 (d, J = 3.6
Hz, 0.7H),
4.65 - 4.51 (m, 2H), 4.21 - 4.12 (m, 0.3H), 4.03 - 3.98 (m, 2H), 3.93 - 3.87
(m, 0.7H),
3.84 (s, 3H), 2.95 - 2.82 (m, 2H), 2.06 - 1.63 (m, 4H), 1.11 - 1.05 (m, 3H).
Compound XI-38-3:
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ethyl 6-(144-(tert-butoxycarbony1)-6-(trifluoromethyppyridin-2-Opiperidin-4-
y1)-4-
(2-chloro-3,4-difluoropheny0-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-
carboxylate (a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB50 and FA12.
1H NMR (400 MHz, DMSO-d6) 6 9.62 (hr s, 0.711), 9.24 (s, 0.311), 7.99 - 7.90
(m, 211),
7.50 - 7.44 (m, 211), 7.25 - 7.17 (m, 211), 6.04 (s, 0.3H), 5.95 (hr s,
0.711), 4.64 - 4.50 (m,
211), 4.25 - 4.18 (m, 0.311), 4.03 - 3.93 (m, 2.711), 3.04 - 2.94 (m, 211),
2.13 - 1.84 (m,
311), 1.77 - 1.67 (m, 111), 1.57 (s, 911), 1.11 - 1.05 (m, 311).
Compound XI-39-S:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(144-(methoxycarbony1)-5-
(trifluoromethyl)pyridin-2-Opiperidin-4-y1)-2-(thiazol-2-y1)-1,4-
dihydropyrimidine-
5-carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB48 and FA12.
LC-MS (ESI): RT = 4.322 min, mass calcd. for C29H25C1F5N504S 669.1, m/z found
669.9 [M+11] . 1H NMR (400 MHz, DMSO-d6) 6 9.62 (d, J= 3.2 Hz, 0.611), 9.32
(s,
0.411), 8.50 (s, 111), 7.99 - 7.90 (m, 211), 7.50 - 7.43 (m, 111), 7.24- 7.15
(m, 211), 6.04
(s, 0.311), 5.95 (d, J= 3.2 Hz, 0.711), 4.71 - 4.58 (m, 211), 4.26 - 4.20 (m,
0.311), 4.03 -
3.95 (m, 2.711), 3.87 (s, 311), 3.07 - 2.98 (m, 211), 2.12 - 1.66 (m, 411),
1.11 - 1.04 (m,
311).
Compound XI-40-B:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(143-fluoro-4-(methoxycarbonyppyridin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB34 and FA12.
111 NMR (300 MHz, CDC13) 68.28 (s, 0.511), 8.18 -8.12 (m, 111), 7.85 - 7.78
(m, 111),
7.52 - 7.48 (m, 111), 7.46 - 7.43 (m, 0.511), 7.38 - 7.30 (m, 111), 7.16 -
7.01 (m, 211),
6.22 (s, 0.511), 6.10 (s, 0.511), 4.26 - 4.08 (m, 211), 4.00 - 3.95 (m, 311),
3.33 - 3.18 (m,
311), 3.12 - 2.90 (m, 111), 2.39 - 2.17 (m, 211), 2.04- 1.80 (m, 311), 1.18 -
1.13 (m, 311).
Compound XI-41-B:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(144-(methoxycarbonyl)pyridin-2-
yDpiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
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By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB18 and FA12.
11-1 NMR (400 MHz, DMSO-d6) 6 9.62 (hr s, 0.7H), 9.13 (s, 0.3H), 8.30 (d, J=
5.2 Hz,
1H), 7.99 - 7.91 (m, 2H), 7.51 - 7.43 (m, 1H), 7.27 - 7.18 (m, 2H), 7.03 (d,
J= 4.8 Hz,
1H), 6.04 (s, 0.3H), 5.95 (s, 0.7H), 4.60 - 4.46 (m, 211), 4.20 - 4.13 (m,
0.3H), 4.01 -
3.97 (m, 2H), 3.96 - 3.90 (m, 0.7H), 3.88 (s, 3H), 2.99- 2.86 (m, 2H), 2.07 -
1.63 (m,
4H), 1.11 - 1.05(m, 3H).
Compound XI-42-3B:
Ethyl 6-(1-(6-(tert-butoxycarbony1)-2-chloropyridin-3-yppiperidin-4-y1)-4-(2-
chloro-
3,4-difluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB44 and FA12.
LC-MS (EST): RT = 7.814 min, mass calcd. for C311131C12F2N504S 677.1, m/z
found
677.9 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 6 9.64 (d, J= 3.2 Hz, 0.8H), 9.07
(s,
0.2H), 8.02 - 8.00 (m, 1.7H), 7.97 - 7.94 (m, 1.3H), 7.69 - 7.65 (m, 1H), 7.51
- 7.45 (m,
1H), 7.26 - 7.22 (m, 1H), 6.06 (s, 0.2H), 5.96 (d, J= 3.2 Hz, 0.8H), 4.02 -
3.96 (m,
2.2H), 3.85 - 3.79 (m, 0.8H), 3.64 - 3.56 (m, 2H), 2.86 - 2.78 (m, 2H), 2.22 -
1.83 (m,
3.3H), 1.70 - 1.67 (m, 0.7H), 1.55 (s, 9H), 1.11 - 1.05 (m, 3H).
Compound XI-43-1:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(145-(methoxycarbonyl)pyridin-2-
yl)piperidin-470-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB19 and FA12.
LC-MS (EST): RT = 2.126 min, mass calcd. for C281126C1F2N504S 601.1, m/z found
602.0 [M+Hi .
Compound XI-45-B:
Ethyl 6-(1-(5-(tert-butoxycarbony1)-3-fluoropyridin-2-yl)piperidin-4-y1)-442-
chloro-
3,4-difluoropheny1)-2-(thiazol-2-y1)-1,4-dihydropyriraidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB33 and FA12.
LC-MS (EST): RT = 3.940 min, mass calcd. for C311131C1F3N504S 661.2, m/z found
662.2 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 69.60 (d, J= 3.6 Hz, 0.7H), 9.13
(s,
0.3H), 8.50 - 8.49 (m, 1H), 7.99 - 7.91 (m, 2H), 7.77 - 7.72 (m, 1H), 7.50 -
7.43 (m, 1H),
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7.24- 7.17 (m, 111), 6.04 (s, 0.311), 5.95 (d, J= 3.2 Hz, 0.711), 4.55 - 4.39
(m, 211), 4.22
- 4.16 (m, 0.211), 4.03 - 3.91 (m, 2.811), 3.10 - 3.01 (m, 211), 2.16 - 1.76
(m, 3.511), 1.68
- 1.64 (m, 0.511), 1.53 (s, 911), 1.11 - 1.04 (m, 311).
Compound XI-46-S:
Methyl 644-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-4-methylpyridazine-3-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB27 and FA12.
1H NMR (300 MHz, CDC13) 6 8.11 (hr s, 0.311), 7.82 - 7.77 (m, 111), 7.49 -
7.44 (m,
111), 7.34 (hr s, 0.711), 7.10 - 7.04 (m, 211), 6.71 - 6.67 (m, 111), 6.21 (s,
0.511), 6.09 (s,
0.511), 4.80 - 4.67 (m, 211), 4.47 - 4.33 (m, 0.511), 4.18 - 4.06 (m, 2.511),
3.98 (s, 111),
3.97 (s, 211), 3.21 - 3.12 (m, 211), 2.55 (s, 311), 2.13 - 2.09 (m, 111), 2.04
- 1.98 (m,
1.511), 1.83 - 1.73 (m, 1.511), 1.14 (t, J= 7.2 Hz, 311).
Compound XI-47-3:
ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(1-(5-methoxy-6-
(methoxycarbonyppyrazin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y0-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB41 and FA12.
LC-MS (ESI): RT = 4.167 min, mass calcd. for C281127C1F2N605S 632.1, m/z found
632.9 [M411+. 1H NMR (400 MHz, DMSO-d6) 69.61 (d, J= 3.6 Hz, 0.711), 9.11 (s,
0.311), 8.21 (s, 0.311), 8.19 (s, 0.711), 8.00 - 7.92 (m, 211), 7.50 - 7.43
(m, 111), 7.25 -
7.17 (m, 111), 6.04 (s, 0.311), 5.95 (d, J= 3.2 Hz, 0.711), 4.43 - 4.27 (m,
211), 4.16 - 4.09
(m, 0.311), 4.02 - 3.95 (m, 211), 3.90 - 3.83 (m, 6.711), 2.95 - 2.80 (m,
211), 2.08 - 1.64
(m, 411), 1.11 - 1.05 (m, 311).
Compound XI-48-B:
Ethyl 442-chloro-3,4-dilluoropheny1)-6-(146-(methoxycarbony1)-5-methylpyrazin-
2-
y1)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB30 and FA12.
LC-MS (ESI): RT = 1.858 min, mass calcd. for C281127C1F2N604S 616.1, m/z found
617.0 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 8.24 (s, 111), 8.15 (s, 0.511),
7.82 (d, J
= 3.2 Hz, 0.511), 7.78 (d, J= 3.2 Hz, 0.511), 7.49 (d, J= 3.2 Hz, 0.511), 7.44
(d, J= 3.2
Hz, 0.511), 7.35 (s, 0.511), 7.11 - 7.00 (m, 211), 6.22 (s, 0.511), 6.10 (d,
J= 2.4 Hz, 0.511),
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4.60 - 4.44 (m, 2H), 4.34 - 4.28 (m, 0.5H), 4.10 - 3.97 (m, 2.5H), 3.96 (s,
3H), 3.10 -
2.98 (m, 2H), 2.66 (s, 1.5H), 2.65 (s, 1.5H), 2.24 - 1.96 (m, 3H), 1.86 - 1.75
(m, 1H),
1.15 (t, J= 7.2 Hz, 3H).
Compound XI-49-B:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(145-(methoxycarbony1)-6-methylpyrazin-
2-
y1)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB29 and FA12.
LC-MS (EST): RT = 2.127 min, mass calcd. for C281127C1F2N604S 616.2, m/z found
617.1 [M+111 .1H NMR (400 MHz, CDC13) 6 8.11 (s, 0.3H), 8.06 (s, 1H), 7.82 -
7.78 (m,
1H), 7.49 - 7.44 (m, 1H), 7.36 (s, 0.7H), 7.10 - 7.00 (m, 2H), 6.22 (s, 0.4H),
6.11 (d, J=
2.8 Hz, 0.6H), 4.79 - 4.62 (m, 2H), 4.40 - 4.35 (m, 0.4H), 4.15 - 4.01 (m,
2.6H), 3.95 -
3.94 (m, 3H), 3.17 - 3.06 (m, 2H), 2.75 (s, 3H), 2.20 - 2.12 (m, 1H), 2.06 -
2.02 (m,
0.8H), 2.00 - 1.96 (m, 0.7H), 1.84 - 1.72 (m, 1.5H), 1.15 (t, J= 7.2 Hz, 3H).
Compound XI-50-S:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-241nazol-2-y0-3,6-
dihydropyrimidin-4-yppiperidin-1-ypoxazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB10 and FA12.
LC-MS (EST): RT = 4.410 min, mass calcd. for C27H26C1F2N505S 605.1, m/z found
605.9 [M+Hi . 1H NMR (400 MHz, CD30D) 6 7.89 - 7.87 (m, 1H), 7.73 (d, J= 3.2
Hz,
1H), 7.61 (s, 1H), 7.26 - 7.22 (m, 2H), 6.16 (s, 0.3H), 6.10 (s, 0.7H), 4.36 -
4.26 (m,
4.2H), 4.09 - 4.02 (m, 2.8H), 3.26 - 3.19 (m, 2H), 2.18 - 1.92 (m, 3.3H), 1.75
- 1.72 (m,
0.7H), 1.34 (t, J= 6.8 Hz, 3H), 1.16 - 1.11 (m, 3H).
Compound XI-52-S:
Methyl 644-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-2-methoxypyriraidine-4-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB40 and FA12.
LC-MS (EST): RT = 2.004 min, mass calcd. for C281-127C1F2N605S 632.1, m/z
found
633.1 [M+111 . 1H NMR (400 MHz, CDC13) 68.12 (s, 0.4H), 7.86 (d, J= 2.8 Hz,
0.6H),
7.83 (d, J= 3.2 Hz, 0.4H), 7.53 (d, J= 3.2 Hz, 0.6H), 7.48 (d, J= 2.8 Hz,
0.4H), 7.39
(hr s, 0.6H), 7.13 - 7.04 (m, 3H), 6.26 (s, 0.4H), 6.14 (d, J= 2.4 Hz, 0.6H),
4.88 - 4.60
(m, 2H), 4.19 - 4.07 (m, 3H), 4.05 (s, 1.4H), 4.04 (s, 1.6H), 4.01 (s, 1.4H),
4.00 (s,
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1.6H), 3.22 - 3.07 (m, 2H), 2.19 - 2.12 (m, 1H), 2.04- 1.95 (m, 2H), 1.82 -
1.71 (m, 1H),
1.18 (t, J= 7.2 Hz, 3H).
Compound XE-53-S:
Methyl 644-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-2-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB28 and FA12.
11-1 NMR (400 MHz, DMSO-de) 6 9.62 (d, J= 3.6 Hz, 0.7H), 9.31 (s, 0.3H), 7.99 -
7.90
(m, 2H), 7.50 - 7.42 (m, 1H), 7.24- 7.15 (m, 2H), 6.03 (s, 0.3H), 5.94 (d, J=
3.6 Hz,
0.7H), 4.73 - 4.56 (m, 2H), 4.27 - 4.20 (m, 0.3H), 4.04 - 3.94 (m, 2.7H), 3.86
(s, 3H),
3.03 - 2.93 (m, 2H), 2.44 (s, 3H), 2.11 - 2.01 (m, 0.311), 1.99 - 1.65 (m,
3.7H), 1.11 -
1.04 (m, 3H).
Compound XI-54-S:
Methyl 644-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yppiperidin-1-yppyriraidine-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB21 and FA12.
LC-MS (EST): RT = 3.966 min, mass calcd. for C27H25C1F2N604S 602.1, m/z found
603.1 [M+1-1] . 11-1 NMR (400 MHz, DMSO-d6) 6 9.61 (d, J= 3.6 Hz, 0.7H), 9.27
(s,
0.3H), 8.61 - 8.60 (m, 1H), 7.98 - 7.90 (m, 2H), 7.50 - 7.37 (m, 2H), 7.24 -
7.15 (m, 1H),
6.04 (s, 0.3H), 5.95 (d, J= 3.2 Hz, 0.7H), 4.61 (hr s, 1.6H), 4.26 - 4.20 (m,
0.4H), 4.03
- 3.93 (m, 3H), 3.88 (s, 1H), 3.87 (s, 2H), 3.07 - 2.98 (m, 2H), 2.14- 1.66
(m, 4H), 1.11
- 1.04 (m, 3H).
Compound XI-56-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-5,6-dimethylpyriraidine-4-carboxylate (a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB37 and FA12.
LC-MS (EST): RT = 2.18 min, mass calcd. for C3oH31C1F2N604S 644.2, m/z found
644.9 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 68.13 (s, 0.6H), 7.82 - 7.77 (m,
1H), 7.50 -
7.48 (m, 0.4H), 7.44 - 7.43 (m, 0.6H), 7.33 (s, 0.4H), 7.12 - 7.01 (m, 2H),
6.21 (s, 0.6H),
6.09 (d, J= 2.4 Hz, 0.4H), 4.47 - 4.40 (m, 2H), 4.32 - 4.24 (m, 1H), 4.11 -
3.98 (m, 2H),
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3.04 - 2.88 (m, 2H), 2.40 (s, 3H), 2.16 (s, 3H), 2.09 - 1.81 (m, 6H), 1.42 (t,
J= 6.8 Hz,
3H), 1.15 (t, J= 7.2 Hz, 3H).
Compound XE-57-S:
methyl 24446-(2-chloro-3,4-difluoropheny1)-5-(ethoxycarbony0-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-6-methoxypyriraidine-4-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB42 and FA12.
LC-MS (ESI): RT = 4.179 min, mass calcd. for C281-127C1F2N605S 632.1, m/z
found
632.9 [M+11] . 111 NMR (400 MHz, DMSO-d6) 6 9.60 (d, J= 3.6 Hz, 0.7H), 9.23
(s,
0.3H), 7.99 - 7.90 (m, 2H), 7.50 - 7.43 (m, 1H), 7.25 - 7.17 (m, 1H), 6.53 (s,
0.3H), 6.52
(s, 0.7H), 6.04 (s, 0.3H), 5.95 (d, J= 3.6 Hz, 0.7H), 4.94- 4.83 (m, 2H), 4.25
- 4.18 (m,
0.3H), 4.03 - 3.93 (m, 2.7H), 3.92 (s, 3H), 3.85 (s, 3H), 3.00 - 2.90 (m, 2H),
2.09 - 1.65
(m, 4H), 1.12 - 1.05 (m, 3H).
Compound XI-58-S:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-241nazol-2-y0-3,6-
dihydropyrimidin-4-yppiperidin-1-y1)-6-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB31 and FA12.
LC-MS (ESI): RT = 4.338 min, mass calcd. for C29H29C1F2N604S 630.2, m/z found
630.9 [M+Hi . 11-1 NMR (400 MHz, CDC13) 68.12 (s, 0.5H), 7.81 (d, J= 2.8 Hz,
0.4H),
7.76 (d, J= 2.8 Hz, 0.6H), 7.47 (d, J= 3.2 Hz, 0.4H), 7.43 (d, J= 2.8 Hz,
0.6H), 7.33
(d, J= 2.4 Hz, 0.5H), 7.14- 6.98 (m, 3H), 6.22 (s, 0.6H), 6.10 (d, J= 2.8 Hz,
0.4H),
5.19 - 4.99 (m, 2H), 4.44- 4.36 (m, 2H), 4.33 - 4.28 (m, 0.6H), 4.13 - 4.00
(m, 2.4H),
3.09 - 2.95 (m, 2H), 2.43 (s, 1.2H), 2.42 (s, 1.8H), 2.25 - 1.90 (m, 2.5H),
1.81 -1.66
(m,1.5H), 1.42 (t, J= 7.2 Hz, 3H), 1.17- 1.13 (m, 3H).
Compound XI-59-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-5-isopropylpyrimidine-4-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB45 and FA12.
LC-MS (ESI): RT = 2.569 min, mass calcd. for C311-133C1F2N604S 658.2, m/z
found
658.9 [M+111 . 11-1 NMR (400 MHz, CDC13) 6 8.42 (d, J= 1.2 Hz, 1H), 8.13 (s,
0.6H),
7.81 (d, J= 3.2 Hz, 0.4H), 7.78 (d, J= 3.6 Hz, 0.6H), 7.48 (d, J= 2.8 Hz,
0.4H), 7.43
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(d, J= 2.8 Hz, 0.6H), 7.34 (d, J= 2.4 Hz, 0.4H), 7.12 - 6.98 (m, 2H), 6.22 (s,
0.6H),
6.09 (d, J= 2.4 Hz, 0.4H), 5.05 - 4.85 (m, 2H), 4.43 (q, J= 7.2 Hz, 2H), 4.35 -
4.27 (m,
0.6H), 4.13 - 3.99 (m, 2.4H), 3.11 - 2.91 (m, 3H), 2.18 - 2.03 (m, 1H), 1.97 -
1.91 (m,
1H), 1.79 - 1.65 (m, 2H), 1.42 (t, J= 7.2 Hz, 3H), 1.27 - 1.24 (m, 6H), 1.15
(t, J= 7.2
Hz, 3H).
Compound XI-60-B:
Ethyl 2-4-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-y1)piperidin-1-y1)-5-ethylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB38 and FA12.
LC-MS (EST): RT = 3.851 min, mass calcd. for C301-131C1F2N604S 644.2, m/z
found
644.9 [M+111 . 1H NMR (400 MHz, CDC13) 68.31 (d, J= 2.8 Hz, 1H), 8.13 (s,
0.6H),
7.81 (d, J= 2.8 Hz, 0.4H), 7.78 (d, J= 3.2 Hz, 0.6H), 7.48 (d, J= 3.2 Hz,
0.4H), 7.43
(d, J= 2.8 Hz, 0.6H), 7.34 (d, J= 2.4 Hz, 0.4H), 7.12 - 7.00 (m, 2H), 6.22 (s,
0.6H),
6.09 (d, J= 2.8 Hz, 0.4H), 5.04 - 4.87 (m, 2H), 4.43 (q, J= 7.2 Hz, 2H), 4.34 -
4.27 (m,
0.6H), 4.13 - 3.99 (m, 2.4H), 3.06 - 2.93 (m, 2H), 2.67 - 2.60 (m, 2H), 2.20 -
1.95 (m,
2.5H), 1.80 - 1.68 (m, 1.5H), 1.42 (t, J= 7.2 Hz, 3H), 1.22 - 1.13 (m, 6H).
Compound XI-61-B:
Ethyl 5-chloro-2444642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony0-2-(thiazol-
2-
y1)-3,6-dihydropyrimidin-4-yOpiperidin-1-Opyriraidine-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB13 and FA12.
LC-MS (ESI): RT = 2.275 min, mass calcd. for C281-126C12F2N604S 650.1, m/z
found
651.0 [M+111 . 1H NMR (300 MHz, CDC13) 68.34 (d, J= 4.8 Hz, 1H), 8.10 (s,
0.5H),
7.81 - 7.78 (m, 1H), 7.48 (d, J= 2.8 Hz, 0.5H), 7.43 (d, J= 3.2 Hz, 0.5H),
7.33 (s,
0.5H), 7.12 - 7.01 (m, 2H), 6.21 (s, 0.5H), 6.09 (d, J= 2.7 Hz, 0.5H), 5.01 -
4.83 (m,
2H), 4.49 - 4.42 (m, 2H), 4.38 - 4.22 (m, 0.5H), 4.11 - 3.98 (m, 2.5H), 3.09 -
2.95 (m,
2H), 2.14- 1.88 (m, 2.5H), 1.80 - 1.65 (m, 1.5H), 1.43 (t, J= 7.2 Hz, 3H),
1.14 (t, J=
7.2 Hz, 3H).
Compound XI-62-B:
Ethyl 244-(642-chloro-3,4-difLuoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yl)piperidin-1-y1)-5-fluoropyrimidine-4-earboxylate (a
single
stereoisomer)
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By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB35 and FA12.
LC-MS (ESI): RT = 2.08 min, mass calcd. for C281-126C1F3N604S 634.1, m/z found
634.8 [M+1-11 . 11-1 NMR (400 MHz, CDC13) 68.36 (s, 1H), 8.11 (s, 0.4H), 7.84 -
7.75
(m, 1H), 7.52 - 7.41 (m, 1H), 7.33 (s, 0.6H), 7.14 - 7.00 (m, 2H), 6.22 (s,
0.6H), 6.10 (s,
0.4H), 5.02 - 4.82 (m, 2H), 4.45 (q, J= 7.2 Hz, 2H), 4.35 - 4.28 (m, 0.6H),
4.11 - 3.99
(m, 2.4H), 3.11 - 2.96 (m, 2H), 2.18 - 2.09 (m, 1H), 2.01 - 1.90 (m, 1.4H),
1.80 - 1.65
(m, 1.6H), 1.43 (t, J= 7.2 Hz, 3H), 1.15 (t, J= 6.8 Hz, 3H).
Compound XI-64-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-y1)piperidin-1-y1)-4-methyloxazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB25 and FA12.
LC-MS (ESI): RT = 3.605 min, mass calcd. for C281-128C1F2N505S 619.2, m/z
found
620.1 [M+1-11 . 11-1 NMR (400 MHz, DMSO-d6) 6 9.63 (d, J= 3.2 Hz, 0.7H), 9.29
(s,
0.3H), 8.00 - 7.91 (m, 2H), 7.50 - 7.42 (m, 1H), 7.24- 7.16 (m, 1H) 6.04 (s,
0.3H), 5.95
(d, J= 3.6 Hz, 0.7H), 4.26 - 4.11 (m, 4.3H), 4.02 - 3.95 (m, 2H), 3.90 - 3.82
(m, 0.7H),
3.16 - 3.06 (m, 2H), 2.30 - 2.29 (m, 3H), 2.23 - 1.80 (m, 3H), 1.72 - 1.64 (m,
1H), 1.29 -
1.23 (m, 3H), 1.10- 1.04(m, 3H).
Compound XI-66-N:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(145-(3-methoxy-3-oxopropyl)pyrimidin-2-
yl)piperidin-4-y0-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB39 and FA12.
LC-MS (ESI): RT = 3.407 min, mass calcd. for C29H29C1F2N604S 630.2, m/z found
631.2 [M+1-11 . 11-1 NMR (400 MHz, DMSO-d6) 69.58 (d, J= 3.6 Hz, 0.7H), 9.12
(s,
0.3H), 8.27 (d, J= 4.8 Hz, 2H), 7.98 - 7.90 (m, 2H), 7.50 - 7.43 (m, 1H), 7.24
- 7.17 (m,
1H), 6.04 (s, 0.3H), 5.94 (d, J= 3.6 Hz, 0.7H), 4.88 - 4.74 (m, 2H), 4.19 -
4.13 (m,
0.3H), 4.02 - 3.93 (m, 2H), 3.90 - 3.87 (m, 0.7H), 3.59 (s, 3H), 2.93 - 2.82
(m, 2H), 2.70
- 2.59 (m, 4H), 2.05 - 1.70 (m, 3.3H), 1.62 - 1.60 (m, 0.7H), 1.11 - 1.04 (m,
3H).
Compound XI-67-B:
Ethyl 442-chloro-3,4-difluoropheny1)-6-(145-(1-ethoxy-2-methyl-1-oxopropan-2-
yl)pyrimidin-2-yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate (a single stereoisomer)
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By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB46 and FA12.
LC-MS (EST): RT = 1.90 min, mass calcd. for C311133C1F2N604S 658.2, m/z found
659.1 [M+111 . 11-1 NMR (400 MHz, DMSO-de) 6 9.61 (d, J= 3.2 Hz, 0.7H), 9.20
(s,
0.3H), 8.37 (s, 0.8H), 8.36 (m, 1.2H), 7.99 - 7.91 (m, 2H), 7.50 - 7.43 (m,
1H), 7.24 -
7.15 (m, 1H), 6.04 (s, 0.3H), 5.94 (d, J= 3.2 Hz, 0.7H), 4.92 - 4.77 (m, 2H),
4.21 - 4.15
(m, 0.3H), 4.11 - 4.06 (m, 2H), 4.02 - 3.97 (m, 2H), 3.95 - 3.87 (m, 0.7H),
2.97 - 2.85
(m, 2H), 2.08 - 1.61 (m, 4H), 1.50 (s, 6H), 1.70 - 1.04 (m, 6H).
Compound XI-68-B:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-5-methyloxazole-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB24 and FA12.
LC-MS (EST): RT = 3.178 min, mass calcd. for C281128C1F2N505S 619.2, m/z found
620.1 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 69.62 (d, J= 3.6 Hz, 0.8H), 9.16
(s,
0.2H), 8.00 - 7.92 (m, 2H), 7.50 - 7.43 (m, 1H), 7.24- 7.16 (m, 1H), 6.04 (s,
0.3H), 5.94
(d, J= 3.6 Hz, 0.7H), 4.26 - 4.20 (m, 2H), 4.08 - 3.95 (m, 4.3H), 3.84 - 3.78
(m, 0.7H),
3.07 - 2.94 (m, 2H), 2.48 (s, 3H), 2.13 - 1.61 (m, 4H), 1.27 (t, J= 6.8 Hz,
3H), 1.10 -
1.04 (m, 3H).
Compound XI-69-B:
Ethyl-442-chloro-3,4-difluoropheny1)-6-(14542-ethoxy-2-oxoethyppyrimidin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB1 and FA12.
LC-MS (EST): RT = 4.550 min, mass calcd. for C29H29C1F2N604S 630.2, m/z found
630.9 [M+111 . 11-1 NMR (400 MHz, DMSO-d6) 69.59 (d, J= 3.6 Hz, 0.7H), 9.16
(s,
0.3H), 8.28 - 8.27 (m, 2H), 7.98 - 7.90 (m, 2H), 7.50 - 7.42 (m, 1H), 7.24 -
7.16 (m, 1H),
6.04 (s, 0.3H), 5.94 (d, J= 3.2 Hz, 0.7H), 4.91 - 4.76 (m, 2H), 4.20 - 4.14
(m, 0.3H),
4.10 (q, J= 6.8 Hz, 2H), 4.00 (q, J= 6.8 Hz, 2H), 3.95 - 3.88 (m, 0.7H), 3.54
(s, 2H),
2.93 - 2.84 (m, 2H), 2.04 - 1.71 (m, 3.3H), 1.63 - 1.60 (m, 0.7H), 1.20 (t, J=
6.8 Hz,
3H), 1.11- 1.04(m, 3H).
Compound XI-70-N:
ethyl 2-(44642-chloro-3,4-difluoropheny0-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yppiperidin-1-ypoxazole-4-carboxylate (a single
stereoisomer)
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By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB6 and FA12.
LC-MS (ESI): RT = 4.433 min, mass calcd. for C27H26C1F2N505S 605.1, m/z found
606.1 [M+Hi . Chiral analysis (Column: Chiralpak IA 5 i.tm 4.6 * 250 mm;
Mobile
Phase: Hex : Et0H = 70 : 30 at 1.0 mL/min; Temp: 30 C; Wavelength: 230 nm; RT
=
8.799 min). 1H NMR (400 MHz, DMSO-d6) 69.60 (s, 0.7H), 9.18 (s, 0.3H), 8.30
(d, J=
5.2 Hz, 1H), 8.00 - 7.97 (m, 1.7H), 7.92 (d, J= 3.2 Hz, 0.3H), 7.50 - 7.43 (m,
1H), 7.24
- 7.17 (m, 1H), 6.04 (s, 0.3H), 5.95 (s, 0.7H), 4.24 (q, J= 7.2 Hz, 2H), 4.14-
3.95 (m,
4.3H), 3.86 - 3.81 (m, 0.7H), 3.12 - 3.01 (m, 2H), 2.18 - 1.70 (m, 3H), 1.66 -
1.63 (m,
1H), 1.27 (t, J= 7.2 Hz, 3H), 1.11 - 1.04 (m, 3H).
Compound XI-72-X and XI-72-S:
Ethyl 244-(642-chloro-3,4-difLuoropheny1)-5-(ethoxyearbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-4-methoxypyriraidine-5-carboxylate (a
single
stereoisomer) and ethyl 4444642-chloro-3,4-difluoropheny1)-5-(ethoxycarbonyl)-
2-
(thiazol-2-y1)-3,6-dihydropyrimidin-4-yppiperidin-1-y1)-2-methoxypyrimidine-5-
carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB43 and FA12.
XI-72-X: 1H NMR (400 MHz, DMSO-d6) 69.63 - 9.62 (m, 0.7H), 9.13 (s, 0.3H),
8.51 -
8.48 (m, 1H), 8.01 - 7.97 (m, 1.7H), 7.93 - 7.92 (m, 0.3H), 7.50 - 7.42 (m,
1H), 7.25 -
7.16 (m, 1H), 6.04 (s, 0.3H), 5.96 - 5.95 (s, 0.7H), 4.30 - 4.11 (m, 4H), 4.05
- 3.89 (m,
6H), 3.12 - 3.02 (m, 2H), 2.13 - 1.76 (m, 3.3H), 1.68 - 1.65 (m, 0.7H), 1.34-
1.30 (m,
3H), 1.12 - 1.05 (m, 3H).
XI-72-S: 1H NMR (400 MHz, DMSO-d6) 6 9.62 - 9.61 (m, 0.7H), 9.28 (s, 0.3H),
8.66 -
8.65 (m, 1H), 7.99 - 7.94 (m, 1.7H), 7.91 - 7.90 (m, 0.3H), 7.50 - 7.43 (m,
1H), 7.25 -
7.16 (m, 1H), 6.04 (s, 0.3H), 5.96 - 5.95 (m, 0.7H), 5.02 - 4.85 (m, 2H), 4.20
(q, J= 7.2
Hz, 2.3H), 4.04- 3.93 (m, 5.7H), 3.06 - 2.97 (m, 2H), 2.16 - 1.67 (m, 4H),
1.28 - 1.23
(m, 3H), 1.11- 1.04(m, 3H).
Compound XI-73-S:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-4-methylpyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB8 and FA12.
LC-MS (ESI): RT = 4.640 min, mass calcd. for C29H29C1F2N604S 630.2, m/z found
631.2 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.61 (d, J= 3.2 Hz, 0.7H), 9.26 (s,
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0.3H), 8.77 - 8.76 (m, 1H), 7.99 - 7.90 (m, 2H), 7.50 - 7.42 (m, 1H), 7.24 -
7.16 (m, 1H),
6.04 (s, 0.3H), 5.95 (d, J= 3.2 Hz, 0.7H), 5.04 - 4.91 (m, 2H), 4.28 - 4.22
(m, 2.3H),
4.03 - 3.92 (m, 2.7H), 3.04 - 2.96 (m, 2H), 2.60 -(s, 1H), 2.59 (s, 2H), 2.10 -
1.66 (m,
4H), 1.30 (t, J= 7.2 Hz, 3H), 1.11 - 1.04 (m, 3H).
Compound XI-75-S:
Ethyl 544-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-1,3,4-thiadiazole-2-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB16 and FA12.
LC-MS (ESI): RT = 2.212 min, mass calcd. for C26H25C1F2N604S2 622.1, m/z found
623.0 [M+11] . 1H NMR (400 MHz, DMSO-d6 (one drop of D20)) 6 7.99 - 7.96 (m,
1.7H), 7.91 - 7.90 (m, 0.3H), 7.49 - 7.42 (m, 1H), 7.24 - 7.17 (m, 1H), 6.04
(s, 0.3H),
5.95 (s, 0.7H), 4.38 - 4.33 (m, 2H), 4.20 - 4.06 (m, 2H), 4.02 - 3.97 (m, 2H),
3.95 - 3.87
(m, 1H), 3.40 - 3.29 (m, 2H), 2.33 - 1.85 (m, 3H), 1.79 - 1.69 (m, 1H), 1.32
(t, J= 6.8
Hz, 3H), 1.10- 1.03 (m, 3H).
Compound XI-76-B:
Ethyl 544-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yppiperidin-1-ypthiazole-2-carboxylate (a single
stereoisomer)
0
Oy=LN_r0H
0 CI 0 H 0 0 CI
N
BB26 (1.2 eq)
_________________________________________ >
I HATU (1.3 eq), DIEA (4 eq) ONN
N DMF, r.t , overnight 0
H H rj
HN
H 0 0
FA12 XI-76-B1
0 CI
Lawesson's Reagent (1.1 eq)
toluene,110 oC, 3h
H rj
NN
S
XI-76-B
OEt
Intermediate XI-76-B1:
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Ethyl 442-chloro-3,4-difluoropheny1)-6-(14242-ethoxy-2-
oxoacetamido)acetyppiperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate
To a solution of 2-(2-ethoxy-2-oxoacetamido)acetic acid BB26 (122 mg, 70 %
purity,
0.488 mmol) and /V,/V-diisopropylethylamine (215 mg, 1.63 mmol) in /V,/V-
dimethylformamide (4 mL) was added o-(7-azabenzotriazol-1-y1)-/V,/V,N,N-
tetramethyluronium hexafluorophosphate (205 mg, 0.528 mmol). The mixture was
stirred at room temperature for 30 minutes, then (8')-ethyl 4-(2-chloro-3,4-
difluoropheny1)-6-(piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate FA12 (200 mg, 95 % purity, 0.407 mmol) was added. After stirred at
room temperature overnight, the mixture was poured into water (30 mL) and
extracted with ethyl acetate (30 mL) twice. The combined organic layers were
washed with water (30 mL) and brine (30 mL), dried over Na2SO4(s) and
filtered. The
filtrate was concentrated to give a residue, which was purified by silica gel
chromatography (petroleum ether : ethyl acetate = 2 : 1 to 2 : 3) to give the
title
compound (130 mg, 90 % purity, 46 % yield) as yellow solids. LC-MS (ESI): RT =
1.45
min, mass calcd. for C27H28C1F2N506S 623.1, m/z found 624.0 [M+Hi .
Compound XI-76-B:
Ethyl 544-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yppiperidin-1-ypthiazole-2-carboxylate
To a solution of ethyl 4-(2-chloro-3,4-difluoropheny1)-6-(1-(2-(2-ethoxy-2-
oxoacetamido)acetyl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-
carboxylate XE-76-B1 (130 mg, 90 % purity, 0.187 mmol) in toluene (2 mL) was
added 2,4-bis(4-methoxypheny1)-1,3,2,4-dithiadiphosphetane 2,4-disulfide
(Lawesson's reagent, 83 mg, 0.205 mmol) under nitrogen atmosphere at room
temperature. After stirred at 110 C for 3 hours and then cooled down to room
temperature, the mixture was concentrated under reduced pressure to remove the
volatile, then poured into brine (10 mL) and extracted with ethyl acetate (20
mL) for
three times. The combined organic layers were dried over Na2SO4(s) and
filtered. The
filtrate was concentrated under reduced pressure to give a crude product,
which was
purified by C18 column (acetonitrile : water = 50 % to 100 %) to give the
title
compound (70 mg, 98 % purity, 59 % yield) as yellow solids. 111 NMR (400 MHz,
DMSO-d6) 6 9.64 (d, J= 4.0 Hz, 0.7H), 9.18 (m, 0.3H), 8.00 - 7.92 (m, 2H),
7.50 - 7.44
(m, 1H), 7.33 - 7.32 (m, 1H), 7.25 - 7.17 (m, 1H), 6.04 (s, 0.3H), 5.95 (d, J=
3.2 Hz,
0.7H), 4.29 (q, J= 3.2 Hz, 0.7H), 4.02 - 3.95 (m, 2H), 3.87 - 3.72 (m, 3H),
3.19 - 3.04
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(m, 211), 2.33 - 1.75 (m, 3.311), 1.69 - 1.65 (m, 0.711), 1.29 (t, J= 7.2 Hz,
311), 1.10 -
1.04 (m, 311).
Compound XE-77-S:
Methyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-4-(methoxymethyl)thiazole-5-earboxylate
(a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB47 and FA12.
LC-MS (ESI): RT = 4.022 min, mass calcd. for C281128C1F2N505S2 651.1, m/z
found
652.1 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.64 (d, J= 3.6 Hz, 0.811), 9.32
(s,
0.211), 8.00 - 7.91 (m, 211), 7.50 - 7.43 (m, 111), 7.25 - 7.16 (m, 111), 6.04
(s, 0.211), 5.95
(d, J= 3.2 Hz, 0.811), 4.59 (s, 211), 4.16 - 4.06 (m, 211), 4.02 - 3.97 (m,
211), 3.95 - 3.87
(m, 111), 3.74 (s, 311), 3.32 (s, 2.411), 3.31 (s, 0.611), 3.24- 3.15 (m,
211), 2.25 - 2.20 (m,
0.211), 2.09 - 1.68 (m, 3.811), 1.11 - 1.04 (m, 311).
Compound XI-78-S:
Ethyl 244-(642-chloro-3,4-difLuoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yppiperidin-1-ypthiazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB3 and FA12.
LC-MS (ESI): RT = 3.944 min, mass calcd. for C27H26C1F2N504S2 621.1, m/z found
622.1 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.64 (d, J= 3.2 Hz, 0.711), 9.31
(s,
0.311), 8.00 - 7.91 (m, 211), 7.87 (s, 111), 7.50 - 7.43 (m, 111), 7.25 - 7.16
(m, 111), 6.04
(s, 0.311), 5.95 (d, J= 3.2 Hz, 0.711), 4.25 - 4.08 (m, 4.211), 4.02 - 3.86
(m, 2.811), 3.26 -
3.17 (m, 211), 2.25 - 1.84 (m, 311), 1.77 - 1.68 (m, 111), 1.26 (t, J= 7.2 Hz,
311), 1.11 -
1.04 (m, 311).
Compound XI-79-S:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-4-(trifluoromethyl)thiazole-5-carboxylate
(a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB15 and FA12.
LC-MS (ESI): RT = 3.656 min, mass calcd. for C281-125C1F5N504S2 689.1, m/z
found
690.0 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.65 (d, J= 3.2 Hz, 0.711), 9.35
(s,
0.311), 8.00 - 7.92 (m, 211), 7.50 - 7.43 (m, 111), 7.25 - 7.12 (m, 111) 6.04
(s, 0.311), 5.95
(d, J= 3.2 Hz, 0.711), 4.28 - 4.02 (m, 4.311), 4.00 - 3.87 (m, 2.711), 3.27 -
3.20 (m, 211),
2.27 - 1.85 (m, 311), 1.76 - 1.70 (m, 111), 1.26 (t, J= 7.2 Hz, 311), 1.11 -
1.03 (m, 311).
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Compound XI-80-S:
Ethyl 2-(4-(6-(2-chloro-3,4-difluorophenyl)-5-(ethoxycarbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yppiperidin-1-ypthiazole-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB11 and FA12.
LC-MS (ESI): RT = 1.84 min, mass calcd. for C27H26C1F2N504S2 621.1, m/z found
622.3 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.63 (d, J= 4.0 Hz, 0.7H), 9.22 (s,
0.3H), 8.00 - 7.96 (m, 1.7H), 7.92 (d, J= 3.2 Hz, 0.3H), 7.70 (s, 1H), 7.50 -
7.43 (m,
1H), 7.25 - 7.17 (m, 1H), 6.04 (s, 0.3H), 5.95 (d, J= 3.2 Hz, 0.7H), 4.24 (q,
J= 7.2 Hz,
2H), 4.13 - 3.95 (m, 4.3H), 3.91 - 3.82 (m, 0.7H), 3.17 - 3.04 (m, 2H), 2.10 -
1.65 (m,
4H), 1.28 (t, J= 7.2 Hz, 3H), 1.01 - 1.04 (m, 3H).Compound XE-81-B:
Ethyl 2-(4-(6-(4-bromo-2-chloropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-Opiperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB4 and FA13.
LC-MS (ESI): RT = 2.17 min, mass calcd. for C281-128BrC1N6O4S 658.1, m/z found
658.7 [M+Hi . 1H NMR (400 MHz, CDC13) 68.29 - 8.28 (m, 1H), 8.14 (s, 0.5H),
7.81
(d, J= 3.2 Hz, 0.5H), 7.77 (d, J= 3.2 Hz, 0.5H), 7.56 (s, 1H), 7.47 (d, J= 3.2
Hz,
0.5H), 7.43 (d, J= 2.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.21 - 7.18 (m, 1H), 6.19
(s, 0.5H),
6.05 (d, J= 2.4 Hz, 0.5H), 5.00 - 4.87 (m, 2H), 4.43 (q, J= 7.2 Hz, 2H), 4.33 -
4.27 (m,
0.5H), 4.07 - 4.02 (m, 0.5H), 3.63 (s, 1.5H), 3.61 (s, 1.5H), 3.06 - 2.98 (m,
2H), 2.28 (s,
1.5H), 2.27 (s, 1.5H), 2.19 - 2.05 (m, 1H), 1.98 - 1.89 (m, 1.4H), 1.78 - 1.67
(m, 1.6H),
1.43 (t, J= 7.2 Hz, 3H).
Compound XI-82-B:
methyl 2-(4-(6-(2-bromo-3,4-difluoropheny1)-5-(methoxyearbony1)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)thiazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB3 and FA14.
LC-MS (ESI): RT = 2.064 min, mass calcd. for C25H22BrF2N5O4S2 637.0, m/z found
637.9 [M+111 . 1H NMR (400 MHz, DMSO-d6) 6 9.67 (d, J= 3.2 Hz, 0.7H), 9.40 (s,
0.3H), 8.00 - 7.95 (m, 2H), 7.90 (s, 1H), 7.53 - 7.46 (m, 1H), 7.25 - 7.21 (m,
0.7H), 7.16
- 7.13 (m, 0.3H), 6.01 (s, 0.3H), 5.94 (d, J= 3.6 Hz, 0.7H), 4.18 - 4.08 (m,
2.5H), 3.93 -
3.87 (m, 0.5H), 3.76 (s, 3H), 3.54 (s, 2H), 3.53 (s, 1H), 3.28 - 3.18 (m, 2H),
2.07 - 1.97
(m, 1.5 H), 1.92 - 1.84 (m, 1.5H), 1.77 - 1.64 (m, 1H).
Compound XI-83-B:
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Methyl 244-(642-bromo-3-fluoropheny0-5-(methoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yOpiperidin-1-yOthiazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB3 and FA15.
LC-MS (ESI): RT = 2.033 min, mass calcd. for C25H23BrFN5O4S2 619.0, m/z found
620.0 [M+111 . 1H NMR (400 MHz, CDC13) 68.14 (s, 0.2H), 7.92 - 7.91 (m, 1H),
7.83
(d, J= 3.2 Hz, 0.8H), 7.79 (d, J= 3.2 Hz, 0.2H), 7.53 (s, 0.8H), 7.50 (d, J=
3.2 Hz,
0.8H), 7.45 (d, J= 3.2 Hz, 0.2H), 7.25 - 7.20 (m, 1H), 7.13 - 7.01 (m, 2H),
6.27 (s,
0.2H), 6.12 (d, J= 2.8 Hz, 0.8H), 4.37 - 4.19 (m, 2H), 4.16 - 4.06 (m, 1H),
3.85 (s,
0.6H), 3.84 (s, 2.4H), 3.61 (s, 2.4H), 3.60 (s, 0.6H), 3.34 - 3.22 (m, 2H),
2.32 - 2.22 (m,
1H), 2.16 - 2.02 (m, 2H), 1.93 - 1.77 (m, 1H).
Compound XI-84-N:
Methyl 244-(642-bromo-4-fluoropheny0-5-(methoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yl)piperidin-1-yl)thiazole-5-carboxylate (a single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB3 and FA16.
LC-MS (EST): RT = 2.745 min, mass calcd. for C25H23BrFN5O4S2 619.0, m/z found
619.7 [M+Hi . 111 NMR (400 MHz, CDC13) 68.12 (s, 1H), 7.91 - 7.90 (m, 1H),
7.83 -
7.79 (m, 1H), 7.50 (d, J= 3.2 Hz, 1.7H), 7.44 (d, J= 2.8 Hz, 0.3H), 7.34 -
7.32 (m, 1H),
7.03 - 6.93 (m, 1H), 6.18 (s, 0.2H), 6.05 (d, J= 2.4 Hz, 0.8H), 4.35 - 4.15
(m, 2.2H),
4.10 - 4.04 (m, 0.8H), 3.85 (s, 0.5H), 3.84 (s, 2.5H), 3.62 (s, 2.5H), 3.61
(s, 0.5H), 3.33
- 3.21 (m, 2H), 2.31 - 2.21 (m, 0.8H), 2.15 - 1.97 (m, 2H), 1.91 - 1.76 (m,
1.2H).
Compound XE-85-M:
Ethyl 2-(3-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-270-
3,6-
dihydropyrimidin-4-yl)pyrrolidin-1-yl)oxazole-4-carboxylate (a single
stereoisomer)
Compound XI-85:
Ethyl 2-(3-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-y1)pyrrolidin-1-y1)oxazole-4-carboxylate (a mixture of 4
stereoisomers)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB6 and FA17.
LC-MS (EST): RT = 4.271 min, mass calcd. for C26H24C1F2N505S 591.1, m/z found
591.9 [M+111 . 111 NMR (400 MHz, CD30D) 6 8.08 - 8.01 (m, 1H), 7.87 - 7.86 (m,
1H),
7.71 - 7.69 (m, 1H), 7.28 - 7.23 (m, 2H), 6.17 (s, 0.2H), 6.11 (d, J= 4.8 Hz,
0.8H), 4.62
- 4.59 (m, 1H), 4.34 - 4.28 (m, 2H), 4.09 - 4.00 (m, 2.4H), 3.88 - 3.62 (m,
3.6H), 2.45 -
2.39 (m, 1H), 2.33 - 2.28 (m, 1H), 1.36 -1.28 (m, 3H), 1.14 (t, J= 7.2 Hz,
3H).
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A stereoisomeric mixture of ethyl-2-(3-(6-(2-chloro-3,4-difluoropheny1)-5-
(ethoxycarbonyl
) -2- (thiazol-2 -y1) -3,6- dihydropyrimidin- 4-yl)pyrrolidin- 1- yl)oxazole -
4- carboxylate XE-
85 (800 mg, 90 % purity, 1.20 mmol) was separated by chiral Prep. HPLC
(Column:
Chiralpak IF 5 i.tm 20 * 250 mm; Mobile Phase: Hex : Et0H : DEA = 70 : 30 :
0.3 at
13 mL/min; Temp: 30 C; Wavelength: 214 nm) to afford the title compounds XI-
85-
M (150 mg, 99.2 % purity, 19 % yield, 100 % stereopure) and Group 1 (mixture
of XI-
85-N, XI-85-P and XI-85-Q, 600 mg) as yellow solids. Group 1 (600 mg, 0.960
mmol)
was separated by chiral Prep. HPLC (Column: Chiralpak IG 5 i.tm 20 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.3 at 15 mL/min; Temp: 30 C;
Wavelength: 214 nm) to afford the title compounds XI-85-N (130 mg, 99.5 %
purity,
16 % yield, 100 % stereopure), XI-85-P (150 mg, 99.4 % purity, 19 % yield, 100
%
stereopure) and XI-85-Q (130 mg, 99.2 % purity, 16 % yield, 100 % stereopure)
as
yellow solids.
XI-85-M: LC-MS (ESI): RT = 3.806 min, mass calcd. for C26H24C1F2N505S 591.1,
m/z
found 592.1 [M+Hi . Chiral analysis (Column: Chiralpak IF 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 8.999 min). 1H NMR (400 MHz, DMSO-d6) 6 9.73 (d, J=
3.6 Hz, 0.9H), 9.42 (s, 0.1H), 8.33 (s, 0.1H), 8.28 (s, 0.9H), 8.00 - 7.93 (m,
2H), 7.50 -
7.43 (m, 1H), 7.27 - 7.23 (m, 1H), 6.05 (s, 0.1H), 5.96 (d, J= 3.2 Hz, 0.9H),
4.47 - 4.43
(m, 1H), 4.23 (q, J= 7.2 Hz, 2H), 3.99 (q, J= 7.2 Hz, 2H), 3.84 - 3.67 (m,
3H), 3.56 -
3.53 (m, 1H), 2.23 - 2.18 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H), 1.09 - 1.02 (m,
3H).
XE-85-N: LC-MS (ESI): RT = 3.805 min, mass calcd. for C26H24C1F2N505S 591.1,
m/z
found 592.1 [M+Hi . Chiral analysis (Column: Chiralpak IF 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 7.434 min). 1H NMR (400 MHz, DMSO-d6) 6 9.72 (d, J=
3.2 Hz, 0.8H), 9.41 (s, 0.2H), 8.33 (s, 0.2H), 8.27 (s, 0.8H), 8.00 - 7.94 (m,
2H), 7.45 (q,
J= 8.8 Hz, 1H), 7.27 - 7.23 (m, 1H), 6.05 (s, 0.1H), 5.96 (d, J= 3.2 Hz,
0.9H), 4.47 -
4.43 (m, 1H), 4.21 (q, J= 7.2 Hz, 2H), 3.98 (q, J= 6.8 Hz, 2H), 3.84 - 3.66
(m, 3H),
3.54 (q, J= 7.2 Hz, 1H), 2.22 - 2.17 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H), 1.09 -
1.02 (m,
3H).
XI-85-P: LC-MS (ESI): RT = 3.786 min, mass calcd. for C26H24C1F2N505S 591.1,
m/z
found 592.1 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 14.636 min). 1H NMR (400 MHz, DMSO-d6) 6 9.72 (s,
0.8H), 9.44 (s, 0.2H), 8.34 (s, 0.2H), 8.27 (s, 0.8H), 8.00 - 7.94 (m, 2H),
7.53 - 7.46 (m,
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1H), 7.28 - 7.24 (m, 1H), 6.07 (s, 0.2H), 5.98 (s, 0.811), 4.47 - 4.44 (m,
111), 4.22 (q, J=
6.8 Hz, 2H), 3.99 (q, J= 7.6 Hz, 2H), 3.80 - 3.54 (m, 4H), 2.34 - 2.29 (m,
2H), 1.28 (t,
J= 6.8 Hz, 3H), 1.11 - 1.05 (m, 3H).
XI-85-Q: LC-MS (ESI): RT = 3.792 min, mass calcd. for C26H24C1F2N505S 591.1,
m/z
found 592.1 [M+Hi . Chiral analysis (Column: Chiralpak IG 5 pm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H : DEA = 70 : 30 : 0.2 at 1 mL/min; Temp: 30 C;
Wavelength: 230 nm, RT = 16.379 min). 111 NMR (400 MHz, DMSO-d6) 6 9.72 (m,
0.8H), 9.44 (s, 0.2H), 8.33 (s, 0.2H), 8.26 (s, 0.8H), 7.99 - 7.93 (m, 2H),
7.52 - 7.45 (m,
1H), 7.27 - 7.22 (m, 1H), 6.06 (s, 0.1H), 5.97 (s, 0.911), 4.48 - 4.44 (m,
1H), 4.21 (q, J=
6.8 Hz, 2H), 3.97 (q, J= 7.2 Hz, 2H), 3.78 - 3.53 (m, 4H), 2.33 - 2.27 (m,
2H), 1.26 (t,
J= 7.2 Hz, 3H), 1.09 - 1.02 (m, 3H).
Compound XI-86-N:
Ethyl 2-(3-(642-chloro-3,4-difLuorophenyl)-5-(ethoxyearbony1)-2-(thiazol-2-y0-
3,6-
dihydropyrimidin-4-yDazetidin-1-ypoxazole-4-carboxylate (a single
stereoisomer)
Intermediate XI-86-R:
Ethyl-2-04642-chloro-3,4-difLuoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-ypazetidin-1-ypoxazole-4-carboxylate (a mixture of 2
stereoisomers)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB6 and FA18.
LC-MS (ESI): RT = 2.189 min, mass calcd. for C25H22C1F2N505S 577.1, m/z found
578.1 [M+Hi . 111 NMR (400 MHz, DMSO-d6) 69.82 (s, 0.9H), 9.48 (s, 0.1H), 8.37
(s,
0.1H), 8.32 (s, 0.9H), 8.02 - 8.00 (m, 1.8H), 9.48 (d, J= 3.2 Hz, 0.2H), 7.48 -
7.42 (m,
1H), 7.31 - 7.28 (m, 1H), 6.05 (s, 0.1H), 5.97 (s, 0.911), 4.93 - 4.88 (m,
0.1H), 4.71 -
4.64 (m, 0.9H), 4.37 - 4.34 (m, 3H), 4.30 - 4.21 (m, 3H), 3.99 (q, J= 7.2 Hz,
2H), 1.26
(t, J= 7.2 H, 3H), 1.08 (t, J= 7.2 H, 3H).
A stereoisomeric mixture of ethyl 2-(3-(6-(2-chloro-3,4-difluoropheny1)-5-
(ethoxycarbonyl) -2- (thiazol-2 -y1) -3,6- dihydropyrimidin- 4-yl)azetidin- 1-
yl)oxazole - 4-
carboxylate XI-86-R (300 mg, 96 % purity, 0.498 mmol) was separated by chiral
prep.
HPLC (separation condition: Column: Chiralpak IE 5 pm 20 * 250 mm; Mobile
Phase: Hex : Et0H = 70 : 30 at 15 mL/ min; Wavelength: 214 nm) to give the
compounds XI-86-M (90 mg, 99.8 % purity, 31 % yield, 100 % stereopure) and XI-
86-
N (80 mg, 99.5 % purity, 28 % yield, 98.6 % stereopure).
XI-86-M: LC-MS (ESI): RT = 4.130 min, mass calcd. for C25H22C1F2N505S 577.1,
m/z
.. found 578.1 [M+111 . Chiral HPLC (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H = 70 : 30 at 1.0 mL/ min; Temp: 30 C; Wavelength:
230
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nm, RT = 16.261 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.83 (s, 1H), 8.33 (s,
1H),
8.00 - 8.02 (m, 2H), 7.42 - 7.49 (m, 1H), 7.28 - 7.32 (m, 1H), 5.97 (s, 1H),
4.64 - 4.69
(m, 1H), 4.35 - 4.37 (m, 3H), 4.21 - 4.31 (m, 3H), 3.98 (q, J= 7.2 Hz, 2H),
1.27 (t, J=
7.2 Hz, 3H), 1.08 (t, J= 6.8 Hz, 3H).
XI-86-N: LC-MS (ESI): RT = 4.135 min, mass calcd. for C25H22C1F2N505S 577.1,
m/z
found 578.1 [M+1-11 . Chiral HPLC (Column: Chiralpak IE 5 i.tm 4.6 * 250 mm;
Mobile Phase: Hex : Et0H = 70 : 30 at 1.0 mL/ min; Temp: 30 C; Wavelength:
230
nm, RT = 18.383 min). 11-1 NMR (400 MHz, DMSO-d6) 6 9.82 (d, J= 3.2 Hz, 0.9H),
9.49 (s, 0.1H), 8.38 (0.1H), 8.33 (s, 0.9H)õ 8.02 - 7.95 (m, 2H), 7.49 - 7.42
(m, 1H),
7.31 - 7.28 (m, 1H), 6.05 (s, 0.1H), 5.97 (d, J= 3.2 Hz, 0.9H), 4.91 (s,
0.1H), 4.71 -
4.63 (m, 0.9H), 4.37 - 4.34 (m, 3H), 4.30 - 4.21 (m, 3H), 3.98 (q, J= 7.2 Hz,
2H), 1.26
(t, J= 7.2 Hz, 3H), 1.08 (t, J= 7.2 Hz, 3H).
Compound XI-87-S:
Methyl 442-chloro-4-fluoropheny1)-6-(1-(4-(methoxycarbony0-5-methylpyridin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB56 and FA7.
LC-MS (ESI): RT = 2.028 min, mass calcd. for C28H27C1FN504S 583.1, m/z found
584.1 [M+H] .
Compound XI-88-4:
Ethyl 244-(642-chloro-3,4-difluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-0-
3,6-
dihydropyrimidin-4-yOpiperidin-1-y0-5-(dimethylamino)pyrimidine-4-carboxylate
(a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB57 and FA10.
LC-MS (ESI): RT = 1.99 min, mass calcd. for C29H30C1F2N704S 645.2, m/z found
645.9 [M+E-1] .
1H NMR (400 MHz, DMSO-d6) 6 9.62 (s, 0.7H), 9.32 (s, 0.3H), 8.51 (s, 0.3H),
8.49 (s, 0.7H),
7.99 - 7.91 (m, 2H), 7.49 - 7.45 (m, 1H), 7.23 - 7.14 (m, 1H), 6.02 (s, 0.3H),
5.94 (s, 0.7H), 4.78 -
4.66 (m, 2H), 4.34 (q, J= 6.8 Hz, 2H), 4.22 - 4.16 (m, 0.3H), 3.92 - 3.87 (m,
0.7H), 3.54 (s, 3H),
2.96 - 2.82 (m, 2H), 2.65 (s, 6H), 2.08 - 1.60 (m, 4H), 1.30 (t, J= 6.8 Hz,
3H).
Compound XI-89-2:
ethyl 5-(bis(2,4-dimethoxybenzypamino)-2-(4-(6-(2-chloro-3,4-difluoropheny1)-5-
(methoxycarbonyl) -2-(thiazol-2-y1)-3, 6-dihydropyrimidin-4-yppiperidin- 1-
yl)pyrimidine-4-carboxylate (a single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB58 and FA10.
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11-1 NMR (400 MHz, CDC13) 6 8.16 (s, 0.6H), 8.04 (s, 0.6H), 8.03 (s, 0.4H),
7.81 (d, J= 3.2 Hz,
0.4H), 7.78 (d, J = 3.2 Hz, 0.6H), 7.49 (d, J = 3.2 Hz, 0.4H), 7.43 (d, J =
3.2 Hz, 0.6H), 7.40 (d, J
= 2.0 Hz, 0.4H), 7.31 - 7.28 (m, 2H), 7.11 - 6.98 (m, 2H), 6.43 (d, J= 8.4 Hz,
2H), 6.39- 6.38 (m,
2H), 6.19 (s, 0.6H), 6.06 (d, J= 2.4 Hz, 0.4H), 4.95 - 4.73 (m, 2H), 4.37 (q,
J= 7.6 Hz, 2H), 4.32
-4.22 (m, 0.6H), 4.11 (s, 2.4H), 4.10 (s, 1.6H), 4.05 -3.96 (m, 0.4H), 3.78
(s, 6H), 3.71 (s, 6H),
3.62 (s, 1.8H), 3.60 (s, 1.2H), 2.99 - 2.87 (m, 2H), 2.18 - 2.03 (m, 0.5H),
2.01 - 1.97 (m, 0.5H),
1.96- 1.86 (m, 1.5H), 1.78 - 1.64 (m, 1.5H), 1.35 (t, J= 7.6 Hz, 3H).
Compound XI-90-3:
methyl 4-(2-ehloro-3,4-difluoropheny1)-6-(1-(4-(methoxycarbonyl)-5-
nitropyridin-2-
yl)piperidin-4-y1)-2-(thiazol-2-y1)-1,4-dihydropyrimidine-5-earboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB59 and FA10.
LC-MS (ESI): RT = 1.81 min, mass calcd. for C27H23C1F2N606S 632.1, m/z found
633.1 [M+Hr.
11-1 NMR (400 MHz, CDC13) 6 8.99 (s, 1H), 8.13 (s, 0.3H), 7.83 - 7.79 (m, 1H),
7.50 (d, J = 3.2
Hz, 0.7H), 7.45 (s, 1H), 7.11 - 7.00 (m, 2H), 6.62 - 6.10 (m, 1H), 6.20 (s,
0.3H), 6.08 (d, J = 2.0
Hz, 0.7H), 4.91 - 4.53 (m, 2H), 4.44 - 4.37 (m, 0.3H), 4.20 - 4.14 (m, 0.7H),
3.96 (s, 3H), 3.63 (s,
3H), 3.25 -3.15 (m, 2H), 2.21 - 1.69 (m, 4H).
Compound XI-91-1:
Ethyl 2-(4-(6-(3,4-difluoro-2-methylpheny1)-5-(methoxycarbony1)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-yppiperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB4 and FAL
LC-MS (ESI): RT = 2.04 min, mass calcd. for C29H30C1F2N604S 596.2, m/z found
597.0 [M+E-1] .
1H NMR (400 MHz, CDC13) 6 8.28 (s, 1H), 8.10 (s, 0.8H), 7.78 - 7.75 (m, 1H),
7.47 (s, 0.2H),
7.40 (d, J = 3.2 Hz, 0.8H), 7.10 (br s, 0.2H), 7.04 (br s, 0.2H), 6.96 - 6.86
(m, 1.8H), 5.95 (s,
0.8H), 5.86 (s, 0.2H), 5.04 - 4.88 (m, 2H), 4.42 (q, J= 7.2 Hz, 2H), 4.32 (t,
J= 12.4 Hz, 1H),
3.61 (s, 3H), 3.07 - 2.98 (m, 2H), 2.57 (s, 2.5H), 2.43 (s, 0.5H), 2.28 (s,
3H), 2.11 -2.08 (m, 1H),
1.97 - 1.94 (m, 1H), 1.82 - 1.68 (m, 2H), 1.42 (t, J= 7.2 Hz, 3H).
Compound XI-92-1:
Ethyl 2-(4-(6-(3,4-difluoro-2-methylpheny1)-5-(methoxycarbonyl)-2-(thiazol-2-
y1)-3,6-
dihydropyrimidin-4-yDpiperidin-1-y1)-5-methoxypyriraidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB60 and FAL
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LC-MS (ESI): RT = 1.69 min, mass calcd. for C29H30F2N605S 612.2, m/z found
613.2 [M+Hr.
1E1 NMR (400 MHz, CDC13) 6 8.26 (s, 1H), 8.11 (s, 0.8H), 7.79 (d, J = 3.2 Hz,
0.2H), 7.76 (d, J=
3.2 Hz, 0.8H), 7.48 (d, J= 3.2 Hz, 0.2H), 7.41 (d, J= 3.2 Hz, 0.8H), 7.12 -
7.08 (m, 0.2H), 7.03
(s, 0.2H), 6.96 - 6.86 (m, 1.8H), 5.94 (s, 0.8H), 5.86 (d, J= 2.0 Hz, 0.2H),
4.95 - 4.77 (m, 2H),
.. 4.44 (q, J= 7.2 Hz, 2H), 4.34 - 4.26 (m, 1H), 3.87 (s, 2.4H), 3.86 (s,
0.6H), 3.61 (s, 3H), 3.07 -
2.91 (m, 2H), 2.57 (d, J= 2.4 Hz, 2.4H), 2.43 (d, J= 2.4 Hz, 0.6H), 2.12 -
2.05 (m, 1H), 1.97 -
1.88 (m, 1H), 1.82 - 1.65 (m, 2H), 1.42 (t, J= 7.2 Hz, 3H).
Compound XI-93-3:
Ethyl 2-4-(642-chloro-3,4-difluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-yl)piperidin-1-y1)-5-ethoxypyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB60 and FA12.
LC-MS (ESI): RT = 1.86 min, mass calcd. For C30I-131C1F2N605S 660.2, m/z found
661.2 [M+Hr.
1H NMR (400 MHz, CDC13) 6 8.25 (s, 1H), 8.14 (s, 0.6H), 7.79 (s, 1H), 7.49 -
7.41 (m, 1H), 7.33
(br s, 0.4H), 7.12 - 7.00 (m, 2H), 6.22 (s, 0.6H), 6.09 (br s, 0.4H), 4.97 -
4.79 (m, 2H), 4.45 (q, J
= 6.8 Hz, 2H), 4.33 - 4.22 (m, 0.6H), 4.08 - 4.04 (m, 4.4H), 3.05 - 2.93 (m,
2H), 2.15 - 1.90 (m,
2.4H), 1.81 - 1.67 (m, 1.6H), 1.43 - 1.38 (m, 6H), 1.15 (t, J = 7.2 Hz, 3H).
Compound XI-94-1:
Ethyl 2-4-(642-bromo-3-fluoropheny0-5-(ethoxycarbony0-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yOpiperidin-1-y0-5-(dimethylaraino)pyrimidine-4-carboxylate
(a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB57 and FA20.
LC-MS (ESI): RT = 2.06 min, mass calcd. for C30I-133BrFN704S 685.1, 687.1, m/z
found 688.2
[M+E1] . 1E1 NMR (400 MHz, CDC13) 6 8.33 (s, 0.5H), 8.32 (s, 0.5H), 8.11 (s,
0.5H), 7.80 (d, J =
2.8 Hz, 0.5H), 7.77 (d, J= 3.2 Hz, 0.5H), 7.46 (d, J= 2.8 Hz, 0.5H), 7.42 -
7.40 (m, 1H), 7.25 -
7.18 (m, 1H), 7.16 - 7.14 (m, 1H), 7.07 - 6.99 (m, 1H), 6.28 (s, 0.5H), 6.13
(d, J= 2.4 Hz, 0.5H),
4.97 - 4.81 (m, 2H), 4.44 (q, J = 7.2 Hz, 2H), 4.35 - 4.26 (m, 0.5H), 4.09 -
3.98 (m, 2.5H), 3.04 -
2.90 (m, 2H), 2.74 (s, 3H), 2.73 (s, 3H), 2.24 - 2.06 (m, 1H), 2.02 - 1.94 (m,
1.5H), 1.81 - 1.68 (m,
1.5H), 1.41 (t, J= 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H).
Compound XI-95S:
Ethyl 2-4-(642-bromo-3-fluoropheny0-5-(methoxycarbony1)-2-(thiazol-2-y0-3,6-
dihydropyrimidin-4-yl)piperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
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By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB4 and FA15.
LC-MS (EST): RT = 2.124 min, mass calcd. for C28H28BrFN604S 642.1, 644.1, m/z
found 645.0
[M+11] .
Compound XI-96-1:
Ethyl 2-(4-(6-(2-bromo-4-fluoropheny1)-5-(methoxycarbony1)-2-(thiazol-2-y1)-
3,6-
dihydropyrimidin-4-y1)piperidin-1-y1)-5-methylpyrimidine-4-carboxylate (a
single
stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB4 and FA16.
LC-MS (EST): RT = 1.81 min, mass calcd. for C28H28BrFN604S 642.1, m/z found
643.0, 645.0
[M+H] . 114 NMR (400 MHz, CDC13) 6 8.28 (d, J= 3.6 Hz, 1H), 8.12 (s, 0.5H),
7.80 (d, J= 3.2
Hz, 0.5H), 7.76 (d, J= 3.2 Hz, 0.5H), 7.47 - 7.44 (m, 1H), 7.41 (d, J= 3.2 Hz,
0.5H), 7.34 - 7.28
(m, 2H), 7.02 - 6.93 (m, 1H), 6.18(s, 0.5H), 6.03 (d, J= 2.4 Hz, 0.5H), 5.03-
4.87(m, 2H), 4.42
(q, J= 7.2 Hz, 2H), 4.34 - 4.28 (m, 0.5H), 4.08 - 4.01 (m, 0.5H), 3.62 (s,
2H), 3.61 (s, 1H), 3.07 -
2.95 (m, 2H), 2.28 (s, 1.4H), 2.26 (s, 1.6H), 2.22 - 2.13 (m, 1H), 2.01 - 1.93
(m, 1.5H), 1.81 -
1.65 (m, 1.5H), 1.42 (t, J = 7.2 Hz, 3H).
Compound XI-97-1:
ethyl 2-(4-(6-(2-bromo-4-fluoropheny1)-5-(ethoxycarbony1)-2-(thiazol-2-y1)-3,6-
dihydropyrimidin-4-yl)piperidin-1-y1)-5-(dimethylamino)pyrimidine-4-
carboxylate (a
single stereoisomer)
By utilizing the analogous procedure of Method E, the title compound was
synthesized from compound BB57 and FA21.
LC-MS (EST): RT = 2.051 min, mass calcd. for C301-133BrFN704S 685.1, m/z found
686.2
[M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.40 (d, J= 3.6 Hz, 0.6H), 9.14 (s, 0.4H),
8.50 (s,
0.4H), 8.49 (s, 0.6H), 7.98 - 7.89 (m, 2H), 7.57 (dd, J= 8.4 Hz, 2.4 Hz, 1H),
7.39 - 7.32 (m, 1H),
7.29 - 7.22 (m, 1H), 6.01 (s, 0.3H), 5.92 (d, J = 3.6 Hz, 0.7H), 4.81 - 4.64
(m, 2H), 4.40 -4.34
(m, 2H), 4.22 - 4.13 (m, 0.4H), 4.06 - 3.95 (m, 2H), 3.93 - 3.84 (m, 0.6H),
2.88 - 2.82 (m, 2H),
2.65 (s, 6H), 1.99- 1.61 (m, 4H), 1.34- 1.30 (m, 3H), 1.12- 1.07 (m, 3H).
Part IX: Hydrolysis of dihydropyrimidines of general formula VII and general
formula
XI to the final products of general formula I and general formula II,
respectively.
Compound I-1-C: (exemplified with Method C)
(trans)-2-4-(6-(2-Chloro-3,4-difluorophenyl)-5-(methoxycarbony0-2-(thiazol-2-
y1)-
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3,6-dihydropyrimidin-4-y0cyclohexyl)oxazole-4-carboxylic acid (a single
stereoisomer)
To a solution of (trans)-methyl 2-(4-(6-(2-chloro-3,4-difluoropheny1)-5-
(methoxycarbony1)-2-(thiazol-2-y1)-3,6-dihydropyrimidin-4-
y1)cyclohexyl)oxazole-4-
carboxylate VII-1-X (120 mg, 0.198 mmol, 95 % purity) in tetrahydrofuran (2
mL),
methanol (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (17.0
mg, 0.397 mmol) at 0 C. After stirred at 0 C for 2 hours, the mixture was
diluted
with water (10 mL) and acidified to pH 5 ¨ 6 with 1 M hydrochloride aqueous
solution. The aqueous layer was extracted with ethyl acetate (10 mL) for three
times.
The combined organic layers were washed with brine (10 mL), dried over
Na2SO4(s)
and filtered. The filtrate was concentrated to give a residue, which was
purified by
Prep. HPLC (Column:Waters X-brige C18 (5 pm 19 * 150 mm), Mobile Phase A:
water (0.1 % ammonium bicarbonate), Mobile Phase B: acetonitrile, UV: 214 nm,
Flow rate: 15 mL/min, Gradient: 5 - 70 % (%B)) to give the title compound
(69.5 mg,
61 % yield, 98.4 % purity) as yellow solids. LC-MS (ESI): RT = 3.683 min, mass
calcd.
for C25H21C1F2N405S 562.1, m/z found 562.9 [M+1-11 . 11-1 NMR (400 MHz, CD30D)
6
8.26 (s, 1H), 7.92 (d, J= 2.8 Hz, 1H), 7.75 (d, J= 3.2 Hz, 1H), 7.26 - 7.18
(m, 2H),
6.11 (s, 1H), 4.10 - 3.74 (m, 1H), 3.60 (s, 3H), 3.03 - 2.90 (m, 1H), 2.33 -
2.18 (m, 2H),
2.10- 1.66 (m, 6H).
Similarly utilizing the above-mentioned analogous procedures of ester
hydrolysis,
the following acids could be prepared; these are indicated in Table 2 below,
thereby
related to the corresponding esters, which are listed with reference to their
compound numbers ("Cpd.#").
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Table 2:
Ester Acid Ester Acid
Cpd.# Cpd.#
VII- 1-X F VIE-2-Y F
F F
0 CI 0 CI
*
0 N 0 N
I I I Ks
trans H I j
0 N trans 0 H \ I
_i
N
¨IN S-N
0 04
OH
OH
Compound I-1-C
Compound I-2-D
VII-3-H F Vil-4-N F
0
*
0 CI
0 N
,01 s 0 N
trans H
0 N 40,,01 N -iN
H)
¨INI 0 H Is /
04 $-1N
OH 04
Compound I-3-D OH
Compound I-4-B
VII-5-Q F VII-6-Q F
0 CI
* 0
0 N
N
, 0
,
0 $-1N N
4
04
OH
OH
Compound I-5-B
Compound I-6-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
1I-7-N F
VIE-8-N F
F F
0 CI 0 CI
0 N F
,s, I * 1 0 N
0. iim 1 N
N
0 N F 0 H Is _.)
O 0
OH OH
Compound I-7-B Compound I-8-B
VII-9-F F VIE-10-P F
0 CI
* 0 CI
0 N
,,,\ I s /0 N
0 110 N H \ I j
N 0 I s
" N
trans H
0 N
OH 0
OH
Compound I-9-B
Compound I-10-C
WI-11- F VIE- 12-P F
Q 0
. 0
N
,so 1 N) /0 N
le r\s
H\) I Ks
0 trans H \ I j
0 N
OH 0
OH
Compound I-11-B
Compound I-12-C
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Ester Acid Ester Acid
Cpd.# Cpd.#
VII-13-P F VII-14-N F
F F
and
VII-13- a o 01
N 0
I IN
I NK,S 0 S
H 1\ j trans
' HN NI j
0 N 0
IN S¨ IN
0 0
OH OH
Compound I-13-C Compound I-14-B
Compound I-13-D
VII-15- F
VII-16-N F
M
el F F
0 CI 0 el CI
0 N o 1 I N N _s
trans H s-)
Oil \N--jss 0 TL)
Compound I-15-A \
0
HO
Compound I-16-B
VII-17- F VII-18-M F
M
0 = CI 0 1.1 Br
o 0 1 N
I _s
1,1,1S
0 PI 11 j te 11 T\ j
0 \O
HO HO
Compound I-17-A Compound I-18-A
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Ester Acid Ester Acid
Cpd.# Cpd.#
VII-19- F F
VIE-20-N
N I.
0 Br 0 I. CI
0 N 0 N
0Th N 0
1 k _s 1 k _s T j = 0 1, ,
N - õ,. 0 õ==
\ gl \ N
0 0
HO HO
Compound I-19-B Compound I-20-B
VII-21- F VIE-22-S F
F
N
0 1.1
0 0 CI
N
N -
igl 0 trans H " j
N
\ N
0
HO OH
Compound I-21-B 0
Compound I-22-B
VII-23- F VIE-24-M F
Y
el F F
0 CI 1 0 CI
0 N KO N
1 s ,01 Ks
trans H \ 1 j trans
0\,== N 0 N
\ gl \ IN
0
HO 0
Compound I-23-B OH
Compound 1-24
Compound I-24-A
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Ester Acid Ester Acid
Cpd.# Cpd.#
VII-25- F VIE-26-8 F
1401 F F
N
0 CI 0 = CI
0
0 N N
I 00 1 *
S S
le T1 ) . IT,
lj
N -
0 õ,= N
0
OH
0 Compound I-26-B
OH
Compound I-25-B
VII-27- F
VIE-28-N F
F F
R
0 N 0 N
2
. IT - 0 N
N
0õ, s= HO--/(_ trans H N\ j
\ 11µµ N
' N 1V¨
HO
Compound I-28-B
o
Compound I-27-B
F F
VII-29-P VIE-30-
01 F
0 CI 0 CI
0 N 0 N
1 NS I Ir
trans H IN__)
trans H NI)
0 r----I
0 N ----'
HO 1\1¨
HO
Compound I-29-C
Compound I-30-D
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Ester Acid Ester Acid
Cpd.# Cpd.#
F F
VII 1II-31 -32-NF
F
o a
0 CI
0 N
I s 0 N
HO N N / I
trans H N'_____
Compound 1-31 11
(:)
OH
Compound I-32-B
F F
VII-33- VIE-34
F F
0 CI
0 CI
0 N
0 N
1 Kr 1 N jr s
õ S
=' N 0 H ri
j
trans H 11.__)
HO)--.0---N
0
1\1--
HO Compound 1-34
Compound I-33-C
F
WI-35-P VII-36-N F
F F
0 CI 0 el CI
0 N 0 N
I 11 I js
\ trans H 1 j trans H \ 1
j
N N N o= N
N\ I
0 0
OH OH
Compound I-35-C Compound I-36-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
VII-37- F
VIE-38-N F
is F F
4C
1 o ci o a
KO N 0
I N I j1\1
OP II 1?
trans H \ )
NOsµµ. N- ===/ N
_IN
1\1
0 0
OH OH
Compound I-37-C Compound I-38-B
F
VII-39- F Vil-40-M
F F
N
and o ci o ci
WI-39-P
0 N 0
1 IN
. 1 s
HO 0 N h trans H N.)
H j N
N I
/ N HO N
¨N
0
Compound I-39-B (cis-)
Compound I-40-A
Compound I-39-C (trans-)
WI-41- F VIE-42-11 F
F F
N
o ci o el ci
0 N /0 N
' N
trans H \ j
N
5¨IN /0 õ, = ENII
S CI TIN --
i
N \ I
HOOC 0
Compound I-41-B OH
Compound I-42-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
VII-43- F
VIE-44-X F
F F
N
o a 1 o
ci
o
I IN cc N 0 N
H-1s ,\I s
' H N,)
N trans H II)
N
0'
0 0
0
OH OH
Compound I-43-B Compound I-44-A
VII-45- F VIE-46-P F
F io F
R
o a
0 ci
0 N
0
I IN 1 NS
N
S N ,. trans H
N j
transNH---
H 1) 0 HO 1
p N
N I
)-N
Compound I-46-C
0/
OH
Compound 1-45
VII-47- F VIE-48-B F
F
N
0 Br 0 = CI
0 N 0 N
I I I j1 N s _
trans H N j trans H TN)
N
H C
1 3
N
0
0 OH
HO
Compound I-47-D Compound I-48-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
F F
VII-49-A VII-50-A
F
0 1.1 CI 0 el CI
o o
N N
1 s 1 N
trans H Nd trans H NI j
,
0 r\j''' 1\1 ,=
N s
0 1
HO)-N
HON
Compound I-49-A Compound I-50-A
XI-1-B F
F
0
o 1
1\1)S
H) N N
0 1 y
HON
Compound II-1-B
FA2IIIX F XI-3-S F
and o
0
B o
0 N
B2 1 1\1
I s NS H NI)
N N N
H \ I j o 1 y
N N N
HON
1 1
N Compound II-3-B
0 OH
Compound II-2-B
XI-4-B F XI-5-B F
0
0
. 0 N
0 N I N S
I S H 11)
N I\L N N
H
N N N 1 Y
Th- ,N
II
N
0 OH
0 OH
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Ester Acid Ester Acid
Cpd.# Cpd.#
Compound II-4-B Compound II-5-B
XI-6-B F
FA5 and F
0 BB2
0 N 0
1 S
N
H NJ 0 N
N N I s
0 1 y
HO H ti j
Ny N N
Compound II-6-B
1 N
0 OH
Compound II-7-B
FAG and F XI-9-B F
BB2- 1
0 ci o a
o o
N N
I s 1 NI Ks
N
H II) H \\ j
N N 1\1 N N
1 1 N N
N
0 OH
0 OH
Compound II-9-B
Compound II-8-B
XE- 10- 1 F
FA7 F
o a and
BB53
0 N 0 CI
1 KiS
N
CDsN H ) 0 N
1 )s
N N II
HO/ -.-N HN'ar,N H II j
/ N
Compound II- 10-B
0
Compound II- 1 1-X
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Ester Acid Ester Acid
Cpd.# Cpd.#
FA7 F XI- 13-S F
and
BB5 o a o ci
o N
I s 0 N
1 jls N ,
N H 1 1 j
N N N
0 r
N
Compound II-12-B
0
OH
Compound II-13-A
XI-14-A F XI-15-S F
0 CI
0 CI
0 N
o 1
N S
1 N
S H NrN )
rj
N
H 11 0
N IN N j
HON
I
N Compound II-
15-A
0 OH
Compound II-14-A
XI-16-B F
FA7 and F
BB7
o . a o a
o o N N
I s 1 s
N N
H 1 j H 1)
N N N I\1 N N
1 I 1 'r
HOy N HOI_N
0 0
Compound II-16-B Compound II-
17-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
XI-18-S F XI-19-2 F
0 CI 0 CI
o 0 N
N I I s )s N
1
N L)
H II) 0
H
\S ,N N
ON N \ ff
HO/ \1--N
Compound II-19-A
HO
0
Compound II-18-B
FA8 F XI-21-B F
and
BB54 ci o a
1 0
0 N 1 NN J
I _1
S H is j
IT) '
N 1\1 N
0 1
Ny N
HON
1 N Compound II-21-B
0 OH
Compound II-20-B
FA9 and F XI-23-B F
BB2-1 o a
0 ci
0 N
1 js 1\11%N
N1
N N N
H \ 1 j H
0 1 y
N N
HO)-.N
I N
Compound II-23-B
0 OH
Compound II-22-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
F F
XI-24-B F XI-25-B
F
0 CI
0 CI
0 N
I NS 0 N
H r1 1 s
HO I NI:Nri N N il
0 ON ) il j
N
Ha H
cis \-----c_ II
0 HO N
Compound II-24-B Compound II-
25-B
XE-26-B F FA10 F
F F
and
o ci BB2-1 o oi
0 N
I s 0 N
I * N
N
H
Ny N N N N H s&
I I I
CI ' m . N
0 OH
0 OH
Compound II-26-B
Compound II-27-B
F F
XI-28-6 XI-29-S
F F
0 CI 0 CI
0 N
1 s 0 N
N
N 1 N N
H NI j
N N H \
)(:) N S -1
0 1 y
HO
HO)" N
Compound II-28-B
Compound II-29-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
XI-30-B F
XI-31-B F
F F
0 CI 0 CI
o N o
I I s N s N
H N N
0 S,y,,,N 11_1
H II)
N
HO' ¨N F3C-____
Compound II-30-B
0
OH
Compound II-31-B
XI-32-B F XI-33-B F
F F
0 CI 0 CI
o N 0 N
I s IN
N
H 11 j Ill
SN N ON S
__\--IIV
UHO 0
0 OH
Compound II-32-B Compound II-33-B
XI-34- F XI-35-5R F
F F
1OF
1 o a
. a
0 N 1 0
1 s 0 1 N
s
N
H \\ 2 N
N, N . N NH) 1\
1 Y N
ON 0
OH
OH
Compound II-34-F
Compound II-35-A
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Ester Acid Ester Acid
Cpd.# Cpd.#
F F
XI-36-S XI-37-2 tiic
F F
0 . CI
0 CI
0 N
1 jr 0 N
S
N I
HON H NO N 1, S
1 I N H 11 j
N
HON
0 N
Compound II-36-B
0 OH
Compound II-37-B
XI-38-3 F XI-39-S F
F F
0
0 N
1 )s 0 N
1 s
N
1\1
H II j N
F3CN N N H TIV) N
1
F3C1
0 OH
0 OH
Compound II-38-B
Compound II-39-B
XI-40-B F XI-41-B F
F F
0 CI 0 CI
0 N /0 N
I I
S S
N N
H \ I ..) H \ I )
1\1 N N 1\1 N N
1 I
F
0 OH HO 0
Compound II-40-B Compound II-41-
B
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Ester Acid Ester Acid
Cpd.# Cpd.#
XI-42- F
XI-43-1 F
F F
3B
o ci o ci
1
0 N 0 N
1 s 1 s
CI N N
NN= N 1\1 N N
0- HO
OH 0
Compound II-42-B Compound II-43-B
FA12 F
F
XI-45-B F
F
and
BB49 o ci o fCI
0 N 0 N
I s 1 js
N N
F3Cr N = N 1\1 N N
1
0 N H (:)
F
OH 0
Compound II-44-B Compound II-45-B
XE-46-S F
XI-47-3 F
F F
0 CI 0 CI
*
0 N N
I )s 0
1s
N
N = N H 11 j
NNN
Oy-----,N, N
o N
OH
Compound II-46-B HO 0
Compound II-47-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
XI-48-B F
XI-49-B F
F F
0 . CI 0 CI
0 N
1 0 N Kr s 0 N
1 s IVJ N
H
N N H NJ HO)-1 NN
le 1
HOr Ni
Compound II-48-B o
Compound II-49-B
XI-50-S F
FA 12 F
F F
and
1 o cl BB22 o CI
KO N 0 N
1 s 1 NH
NS
s
HO\ ,(DN H \ I j
N 1 j
N N HN
0
-----IIV 1
HON
Compound II-50-B o
Compound II-51-B
XI-52-S F XI-53-S F
F F
0 CI 0 CI
0 N 0 N
1 Kr s 1 Kr 0 N 0 N s
H IV) H IV)
N
H0 H0). N -
N N N N
1
0
Compound II-52-B Compound II-
53-B
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Ester Acid Ester Acid
Cpd.# Cpd.#
XI-54-S F
FA12 F
F F
and
o a BB55
0 N
0 N 1 ji
1 )r S
S
H 11 Ni j
N
N N NI j H9 ' ' "
1 1 N O Hy=
0 OH OH
Compound II-54-B Compound II-55-B
XI-56-B F XI-57-S F
F F
0 CI 0 CI
* *
N
IN I N 1s
H s / 0 N N N
--- ------ --*----
,N N H
I
I N N
H
0 OH O 0
Compound II-56-B Compound II-57-B
XI-58-S F XI-59-B F
F F
1 0
* CI 0
* CI
0 N 0 N
- H 1 1 N 1,s
...)N ' 1\1 N
N
Ny N I Y
1 N
N
,...-
H
0 OH O 0
Compound II-58-B Compound II-59-B
322
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 322
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
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