Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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D~ L~d vv~ im; dines and Uses Thereof
Throughout this application, various references are
referred to within parenthe9es- Disclosures of these
publications in their entireties are here~y
incorporated by reference into this application to more
fully describe the state of the art to which this
invention pertains.
Bach4~,d of the In~ention
The designation ~lA~' is the appellation recently
approved by the IUPHAR Nomenclature Co~mittee for the
previously designated "~c" cloned subtype as outlined
in the 1995 Receptor and Ion Channel Nomenclature
Supplement (Watson and Girdlestone, 1995). The
designation a~A is used throughout this application and
the supporting tables and figures to refer to this
receptor subtype. At the same time, the receptor
formerly designated ~lA was renamed ~lD. The new
nomenclature is used throughout this application.
Stable cell lines expressing these rece~tors are
described hereini however, these cell lines were
deposited with the American Type Culture Collection
~ATCC) under the old nomenclature (infra~.
Benign ProstatiC Hyperplasia (BPH), also called Benign
Prostatic Hypertrophy~ is a progressive condition which
is characterized by a nodular enlargement of prostatic
tissue resulting in obstruction of the urethra. This
results in increased frequency of urination, nocturia,
a poor urine stream and hesitancy or delay in starting
the urine flow. Chronic consequences of EPH can
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include hypertrophy of bladder smooth muscle, a
decompensated bladder and an increased incidence of
urinary tract infection. The specific biochemical,
histological and pharmacological properties of the
prostate adenoma leading to the bladder outlet
obstruction are not yet known. However, the
development of BPH is considered to be an inescapable
phenomenon for the aging male population. BPH is
observed in approximately 70~ of males over the age o~
70. Currently, in the United States, the method of
choice for treating BPH is surgery (Lepor, H., Urol.
Clinics North Amer., 17, 651 ~1990)). Over 400,000
prostatectomies are performed annually (data from
1986). A medicinal alternative to surgery is clearly
very desirable. The limitations of surgery for
treating BPH include the morbidity rate of an operative
procedure in elderly men, persistence or recurrence of
obstructive and irritative symptoms, as well as the
significant cost of surgery.
~-Adrenergic receptors (McGrath, et. al. Med. Res.
Rev., 9, 407-533, 1989) are specific neuroreceptor
proteins located in the peripheral and central nervous
systems on tissues and organs throughout the body.
These receptors are important switches for controlling
many physiological functions and, thus, represent
important targets for drug development. In fact, many
~-adrenergic drugs have been developed over the past 40
years. Examples include clonidine, phenoxybenzamine
and prazosin (treatment of hypertension), naphazoline
(nasal decongestant), and apraclonidine (treating
glaucoma). ~-Adrenergic drugs can be broken down into
two distinct classes: agonists (clonidine and
naphazoline are agonists), which mimic the receptor
activation properties of the endogenous
neurotransmitter norepinephrine, and antagonists
(phenoxybenzamine and prazosin are antagonists), which
act to block the effects of norepinephrine. Many of
these drugs are effective but also produce unwanted
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--3--
side effects (for example, clonidine produces dry mouth
and sedation in addition to its antihypertensive
effects).
During the past 15 years a more precise understanding
of ~-adrenergic receptors and their drugs has evolved
~ through increased scientific scrutiny. Prior to 1977,
only one ~-adrenergic receptor was known to exist.
Between 1977 and 19~8, it was accepted by the
scientific community that at least two ~-adrenergic
receptors--~l and ~2--existed in the central and
peripheral nervous systems. Since 1988, new techniques
in molecular biology have led to the identification of
at least six ~-adrenergic receptors which exist
throughout the central and peripheral nervous systems:
~lA (new nomenclature), ~ lD (new nomenclature), ~2A~
~2~ and ~2C (Bylund, D.B., FASEB J., 6, 832 (1992)). In
many cases, it is not known precisely which
physiological responses in the body are controlled by
each of these receptors. In addition, current
~-adrenergic drugs are not selective for any particular
~-adrenergic receptor. Many of these drugs produce
untoward side effects which may be attributed to their
poor ~-adrenergic receptor selectivity.
Since the mid 1970's, nonselective ~-antagonists have
been prescribed to treat BPH. In 1976, M. Caine, et
al. (Brit. J. Urol., 48, 255 (1976)l, reported that
the nonselective ~-antagonist phenoxybenzamine was
useful in relieving the symptoms of BPH. This drug may
produce its effects by interacting with ~-receptors
located on the prostate. However, this drug also
produces significant side effects such as dizziness and
asthenia which severely limit its use in treating
patients on a chronic basis. More recently, the
~-adrenergic antagonists prazosin and terazosin have
also been found to be useful for treating BPH.
.... . ..
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--4--
However, these drugs also produce untoward side
effects. It has recently been discovered that the ~lA
receptor is responsible for mediating the contraction
of human prostate smooth muscle (Gluchowski, C. et.
al., WO 94/10989, 1994; Forray, C. et. al., Mol.
Pharmacol. 45, 703, 1994). This discovery indicates
that the ~lA antagonists may be effective agents for the
treatment of BPH with decreased side effects. Further
studies have indicated that the ~lA receptor may also be
present in other lower urinary tract tissues, such as
urethral smooth muscle (Ford et al. Br. J. Pharmacol.,
114, 24P, (1995)).
This invention is directed to dihydropyrimidine
compounds which are selective antagonists for cloned
human ~lA receptors. This invention is also related to
uses of these compounds for lowering intraocular
pressure (Zhan, et. al. O~hthalmol. Vis. Sci., 34 Abst.
#1133, 928, 1993), inhibiting cholesterol synthesis
(D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13
(Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia,
impotency (Milne and Wyllie, EP 0 459 666 A2, 1991),
sympathetically mediated pain (Campbell, WO 92/14453,
1992), cardiac arrhythmia (Spiers, et. al.,J
Cardiovascular Pharmacol., 16, 824-830, 1990) and for
the treatment of any disease where antagonism of the ~lA
receptor may be useful.
. _
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_5_
Summarv of the Invention
This invention is directed to dihydropyrimidine
compounds which are selective antagonists for human ~A
receptors. This invention is also related to uses o~
these compounds for lowering intraocular pressure,
inhibiting cholesterol synthesis, relaxing lower
urinary tract tissue, the treatment of ~enign prostatic
hyperplasia, impotency, cardiac arrhythmia and for the
treatment of any disease where antagonism of the ~lA
receptor may be useful. The invention further provides
a pharmaceutical composition comprising a
therapeutically effective amount of the above-defined
compounds and a pharmaceutically acceptable carrier.
,
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-6-
Detailed Description of the Invention
The present invention is directed to compounds having
the structure:
1 1 1 N~ 4 R~ X R4 ~ ~ ~R4
R2 N X ~ or X ~ ~ ;
3 , R3 R R3
wherein A is
~ Y4 1 ~ y4
V2~ Yl ~
Yl- ~\ V r = N
/ ' X"'
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W097/42956 PCT~S97/08335
wherein each of Yl, Y2, Y3, Y4 and Ys is
independently -H; straight chained or branched
Cl- C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2- C7 alkenyl or
alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl~
polyfluorocycloalkyl or cycloalkenyl; -F, -Cl,
-Br, or -Ii -NO2i -N3; -CN; -OR3, -OCOR3, -COR3,
-CONHR3, -CON(R3)2, or -COOR3; or any two of Yl, Y2,
Y3, Y4 and Y5 present on adjacent carbon atoms can
constitute a methylenedioxy group;
wherein X is S; O; or NR3;
wherein Rl is -H; -NO2; -CN; straight chained or
branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyli straight chained or branched C2-C7
alkenyl or alkynyl;. C3-C7 cycloalkyI,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; - N ( R3 ) 2 i - OR3; - ( CH2 ) pOR3; - COR3;
2 O COzR3; or - CON ( R3 ) 2i
wherein R2 is -H; straight chained or branched
Cl-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight
2 5 chained or branched C2- C7 alkenyl or alkynyl; C3 - C7
cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; C3-Clo
cycloalkyl-Cl-C1O-alkyl, C3-Clo cycloalkyl-Cl-C1O-
monofluoroalkyl or C3-Clo cycloalkyl-Cl-Clo~
polyfluoroalkyl; - CN; - CH2XR3, - CH2X ( CH2 ) pNHR3,
- ( CH2 ) nNHR3 ~ - CH2X ( CH2 ) pN ( R3 ) 2 ~ - CH2X ( CH2 ) pN3, or
- CH2X ( CH2 ) pNHCXR7; or - OR3;
wherein each p is independently an integer from 1
to 7; wherein each n is independently an integer
~ from 0 to 5;
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-8-
wherein each R3 is independently -H; straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; c3-c7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R4 is
R ~ R6 R
R m~ V ~ l]m
m[~V
R7 R6
wherein Z' is (CH2)o~ CO, (CH2)oCO~ or CO(CH2)o;
wherein each V is independently O; S; CH2; CRsR7;
C (R7) 2; or NR7;
wherein each m is independently an integer from 0
to 3; wherein o is an integer from 1 to 3;
wherein each R is independently -H; -F; straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; -N (R3) 2; -NO2; -CN; -CO2R3; or
-OR3;
wherein R5 and R7 each independently may be -H; F;
C1; Br; I; -COR3; -CO2R3; -CON ( R3) 2; -CN; -NO2;
-N (R3)2; -OR3; -SR3; - (CH2)pOR3; - (CH2)pSR3; straight
chained or branched C~-C7 alkyl, aminoalkyl,
carboxamidoalkyl; straight chained or branched
C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or
cycloalkenyl; wherein the alkyl, aminoalkyl,
carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or
cycloalkenyl may be substituted with one or more
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_g_
aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with -F, -C1, -Br, -I, -NO2, -
CN, -OR3, -SR3, Cl-C3 alkyl, or carboxamido; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more -F, -C1, -Br,
-I, COR3, CO2R3, -CON(R3)2, -CN, -NO2, -N~R3)2, -OR3,
-SR3, (CH2)~OR3, ~CH2)0SR3; straight chained or
branched C~- C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; and
wherein each R6 is independently -H; straight
chained or branched C1-C7 alkyl, hydroxyalkyl,
aminoalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C,
alkenyl or alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; or -OR3;
or a pharmaceutically acceptable salt thereof.
The invention further provides for the (+) enantiomer
of any of the compounds described herein which is a cis
isomer or a trans isomer. The invention also provides
for the ~-) enantiomer of any of the compounds
described herein which is a cis or a trans isomer.
The compounds of the present invention are preferably
at least 80% pure, more preferably 90% pure, and most
preferably 95% pure.
Ten fold selectivity differences are a minimum, but one
3~ skilled in the art will appreciate that compounds can
be found that collectively have almost infinitely
variable selective profiles. Compounds collectively
having all possible combinations of selectivities are
intended within the scope of this invention, provided
,
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--10--
that each of these compounds has at least ten-fold
greater affinity for the a,A receptor over the a~ and/or
a~D receptors.
S In one embodiment of the present invention the compound
has the structure:
m[ll~ \V
R7 R6
In one embodiment of the present invention Z' is CO and
n is 0.
20 In another embodiment of the present invention the
compounds have the structure:
o~o
~ ~ ~ N~
COOCH3
The invention provides for compounds having the
following structures:
~P
o ~ O
H3C~o~NJ~N~/~N~ N~2
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~ F
o ~ ~ N~ ~N
H3C H3C
0 F
~F
~ ~ o
'O ~ ~N~,CN
H
[~F
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-12-
~3,,F
H,C~ N ~ ~J3
and
0 F~ ~,F
H3C~o ' ,I' ~,N N~
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-13-
The present invention is also directed to compounds
having the structure:
A
A O A
R 2 N ~ XX ~ R or
R3 R3 R R3
wherein A is
~ ~ Y4
Y5
y
2 ~ N~ Z ~ N ~ ,-Y3
Yl ~ NH
Yl I N ~ ~ / ~ N
~ ' X
wherein each of Y~, Y2, Y3, Y4 and Ys is
independently -H; straight chained or branched
C,-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or
alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl,
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-14-
polyfluorocycloalkyl or cycloalkenyl; -F, -Cl,
-Br, or - I; - NO2 i - N3; - CN i - OR3, - OCOR3, - COR3,
-CONHR3, -CON tR3) 2, or - COOR3; or any two of Yl, Y.,
Y3, Y4 and Ys present on adjacent carbon atoms can
constitute a methylenedioxy group;
wherein X is S; O; or NR3 i
wherein R, is -H; -NO2; -CN; straight chained or
branched Cl-C, alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; C3- C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyli - N ( R3 ) 2 i - OR3; - ~ CH2 ) pOR3; - COR3;
CO2R3; or - CON ( R3 ) 2 i
wherein R2 is -H; straight chained or branched
C~-C, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C, alkenyl or alkynyl; C3-C7
cycloalkyl, monof luorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; C3-Clo
cycloalkyl-C,-C10-alkyl, C3 - Clo cycloalkyl-C1-CIc-
monofluoroalkyl or C3-Clo cycloalkYl-Cl-clo~
polyfluoroalkyl; - CN; - CH2XR3, - CH2X ( CH2 ) pNHR3,
- ( CH2 ) nNHR3, - CH2X ~ CH2 ) pN ( R3 ) 2 ~ - CH2X ( CH2 ) pN3, or
- CH2X ( CH2 ) pNHCXR,; or - OR3;
wherein each p is independently an integer from 1
to 7; wherein each n is independently an integer
from 0 to 5;
wherein each R3 is independently -H; straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyli
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-15-
wherein R4 is
R ~ / 5
m
/ Z ~ N
R7
~ ~ N
R7
Y
0 ~ L
R ~ / R6
/ Z
l ~ V
R7
SU~S 111 ~JTE SHEET (RULE 26)
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- 16-
Z [ ] n [ ~ [ ] n N V R5
R n
R R ~ / R5
m
--C H 2 [I ~]n Z [I ] N
R7
2 0 R R ~Yl
~ N ~ Y2
2 5 R m D oY3
R R
3 0 Z ~ ] ~ X ~ ] R8
R R
3 5 z ~ R 8
SUBSTITUTE SHEET (RULE 26)
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-17-
R R ~ , R5
Z- ~ W ~ N R6
R7
or
R ~ R6
~]n N ~ V~ R]m
m [ ~ V
R7 R6
wherein Z is C2-C7 alkenyl or alkynyl; CH2; O; CO;
CO2; CONR3; S; SO; SO2; or NR3;
wherein Z' is (CH2)o~ CO, (CH2)oCO~ or CO(CH2)o;
wherein each D is independently CH2; O; S; NR3; CO;
or CS;
wherein W is C=O; C=NOR3; substituted or
unsubstituted phenyl, pyridyl, thiophenyl,
furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,
imidazolyl, benzfurazanyl, benzfuranyl or
benzyimidazolyl, wherein the phenyl, pyridyl,
thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl,
indolyl, imidazolyl, benzfurazanyl, benzfuranyl or
benzyimidazolyl is substituted with -H, -F, -Cl, -
Br, -I, -NO2, -CN, straight chained or branched
C,-C7 alkyl, straight chained or branched C,-C7
monofluoroalkyl, straight chained or branched C,-C7
polyfluoroalkyl, straight chained or branched C2-C7
alkenyl, straight chained or branched C2-C~
SIJ~ 111 UTE SHEET (RULE 26)
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W097/42956 PCT~S97108335
-18-
alkynyl, C3- C7 cycloalkyl, C3- C7
monofluorocycloalkyl, C3 ~ C7 polyfluorocycloalkyl,
C3-C7 cycloalkenyl, -N(R3)2, -OR3~ -COR3, -CO2R~ or
-CON~R3) 2i
wherein each V is independently O; S; CH2; CRsR,;
C (R7) 2i or NR7; provided that when V is CRsR7 the
rem~; ni ~g carbons on the ring may only be
substituted with R
wherein each m is independently an integer from 0
to 3; wherein o is an integer from l to 3;
wherein each R is independently -H; -F; straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; -N(R3)2i -NO2; -CN; -CO2R3; or
- OR3;
wherein Rs is aryl or heteroaryl substituted with
one or more of F; Cl; Br; I; COR3; C02R3; ~ CON( R3 ) 2 i
CN; - NO2; ~ N(R3) 2 i ~ OR3, ~ SR3; ( CH2) oOR3 i ( ~H2) CSR3;
straight chained or branched Cl- C7 alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyli straight chained or branched
C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R6 is independently -H; straight
chained or branched Cl- C7 alkyl, hydroxyalkyl,
aminoalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyli straight chained or branched C2-C7
alkenyl or alkynyl; c3 - c7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; or -OR3;
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W097/42956 PCT~S97/08335
-19--
wherein R, is aryl or heteroaryl substituted with
one or more of F; Cl; Br; I; COR3; CO2R3; -CON(R3)2;
CN; -NO2; -N(R3)2; -OR3, -SR3; (CH2)0OR3; (CH2)0SR3;
straight chained or branched Cl-C, alkyl,
~ 5 monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched
C2-C, alkenyl, C2-C7 alkynyl, C3-C, cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; and
wherein ~ is -H; substituted or unsubstituted
benzyl, benzoyl, phenyl, pyridyl, thiophenyl,
furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,
imidazolyl, benzfurazanyl, benzfuranyl,
benzimidazolyl or 2-keto-1-benzimidazolinyl,
wherein the benzyl, benzoyl, phenyl, pyridyl,
thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyI,
indolyl, imidazolyl, benzfurazanyl, benzfuranyl,
benzimidazolyl or 2-keto-1-benzimidazolinyl is
substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN,
straight chained or branched Cl-C, alkyl, straight
chained or branched Cl-C,monofluoroalkyl, straight
chained or branched Cl-C7polyfluoroalkyl, straight
chained or branched C2-C7 alkenyl, straight chained
or branched C2-C, alkynyl, C3-C7 cycloalkyl, C3-C7
monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl,
C3-C7 cycloalkenyl, -N(R3) 2~ -OR3, -COR3, -CO2R3, or
-CON(R3) 2; substituted or unsubstituted straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; substituted or unsubstituted
straight chained or branched C2-C7 alkenyl or
alkynyl; C3-C, cycloalkyl or cycloalkenyl, wherein
the alkyl, monofluoroalkyl, polyfluoroalkyl,
alkenyl, alkynyl, cycloalkyl or cycloalkenyl is
substituted with -H, phenyl, pyridyl, thiophenyl,
furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,
imidazolyl, benzfurazanyl, benzfuranyl,
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-20-
benzimidazolyl, -N(R3) 2, -NO2, -CN, -CO2R3, -OR3;
~ = Y3 ~ R.j, or N ~ R7
or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention the
compounds have the following structure:
[ ~ " R5
~ ~ X 7
R3
In a further embodiment of the present invention the
compounds have the structure:
y3
Yl ~ 5 R [ ~ -~ ~R5
~ ~ ~ N V
R2 N X
R3
SU~:i 111 ~JTE SHEET (RULE 26)
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-21-
In one embodiment of the present invention the
compounds have the structure:
o o R / R
R3 1 N N ~ N v
R2 N X
R3
wherein V is selected from CR5R7 or NR7 and p is
selected from 1-3.
In a preferred embodiment of the present invention the
compounds have the following structures:
p
20 ~ F
O ~ O
H ~ N ~ O ' "~'~
H
S~CH3
[ ~ ~,p
N,< ~ ~ 5'
and
SUv~lllUTESHEET(RULE26)
-
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-22 -
II~C'~ N~ o ~
_ _
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-23-
The present invention is also directed to compounds
having the structure:
A A
Rl ~ ~R3 R1~N ~ R2
wherein A is
~ 3 ~ ~ ~ Y4
Y5
Y~ NH
Y2 ~/ 3
Y~, Y3
or Y~
wherein each of Y~, Y2, Y3, Y4 and Y5 is
independently -H; straight chained or branched
C~-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or
alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl,
SUBSTITUTE SHEET (RULE 26)
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-24-
polyfluorocycloalkyl or cycloalkenyl; -F, -Cl,
-Br, or - I; - NO2 i - N3; -CN; - OR4 ~ ~ OCOR4 ~ ~ COR
-CONHR4, -CON (R4) 21 or -COOR4; or any two of Yl, Y~,
Yl ~ Y4 and Ys present on adjacent carbon atoms can
constitute a methylenedioxy group;
wherein X is S; O; or NR4;
wherein B is -H; straight chained or branched C.-C7
alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or
thioalkyl; straight chained or branched C2 - C7
alkenyl; - SCH2C6H40R4; ~ ~ CH2 ) nC6Hs; ~ CH2X ( CH2 ) nNHR4;
~ ( CH2 ) nNHR4; or - OR4;
wherein Rl is -H; -NO2; -CN; straight chained or
branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C,
alkenyl or alkynyl; C3-C, cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R4) 2i -OR4; ~ (CH2) pOR4; -COR4;
CO2R4; or - CON ( R4 ) 2;
wherein R2 is -H; straight chained or branched
Cl-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C7 alkenyl or alkynyl; C3-C7
cycloalkyl, monof luorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; c3-clo
cycloalkyl-Cl-C,O-alkyl, C3-Clo cycloalkyl-Cl-C1O-
monofluoroalkyl or C3-clo CyC loalkyl-C1-C10-
polyfluoroalkyl; - CN i ~ CH2XR4, ~ CH2X ( CH2 ) pNHR4,
- ( CH2 ) nNHR4 1 - CH2X ( CH2 ) pN ( R4 ) 2 1 ~ CH2X ~ CH2 ) pN3 ~ or
~ CH2X ( CH2) pNHCXR7; or - OR4;
wherein each p is independently an integer from 1
to 7; wherein each n is independently an integer
from 0 to 5;
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-25-
wherein R3 is
R ~ R5
/ R
R7
R ~ / Rs
~ 6
20~ ~t ~ ¦ : Y3
301~ , v
R7
SUBSTITUTE SHEET (RULE 26)
CA 02253862 1998-11-09
WO 97142956 -2 6- ~CT/US97/08335
S R ~~ 6
R7
R R ~3~ ~R5
CH2 [ I]n Z [ ] O N~
R7
l~]v ~ ~YZ
D o Y3
Z--E~X~ ] RB
--Z--~3~ R
SUBSTITUTE SHEET (RULE 26)
CA 022~3862 1998-11-09
W097/42956 - PCT~S97/08335
-27-
R R ~ / R5
- Z ~ W ~ N V
R ~ R6
[] m R
m[~ V
R7 R6
wherein Z is C2-C7 alkenyl or alkynyl; CH2; O; CO;
CO2; CON~; S; SO; SO2; or N~;
wherein Z' is ~CH2)o~ CO, (CH2)oCO~ or CO(CH2)o;
wherein each D is independently CH2; O; S; N~; CO;
or CS;
wherein W is C=O; C=NO~; substituted or
unsubstituted phenyl, pyridyl, thiophenyl,
furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,
imidazolyl, benzfurazanyl, benzfuranyl or
benzyimidazolyl, wherein the phenyl, pyridyl,
thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl,
indolyl, imidazolyl, benzfurazanyl, benzfuranyl or
benzyimidazolyl is substituted with -H, -F, -Cl, -
Br, -I, -NO2, -CN, straight chained or branched
C,-C7 alkyl, straight chained or branched Cl-C7
monofluoroalkyl, straight chained or branched C,-C7
polyfluoroalkyl, straight chained or branched C2-C7
SUBSTITUTE SHEET (RULE 26)
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alkenyl, straight chained or branched C~- C7
alkynyl, C3-C7 cycloalkyl, C3-C7
monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl,
C3- C7 cycloalkenyl, -N (R4) 2, -OR4, -COR4, -CO2R4, or
-CON (R4) 2i
wherein each V is independently Oi S; CH2; CRsR7;
C(R7)2; or NR7; provided that when V is CRsR. the
remaining carbons on the ring may only be
substituted with R6;
wherein each m is independently an integer from 0
to 3; wherein o is an integer from 1 to 3;
wherein each R is independently -H; -F; straight
chained or branched C1-C7 alkyl, monofluoroalkyl or
polyfluoroalkyli straight chained or branched C2-C7
alkenyl or alkynyl; -N (R4) 2; -NO2; -CN; -CO2R4; or
- OR4;
wherein each R4 is independently -H; straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C,
alkenyl or alkynyl; C3-C, cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein Rs is aryl or heteroaryl substituted with
one or more of F; Cl; Br; I; COR3; CO2R3; -CON (R3) 2;
CN; - NO2; - N ( R3 ) 2; - OR3 ~ - SR3; ( CH2 ) oOR3; ( CH2 ) oSR3;
straight chained or branched C1-C, alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched
C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
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wherein each R6 is independently -H; straight
chained or branched C1- C7 alkyl, hydroxyalkyl,
aminoalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyli straight chained or branched C~-C-
alkenyl or alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; or -OR4;
wherein R7 is aryl or heteroaryl substituted with
one or more of F; Cl; Br; I; COR3 i CO2R3; - CON ( R3 ) 2i
CN; -NO2; -N(R3) 2; -OR3~ -SR3; (CH2) oOR3; (CH2) oSR3;
straight chained or branched C1- C7 alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched
C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; and
wherein R8 is -H; substituted or unsubstituted
benzyl, benzoyl, phenyl, pyridyl, thiophenyl,
furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,
imidazolyl, benzfurazanyl, benzfuranyl,
benzimidazolyl or 2-keto-1-benzimidazolinyl,
wherein the benzyl, benzoyl, phenyl, pyridyl,
thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl,
indolyl, imidazolyl, benzfurazanyl, benzfuranyl,
benzimidazolyl or 2-keto-1-benzimidazolinyl is
substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN,
straight chained or branched Cl-C7 alkyl, straight
chained or branched Cl-C7monofluoroalkyl, straight
chained or branched C1-C7polyfluoroalkyl, straight
chained or branched C2-C7 alkenyl, straight chained
or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C,
monofluorocycloalkyl, C3-c7 polyfluorocycloalkyl,
C3-C7 cycloalkenyl, -N(R4)2, -OR4, -COR4, -CO.R4, or
-CON(R4)2; substituted or unsubstituted straight
chained or branched Cl-C7 alkyl, monofluoroalkyl or
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~30~
po}yfluoroalkyl; substituted or unsubstituted
straight chained or branched C2-C7 alkenyl or
alkynyl; C3-C7 cycloalkyl or cycloalkenyl, wherein
the alkyl, monofluoroalkyl, polyfluoroalkyl,
alkenyl, alkynyl, cycloalkyl or cycloalkenyl is
substituted with -H, phenyl, pyridyl, thiophenyl,
furanyl, pyrazinyl, pyrryl, naphthyl, indolyl,
imidazolyl, benzfurazanyl, benzfuranyl,
benzimidazolyl, -N(~)2, -NO2, -CN, -C02~, -o~;
Yl
m ~ R7 or N~ ~ R7
or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention the
compounds have the following structure:
R~ ~I N R ~ R5
~ R6
R2 N B
SUBSTITUTESHEET(RULE26)
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-31-
In a further embodiment of the present invention the
compounds have the structure:
Y~ Y,~
5Y2
Yl~Y5
loR4 ~ ~ R ,~ R5
Rz N B
The invention further provides for the embodiment
having the following structures:
H ~ ~ N
¢~
p
and
0 ~ '~'~ ~ N ~
O'CH3
SUtsS 111 ~JTE SHEET (RULE 26~
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-32-
The present invention is also directed to compounds
having the structure:
A A
Rz N B 3 N R3
wherein A is
Yl ~ Y4 Yl ~X /
Y2 ~ N q ~ ~ Y3
Yl ~ NH Yl
~X , Yl ~,0
~r Yl~l ;
wherein each of Y1, Y2, Y3, Y4 and Y5 iS
independently -H; straight chained or branched
C~-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or
alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; -F, -Cl,
-Br, or -I; -NO2; -N3; -CN; -OR4, -OCOR4, -COR4,
SU~S 111 UTE SHEET (RULE 26)
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WO 97/42956 PCT/US97/08335
~33~
-CONHR4~ -CON (R4) 2, or -COOR4; or any two of Yl, Y2,
Y3~ Y4 and Ys present on adjacent carbon atoms can
constitute a methylenedioxy group;
wherein X is S; O; or NR4;
wherein B is -H; straight chained or branched Cl-C7
alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or
thioalkyl; straight chained or branched C2-C7
alkenyl; -SCH2C6H4OR4; ~ (CH2)nC6Hs; -CH2X (CH2)oNHR4;
~ (CH2)nNHR4; or -OR4;
wherein Rl is -H; -NO2; -CN; straight chained or
branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; c3-c7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N(R4)2; -OR4; ~ (CH2)pOR4; -COR4;
CO2R4; or -CON ( R4)2;
wherein R2 is -H; straight chained or branched Cl-C7
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2~C7 alkenyl or alkynyl; C3-C7
cycloalkyl, monof luorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; C3-Clo
cycloalkyl-C~-C1O-alkyl, C3-CIo cycloalkyl-CI-ClO-
monofluoroalkyl or C3-CIo cycloalkyl-CI-ClO-
polyfluoroalkyl; -CN; -CH2XR4, -CH2X ( CH2)pNHR4,
~ (CH2)nNHR4~ -CH2X (CH2)pN (R4)2, -CH2X (CH2)pN3, or
-CH2X (CH2)pNHCXR7; or -OR4;
wherein each p is independently an integer from 1
to 7; wherein each n is independently an integer
from O to S;
Sl~ 1 1 UTE SHEET (RULE 26)
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W O 97/42956 34 PCT~US97/08335
wherein R3 is
R ~ R6 R
R m~ ~]m
m[~V
R7 R6
wherein Z' is (CH2)o~ C0, (CH2)oC0~ or CO(CH2)o;
wherein each V is independently 0; S; CH2; CR5R7;
C(R7)2; or NR7;
~5 wherein each m is independently an integer from 0
to 3; wherein o is an integer from 1 to 3;
wherein each R is independently -H; -F; straight
chained or branched C,-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; -N(R4)2; -N02; -CN; -C02R4; or
-OR4;
wherein each R4 is independently -H; straight
chained or branched C,-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C7
alkenyl or alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R5 and R7 each independently may be -H; F;
Cl; Br; I; -COR3; -CO2R3; -CON(R3)2; -CN; -NO2;
-N (R3) 2; -OR3; -SR3; - (CH2)pOR3; - (CH2)pSR3; straight
chained or branched Cl-C7 alkyl, aminoalkyl,
carboxamidoalkyl; straight chained or branched
~ C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or
cycloalkenyl; wherein the alkyl, aminoalkyl,
carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or
cycloalkenyl may be substituted with one or more
SIJL~S 1 l l UTE SHEET (RULE 26)
. _ .
CA 022~3862 1998-11-09
W097l42956 PCT~S97/08335
-3S-
aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with -F, -Cl, -Br, -I, -NO7, -
CN, -OR3, -SR3, Cl-C3 alkyl, or carboxamido; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more -F, -Cl, -Br,
- I, COR3, CO2R3, - CON ~ R3 ) 2~ - CN, -N02, -N~ R3 ) 2 ~ - OR3,
-SR3, ~CH2)oOR3l ~CH2)oSR3; straight chained or
branched Cl-C7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C7-C7
alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; and
wherein each R6 is independently -Hi straight
chained or branched C1-C7 alkyl, hydroxyalkyl,
aminoalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyli straight chained or branched C2-C7
alkenyl or alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; or -OR4;
or a pharmaceutically acceptable salt thereof.
In the present invention aryl includes phenyl, benzyl,
benzoyl or naphthyl and heteroaryl includes pyrazinyl,
pyrryl, furanyl, thiophenyl, pyridyl, imidazolyl,
indolyl, aminophenyl, benzamidyl, benzimidazolyl,
benzfurazanyl, benzfuranyl, 2-keto-1-benzimidazolinyl
or quinolyl.
The invention further provides for a pharmaceutical
composition comprising a therapeutically effective
amount of any of the compounds described above and a
pharmaceutically acceptable carrier. In the subject
3S invention a "therapeutically effective amount" is any
amount of a compound which, when administered to a
subject suffering from a disease against which the
compounds are effective, causes reduction, remission,
or regression of the disease. In one embodiment the
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-36-
therapeutically effective amount is an amount from
about 0.01 mg per subject per day to about 500 mg per
subject per day, preferably from about 0.1 mg per
subject per day to about 60 mg per subject per day and
S most preferably from about 1 mg per subject per day to
about 20 mg per subject per day. In the practice of
this invention the "pharmaceutically acceptable
carrier" is any physiological carrier known to those of
ordinary skill in the art useful in formulating
pharmaceutical compositions.
In one preferred embodiment the pharmaceutical carrier
may be a liquid and the pharmaceutical composition
would be in the form of a solution. In another equally
preferred embodiment, the pharmaceutically acceptable
carrier is a solid and the composition is in the form
of a powder or tablet. In a further embodiment, the
pharmaceutical carrier is a gel and the composition is
in the form of a suppository or cream.
The invention provides a method of treating a subject
suffering from benign prostatic hyperplasia which
comprises administering to the subject any one of the
compounds described herein effective to treat benign
prostatic hyperplasia. In a preferred embodiment the
compound of the pharmaceutical composition additionally
does not cause a fall in blood pressure at dosages
effective to alleviate benign prostatic hyperplasia.
In one preferred embodiment the compound effects
treatment of benign prostatic hyperplasia by relaxing
lower urinary tract tissue and in particular where
lower urinary tract tissue is prostatic smooth muscle.
The invention further provides a method of treating a
subject suffering from elevated intraocular pressure
which comprises administering to the subject one of the
compounds described herein effective to lower
intraocular pressure.
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The invention further provides a method of treating a
subject suffering from a disorder associated with
elevated blood cholesterol which comprises
administering to the subject one of the compounds
~ 5 described herein effective to inhibit cholesterol
synthesis.
The invention also provides a method of treating a
disease which is susceptible to treatment by antagonism
of the ~lA receptor which comprises administering to the
subject one of the compounds described herein effective
to treat the disease.
The invention further provides a method of treating a
subject suffering from impotency which comprises
administering to the subject one of the compounds
described herein effective to treat impotency.
The invention further provides a method of treating a
subject suffering from sympathetically mediated pain
which comprises administering to the subject one of the
compounds described herein effective to treat
sympathetically mediated pain.
The invention provides a method of treating a subject
suffering from cardiac arrhythmia which comprises
administering to the subject one of the compounds
described herein effective to treat cardiac arrhythmia.
The invention provides a method of treating a subject
suffering from benign prostatic hyperplasia which
comprises administering to the subject one of the
compounds described herein in combination with a 5
alpha-reductase inhibitor effective to treat benign
prostatic hyperplasia. In one preferred embodiment the
- 5-alpha reductase inhibitor is finasteride. The dosage
administered to the subject is about 0.01 mg per
subject per day to 50 mg per subject per day of
finasteride in combination with an ~l~ antagonist. A
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W097/42956 PCT~S97/08335
-38-
more preferred dosage administered to the subject is
about 1 mg per subject per day to 7 mg per subject per
day of finasteride in combination with an
antagonist. The most preferred dosage administered to
the subject is about 5 mg per subject per day of
finasteride in combination with an ~lA antagonist.
The invention also provides for a pharmaceutical
composition comprising a therapeutically effective
amount of a combination of any of the compounds
described herein in combination with finasteride and a
pharmaceutically acceptable carrier. In one embodiment
the pharmaceutical composition is a therapeutically
effective amount of a combination comprising an amount
from about 0.01 mg per subject per day to about 500 mg
per subject per day of any one of the compounds
described herein and an amount of finasteride of about
5 mg per subject per day. A more preferred embodiment
of the pharmaceutical composition is a therapeutically
effective amount of a combination comprising an amount
from about 0.1 mg per subject per day to about 60 mg
per subject per day of any one of the compounds
described herein and an amount of the finasteride of
about 5 mg per subject per day. The most preferred
embodiment of the pharmaceutical composition is a
therapeutically effective amount of a combination
comprising from about 1 mg per subject per day to about
20 mg per subject per day of any one of the compounds
described herein and an amount of finasteride of about
5 mg per subject per day.
The invention further provides a method of relaxing
lower urinary tract tissue which comprises contacting
the lower urinary tract tissue with an amount of one of
the compounds described herein effective to relax lower
urinary tract tissue. In one embodiment the lower
urinary tract tissue is prostatic smooth muscle. In
one preferred embodiment the compound additionally does
not cause a fall in blood pressure when it is effective
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W097/42956 PCT~S97108335
-39-
to relax lower urinary tract tissue.
The invention provides a method of relaxing lower
urinary tract tissue in a subject which comprises
administering to the subject an amount of one of the
compounds described herein effective to relax lower
urinary tract tissue. In one preferred embodiment the
compound does not cause a fall in blood pressure and
the lower urinary tract tissue is prostatic smooth
muscle.
The invention further provides for a method of
inhibiting contraction of prostatic tissue, which
comprises administering to the subject an amount of any
lS of the compounds described herein effective to inhibit
contraction of prostatic tissue. In one preferred
embodiment the prostatic tissue is prostatic smooth
muscle and the compound additionally does not cause a
fall in blood pressure.
The invention provides for the use of the compounds
described herein for the preparation of a
pharmaceutical composition for lowering intraocular
pressure, inhibiting cholesterol synthesis, and the
treatment of: benign prostatic hyperplasia, impotency,
cardiac arrhythmia and any disease where antagonism of
the ~lA receptor may be useful. The invention provides
for the use of the compounds described herein for the
preparation of a pharmaceutical composition for
~30 relaxing lower urinary tract tissue and in particular
prostatic smooth muscle. The invention further
provides for the use of any of compounds described
herein for the preparation of a pharmaceutical
composition, where the compound additionally does not
cause a fall in blood pressure at dosages effective tc
lower intraocular pressure, to inhibit cholesterol
synthesis, and for the treatment of: benign prostatic
hyperplasia, impotency, cardiac arrhythmia and any
disease where antagonism of the ~lA receptor may be
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W O 97/42956 40 PCTAUS97/08335
useful.
The invention provides for the use of the compounds
described herein in the preparation of a medicament for
lowering intraocular pressure, inhibiting cholesterol
synthesis, and for the treatment of: benign prostatic
hyperplasia, impotency, cardiac arrhythmia and any
disease where antagonism of the ~A receptor may be
useful. The invention provides for the use of the
compounds described herein in the preparation of a
medicament for relaxing lower urinary tract tissue and
in particular prostatic smooth muscle. The invention
further provides for the use of any of compounds
described herein in the preparation of a medicament,
where the compound additionally does not cause a fall
in blood pressure at dosages effective to lower
intraocular pressure, to inhibit cholesterol synthesis,
and for the treatment of: benign prostatic hyperplasia,
impotency, cardiac arrhythmia and any disease where
antagonism of the ~lA receptor may be useful.
The invention provides for a drug which is useful for
lowering intraocular pressure, inhibiting cholesterol
synthesis, and the treatment of: benign prostatic
hyperplasia, impotency, cardiac arrhythmia and any
disease where antagonism of the ~lA receptor may be
useful, the effective ingredient of the said drug being
any of the compounds described herein. The invention
further provides the drug described herein additionally
does not cause a fall in blood pressure at dosages
effective to lower intraocular pressure, to inhibit
cholesterol synthesis, and for the treatment of: benign
prostatic hyperplasia, impotency, cardiac arrhythmia
and any disease where antagonism of the ~lA receptor may
be useful.
The invention provides for a drug which is useful for
relaxing lower urinary tract tissue and in particular
prostatic smooth muscle, the effective ingredient of
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the drug being any of the compounds described herein.
The invention further provides the drug which is useful
for relaxing lower urinary tract tissue additionally
does not cause a fall in blood pressure at dosages
effective to relax lower urinary tract tissue.
The invention also provides for the (-) and (+)
enantiomers of all compounds of the subject application
described herein. Included in this invention are
pharmaceutically acceptable salts and complexes of all
of the compounds described herein. The salts include
but are not limited to the following acids and bases.
The following inorganic acids; hydrochloric acid,
hydrofluoric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid and boric acid. The organic acids;
acetic acid, trifluoroacetic acid, formic acid, oxalic
acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, maleic acid, citric acid,
methanesulfonic acid, trifluoromethanesulfonic acid,
benzoic acid, glycolic acid, lactic acid and mandelic
acid. The following inorganic bases; ammonia,
hydroxyethylamine and hydrazine. The following organic
bases; methylamine, ethylamine, propylamine,
dimethylamine, diethylamine, trimethylamine,
triethylamine, ethylenediamine, hydroxyethylamine,
morpholine, piperazine and guanidine. This invention
further provides for the hydrates and polymorphs of all
of the compounds described herein.
In one preferred embodiment the pharmaceutical carrier
may be a liquid and the pharmaceutical composition
would be in the form of a solution. In another equally
preferred embodiment, the pharmaceutically acceptable
carrier is a solid and the composition is in the form
of a powder or tablet. In a further embodiment, the
pharmaceutical carrier is a gel and the composition is
in the form of a suppository or cream. In a further
embodiment the compound may be formulated as a part of
a pharmaceutically acceptable transdermal patch.
.
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-42-
A solid carrier can include one or more substances
which may also act as flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating
agents; it can also be an encapsulating material. In
powders, the carrier is a finely divided solid which is
in admixture with the finely divided active ingredient.
In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in
suitable proportions and compacted in the shape and
size desired. The powders and tablets preferably
contain up to 99~ of the active ingredient. Suitable
solid carriers include, for example, calcium phosphate,
magnesium stearate, talc, sugars, lactose, dextrin,
starch, gelatin, cellulose, polyvinylpyrrolidine, low
melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved
or suspended in a pharmaceutically acceptable liquid
carrier such as water, an organic solvent, a mixture of
both or pharmaceutically acceptable oils or fats. The
liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers,
emulsifiers, buffers, preservatives, sweeteners,
flavoring agents, suspending agents, thickening agents,
colors, viscosity regulators, stabilizers or osmo-
regulators. Suitable examples of liquid carriers for
oral and parenteral administration include water
(partially containing additives as above, e.g.
cellulose derivatives, preferably sodium carboxymethyl
cellulose solution), alcohols (including monohydric
alcohols and polyhydric alcohols, e.g. glycols) and
their derivatives, and oils (e.g. fractionated coconut
oil and arachis oil). For parenteral administration,
the carrier can also be an oily ester such as ethyl
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W097/42956 PCT~S97/0~35
-43-
oleate and isopropyl myristate. Sterile liquid
carriers are useful in sterile liquid form compositions
for parenteral administration. The liquid carrier for
pressurized compositions can be halogenated hydrocarbon
or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by for
example, intramuscular, intrathecal, epidural,
intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. The
compounds may be prepared as a sterile solid
composition which may be dissolved or suspended at the
time of ~ n-stration using sterile water, saline, or
other appropriate sterile injectable medium. Carriers
are intended to include necessary and inert binders,
suspending agents, lubricants, flavorants, sweeteners,
preservati~es, dyes, and coatings.
The compound can be administered orally in the form of
a sterile solution or suspension containing other
solutes or suspending agents, for example, enough
saline or glucose to make the solution isotonic, bile
salts, acacia, gelatin, sorbitan monoleate, polysorbate
(oleate esters of sorbitol and its anhydrides
copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in
liquid or solid composition form. Compositions
suitable for oral administration include solid forms,
such as pills, capsules, granules, tablets, and
powders, and liquid forms, such as solutions, syrups,
elixirs, and suspensions. Forms useful for parenteral
administration include sterile solutions, emulsions,
and suspensions.
.
Optimal dosages to be administered may be determined by
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those skilled in the art, and will vary with the
particular compound in use, the strength of the
preparation, the mode of administration, and the
advancement of the disease condition. Additional
factors depending on the particular subject being
treated will result in a need to adjust dosages,
including sub~ect age, weight, gender, diet, and time
of administration.
One skilled in the art will readily appreciate
that appropriate biological assays will be used to
determine the therapeutic potential of the claimed
compounds for the treating the above noted disorders.
This invention will be better understood from the
Experimental Details which follow. However, one
skilled in the art will readily appreciate that the
specific methods and results discussed are merely
illustrative of the invention as described more fully
in the claims which follow thereafter.
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Experimental Detail6
For Examples 1-92 Scheme l describes the general
synthetic preparation. All NMRs were obtained using a
300MHz GE QEPLUS NMR machine.
Example 1
1,6-Dihydro-5-methoxycarh~nyl-2-l{(4-methoxyphenyl)me
thyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-
(4,4-diphenylpiperidin-1-yl)propyl]}carhnx~;do
pyrimidine.
a. 4,4-Diphenylpiperidine hydrochloride. A mixture of
4-piperidone monohydrate hydrochloride (15.0 g, 0.0976
mol) and AlCl3 (130 g, 0.976 mol, 10.0 eq) in anhydrous
benzene (600 mL) were stirred at reflux for 4 hours.
The mixture was cooled to room temperature, poured into
ice (300 g) and water (50 mL), and filtered. The solid
was washed with toluene and dried to afford 19.2 g
(72~) of an off-white solid, which was characterized
spectroscopically.
b. 3-(4,4-Diphenylpiperidin-1-yl)propionitrile. To a
suspension of 4,4-diphenylpiperidine hydrochloride
(0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et3N
(0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile
(0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution
was stirred at room temperature under argon for 15 min
and then concentrated. Water was added, and the
mixture was extracted with EtOAc (3 X 10 mL). The
combined organic extracts were dried ~MgSO4) and
concentrated to give 170 mg (87%) of a tan solid, which
was characterized spectroscopically and used in the
next reaction without purification.
c. 3-(4,4-Diphenylpiperidin-l-yl)propylamine. To a
stirred solution of 3-(4,4-diphenylpiperidin-1-
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yl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF
(20 mL) under argon was added a solution of BH3 in THF
(1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature.
The mixture was refluxed for 4.5 hours and then cooled
to room temperature. Aqueous HCl (6 N, 50 mL) was
added and stirring was continued for 1 hour. The
mixture was basified to pH 9 by addition of 6 N aq.
NaOH, extracted with CH2C12 (3 X 10 mL), dried (MgSO4)
and concentrated. The residue was purified by flash
chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0to
4:1:0.2) to give 1.35 g (66~) of tan solid, which was
characterized spectroscopically.
d. 2-(4-Methoxybenzyl)-2-thiopseudourea
hydrochloride.
To a well-stirred suspension of thiourea (7.6 g, 0.1
mol) in THF (50 mL) at 0 ~C, 4-methoxybenzyl chloride
(16 g, 0.1 mol) was added in 10 min and the mixture was
allowed to warm to room temperature. After 2 hours the
mixture was heated to 65 ~C and kept at that temperature
for 5 hours. It was cooled to room temperature and
diluted with diethyl ether (200 mL). The white
precipitate formed was filtered and dried (22.5 g,
96~); ~. p. 161-163 ~C.
e. Methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate.A
mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol),
methyl acetoacetate (12.773 g, 0.11 mol), piperidine
(0.41 g, 476 mL, 4.8 ~mol), and acetic acid (0.288 g,
274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at
room temperature for 48 hours. The white solid, methyl
2-{(4-nitrophenyl)methylene}-3-oxobutyrate, formed was
filtered, washed with 2-propanol (2 X 50 mL) and dried
(21.80 g, 93%).
f.l,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)
methyl}th~o~-4-methyl-6-(4-nitrophenyl)pyrimidine. A
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mixture of methyl 2-{(4-nitrophenyl)methylene}-3-
oxobutyrate (3:96 g, 0.04 mol), 2-(4-methoxybenzyl)-2-
thiopseudourea hydrochloride (9.28 g, 0.04 mol), and
NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred
and heated at 70-75 ~C for 4.5 hours. The mixture was
cooled, poured into ice-water (300 mL), extracted with
EtOAc (2 X 400 mL). The com~ined EtOAc extracts were
washed with 10~ NaHCO3 solution (2 X 60 mL), brine (100
mL), and dried (MgSO4). Solvent was evaporated and the
crude product was purified by flash column
chromatography on silica gel using 10~ through 30%
EtOAc in hexane as the gradient eluent, to leave the
product as an oil, which on trituration with
EtOAc/hexane became a yellow solid (11.4 g, 66.7~);
m.p. 13B-139 ~C; lH-NMR (CDCl3): ~ 2.15 (s, 3 H), 3.62
(s, 3 H), 3.72 (s, 3 H), 4.05, 5.78 (s, d, J = 3 Hz, 1
H), 4.08, 4.20 (AB q, J = 12.5 Hz, 2 H), 4.21, 6.40 (s,
d, J = 3 Hz, 1 H), 6.66 (2 d, J = 8.5 Hz, 2 H), 7.08 (2
d, J = 8.5 Hz, 2 H), 7.37 (2 d, J = 8.8 Hz, 2 H), 8.7
(2 d, J = 8.8 Hz, 2 H); Anal. Calcd. for C2lH2lN3O5S: C,
59.00; H, 4.95; N, 9.83. Found: C, 59.02; H, 4.93; N,
9.77.
g. 1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)
methyl}thio~-4-methyl-6-(4-nitrophenyl)-1-[(4-nitroph
enyloxy)carbonyl]pyrimidine.
To a well-stirred mixture of 1,6-dihydro-5-methoxy
car~onyl-2-[~(4-methoxyphenyl)methyl)thio]-4-methyl-6
-(4-nitrophenyl)pyrimidine (4.5 g, 0.0105 mol), NaHCO
(3.69 g, 0.044 mol), CH2C12 (200 mL), and water (50 mL)
at 0-5 ~C, 4-nitrophenyl chloroformate (2.4 g, 0.0119
mol) was added in 5 min and the mixture was allowed to
warm to room temperature. After 10 hours, the TLC
analysis of the reaction mixture showed the presence of
a small amount of starting pyrimidine, therefore, more
4-nitrophenyl chloroformate (0.65 g, 0.C032 mol) was
added and the stirring continued for an additional 4
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hours. The two layers were separated, the CH Cl2 layer
was washed with saturated aqueous NaHCO3 solution ~3 X
50 mL), dried (MgSO4), and the solvent evaporated. The
residue was recrystallized from CH2Cl2 and hexane to
give the product as white crystals (5.5 g, 88.4%); m.p.
156-157 ~C; lH-NMR (CDCl3): ~ 2.53 ~s, 3 H), 3.70 (s, 3
H), 3.81 (s, 3 H), 4.06, 4.36 (AB q, J = 13.5 Hz, 2 H),
6.30 (s, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 7.17 (d, J =
8.5 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.32 (d, J =
8.8 Hz, 2 H), 7.97 (d, J = 8.8 Hz, 2 H), 8.25 (d, J =
8.8 Hz, 2 H); Anal. Calcd. for C2BH24N4O9S: C, 56.75; H,
4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.
h. 1,6-Dihydro-5-methoxycarbonyl-2-~{(4-methoxyphenyl)
methyl}thio~-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-
diphenylpiperidin-1-yl)prop-yl]}carboxamido
pyrimidine.
To a stirred solution of 1,6-dihydro-5-methoxycarbonyl
-2-[{(4-methoxyphenyl)methyl)thio]-4-methyl-6-(4-nitr
ophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine
(0.592 g, 1 mmol) in anhydrous TH~ (10 mL) at room
temperature under argon atmosphere, a solution of 3-
[4,4-diphenylpiperidin-1-yl]propylamine (0.441 g, 1.5
mmol, 1.5 eq) in THF (5 mL) was added and the stirring
continued for 1 hours. Solvent was evaporated from the
reaction mixture and the residue was redissolved in
CH2C12 (50 mL), washed with 5% NaHCO3 (3 X 25 mL), brine
(50 mL), and dried ~MgSO4). Solvent was evaporated and
the residue was purified by flash chromatography on
silica gel using 10% methanol in EtOAc as the eluent to
give the desired product as an oil, which on
trituration with hexane and drops of EtOAc became a
white powder (0.32 g, 43%); m.p. 79-80 ~C; lH-NMR
~CDCl3): ~ 1.61-1.82 (m, 4 H), 2.27 (s, 3 H), 2.30-2.51
(m, 8 H), 3.19-3.36 (m, 1 H), 3.42-3.60 (m, 1 H), 3.68
(s, 3 H), 3.76 (s, 3 H), 3.95, 4.22 (AF3 q, J = 13.6 Hz,
2 H), 6.16 ~s, 1 H), 6.70 (d, J = 8.6 Hz, 2 H), 7.04
, . . ..
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(d, ~ = 8.6 Hz, 2 H), 7.11-7.29 (m, 12 H), 7.68 (br t,
1 H, NH), 7.91 (d, J = 8.8 Hz, 2 H); Anal. Calcd. for
C42H45N5O6SØ33 CH2C12: C, 65.52; H, 5.93; N, 9.03
Found: C, 65.52; H, 6.01; N, 9.20.
- Example 2
1,6-Dihydro-5-methoxyC~r~nyl-2-~{(4-methoxyphenyl)me
thyl}thio~-4-methyl-6-(4-nitrophenyl)-1-{N-[3-
(4-phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine.
a. 3-(4-Phenylpiperidin-1-yl)propionitrile.
Acrylonitrile (3.1 mL, 44 mmol, 2.5 eq) was added to a
solution of 4-phenylpiperidine (3.0 g, 18 mmol) in EtOH
(40 mL) and the mixture was stirred at room temperature
for 1.5 hours. The volatiles were removed to give 3.8
g of pure product (brown oil, 99~), which was
characterized spectroscopically.
b. 3-(4-Phenylpiperidin-1-yl)propylamine. To a stirred
solution of 3-(4-phenylpiperidin-1-yl)propionitrile
(5.1 g, 24 mmol) in anhydrous THF ~20 mL) under argon
was added a solution of BH3 in THF (1.0 M, 83 mL, 83
mmol, 3.5 eq) at room temperature. The mixture was re-
fluxed for 4.5 hours and then cooled to roomtemperature. Aqueous HCl (6 N, 130 mL) was added and
stirring was continued for 2 hours at 50-70 ~C. The
mixture was basified to pH 9 by addition of 6 N aq.
NaOH and extracted with EtOAc (100 mL) and CH2Cl2 (3 x
100 mL). The combined organic extracts were dried
(MgSO4) and concentrated. The residue was dissolved in
CH2Cl2 (20 mL) and treated with HCl in ether (1.0 M, 50
mL). The solvents were removed, ether ~250 mL) was
added, the mixture was filtered, and the filter cake
was washed with ether. Water (60 mL) was added to the
resulting white solid, the pH was adjusted to 10-11
with 1 N NaOH, and the aqueous phase was extracted with
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CH2Cl2 t3 X 50 mL). The combined extracts were dried
~MgSO4) and the solvents evaporated to give 4.5 g ~87~)
of pure product (light brown solid), which was
characterized spectroscopically.
c. 1,6-Dihydro-5-methoxyrarho~yl-2-[{(4-methoxyphenyl)
methyl}thio]-4-methyl-6-(4-nitrophenyl~-1-{N-~3-
~4-phenylpiperidin-1-yl)propyl]}carboxamido
pyrimidine. This compound was prepared from
1l6-dihydro-5-methoxycarbonyl-2-[~(4-methoxyphenyl)
methyl~thio]-4-methyl-6-(4-nitrophenyl)-1-[~4-nitroph
enyloxy)carbonyl]pyrimidine (0.77 g, 1.3 mmol), 3-~4-
phenylpiperidin-1-yl] propylamine (0.34 g, 1.56 mmol,
1.2 eq) and purified using similar conditions described
in Example 1 (0.63 g, 72~); m.p. 123-124 ~C; lH-NMR
(CDC13): ~ 1.65-2.10 (m, 8 H), 2.41 (s, 3 H), 2.41-2.55
(m, 3 H), 2.99-3.06 (m, 2 H), 3.2-3.35 (m, 1 H), 3.45-
3.60 (m, 1 H), 3.67 (s, 3 H), 3.75 (s, 3 H), 4.10, 4.33
(AB q, J = 13.6 Hz, 2 H), 6.19 (s, 1 H), 6.71 (d, J =
8.6 Hz, 2 H), 7.09 (d, ~ = 8.6 Hz, 2 H), 7.20-7.34 (m,
7 H), 7.97 ~br t, 1 H, NH), 7.97 (d, J = 8.8 Hz, 2 H);
Anal. Calcd. for C36H4lNsO6SØ25 CH2Cl2: C, 62.82; H,
6.04; N, 10.11. Found: C, 62.54; H, 6.13; N, 10.03.
Example 3
1-{N-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-1,6-dihydro-5-methoxycarbonyl-2-t{(4-meth
oxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)
pyrimidine.
a. 3-(4-Cyano-4-phenylpiperidinlyl)propyl a~i ne . 4-
Cyano-4-phenylpiperidine hydrochloride (5.01 g, 22.5
mmol) was added to water (100 mL~, and the solution was
basified to pH 10-11 by addition of 6 N aqueous NaOH.
The mixtùre was extracted with CH2Cl2 (3 x 100 mL). The
combined organic extracts were dried (MgSO4) and
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concentrated. To the residue were added 3-
bromopropylamine hydrobromide ~4.92 g, 22.5 mmol),
anhydrous K2CO3 (3.42 g, 24.8 mmol, 1.10 eq), and 1,4-
dioxane (100 mL). The mixture was stirred at reflux
for 24 hours under a CaSO4 drying tube. The solvent was
evaporated, and the product was purified by flash
chromatography (SiO2, CHCl3/MeOH/2 M NH3 in MeOH
(100:8:4 to 100:20:B) to give 3.23 g (59~) of colorless
oil, which was characterized spectroscopically.
b. 1-{N- t3- (4-Cyano-4-phenylpiperidin-1-yl)propyl] }
carboxamido -1, 6 - dihydro - 5 -methoxycarbonyl - 2 [ { ( 4 -metho
xy-phenyl)methyl}thiol -4-methyl-6- (4-nitrophenyl)
pyrimidine .
This compound was prepared from 1,6-dihydro-5-methoxy
carbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6
-(4-nitrophenyl)-1-~(4-nitrophenyloxy)carbonyl~pyrimi
dine (0.592 g, 1 mmol), 3-[4-cyano-4-phenyl
piperidin-1-yl]propylamine (0.292 g, 1.2 mmol, 1.2 eq)
and purified using similar conditions described in
Example 1 (0.445 g, 64~); m.p. 143-144 ~C; lH-NMR
(CDCl3): ~ 1.70-1.86 (m, 2 H), 2.02-2.09 (m, 4 H), 2.38
(s, 3 H), 2.41-2.56 (m, 4 H), 2.95-3.02 (m, 2 H), 3.24-
3.40 ~m, 1 H), 3.42-3.58 (m, 1 H), 3.68 (s, 3 H), 3.76
(s, 3 H), 4.08, 4.23 (AB q, J = 13.5 Hz, 2 H), 6.23 (s,
1 H), 6.72 (d, J = 8.6 Hz, 2 H), 6.94 (br t, 1 H, NH),
7.08 (d, J = 8.6 Hz, 2 H), 7.29 (d, ~ = 8.7 Hz, 2 H),
7.33-7.49 (m, 5 H), 7.94 (d, J = 8.8 Hz, 2 H); Anal.
Calcd. for C37H40N6O6S: C, 63.78; H, 5.79; N, 12.06.
Found: C, 63.86; H, 5.90i N, 11.92.
Example 4
1, 6 -Dihydro- 5 -methoxycarbonyl -1- {N- [ 3 - ( 4 -
methoxycarbonyl - 4 -phenylpiperidin- 1 -yl ) propyl ] }
carboxsmido - 2 - [ { ( 4 -mothoxyphenyl ) methyl } thio~ - 4 -~nethyl -
6 - ~ 4 -nitrophenyl ) pyrimidine .
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a. 4-Methoxycarbonyl-4-phenylpiperidine. T o a
stirred solution of H2SO4 (16 mL) in MeO~ (400 mL), 4-
phenyl-4-piperidinecarboxylic acid 4-methyl
benzenesulfonate ~37.7 g, 0.1 mole) was added and the
mixture was stirred and refluxed for 8 hours. Excess
methanol was evaporated at reduced pressure and the
residue was poured into a mixture of ice and 6 N NaOH.
The pH was adjusted to 10-11 by adding more 6 N NaOH
and extracted with CH2Cl2 (3 X 150 mL). The combined
CH2Cl2 extracts were dried ~MgSO4) and the solvent
evaporated to leave the desired product as a viscous
oil. The product (20.2 g, 92%) was used without
further purification.
b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1-
yl)propylamine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5
g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g,
0.058 mol), potassium carbonate (13.475 g, 0.0957
mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200
mL) was stirred and refluxed for 24 hours. Dioxane was
evaporated at reduced pressure, the residue was treated
with ice-cold 6 N NaOH (400 mL) and extracted with
CH2Cl2 t4 X 120 mL). Sol~ent was evaporated from the
combined dried (K2CO3) extracts and the residue was
purified by column chromatography on silica gel using
CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent to
afford the product as a viscous oil (7.8 g, 72~).
c. 1,6-Dihydro-5-methoxycarbonyl-1-{N-[3-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)propyl~}carbox
amido-2-~{(4-methoxyphenyl)methyl}thio]-4-methyl-
6-(4-nitrophenyl)pyrimidine. This compound was
prepared from 1,6-dihydro-~-methoxycarbonyl
-2-[~(4-methoxyphenyl)methyl)thio]-4-methyl-6-(4-nitr
ophenyl)-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine (1.0
g, 1.69 mmol), 3-[4-methoxycarbonyl-4-phenyl
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piperidin-l-yl]propylamine (0.56 g, 2.03 mmol, 1.2 eq)
and purified using similar conditions described in
Example 1 (1.085 g, 88%); m.p. 140-141 ~C; ;H-NMR
(CDCl3): ~ 1.62-1.74 (m, 2 H), 1.82-2.18 (m, 4 H), 2.21
(s, 3 H), 2.35-2.58 (m, 4 H), 2.75-2.89 (m, 2 H), 3.18-
3.30 (m, 1 H), 3.42-3.58 (m, 1 H), 3.61 (s, 3 H), 3.66
(s, 3 H), 3.75 (s, 3 H), 3.91, 4.15 (A~3 q, ~ = 13.6 Hz,
2 H), 6.14 (s, 1 H), 6.69 (d, J = 8.6 Hz, 2 H), 7.02
(d, J = 8.6 Hz, 2 H), 7.20-7.37 (m, 7 H), 7.56 (br t,
1 H, NH), 7.90 (d, J = 8.8 Hz, 2 H); Anal. Calcd. for
C3eH43NsO8S: C, 62.54; H, 5.94; N, 9.60. Found: C, 62.41;
H, 6.06; N, 9.34.
Example 5
5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[3-
(4,4-diphenyl-piperidin-1-yl)propyl~}carboxamido-1,2,
3,6-tetrahydro-2-thioxo-pyrimidine.
To a stirred solution of 1,6-dihydro-6-methoxycarbonyl-
2-[{(4-methoxyphenyl)methyl~thio]-4-methyl-6-(4-nitro
phenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl]}
carboxamidopyrimidine (0.14 g, 0.187 mmol) and
ethanethiol (0.5 mL) in CH2C12 (5 mL) at 5 ~C under
argon, TFA (0.5 mL) was added and the mixture was
allowed to warm to room temperature. After 3 hours,
solvents were evaporated completely, the residue was
redissolved in EtOAc (10 mL), washed with 5~ NaHCO~ (5
X 1 mL) and dried (MgSO4). Solvent was evaporated and
the residue was purified ~y column chromatography using
1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The
oily product was crystallized from hexane and EtOAc
(0.096 g, 82~); m.p. 130-131 ~C; lH-NMR (CDCl3): ~ 1.65-
1.80 (m, 2 H), 2.31 (s, 3 H), 2.31-2.49 (m, 10 H),
3.25-3.55 (m, 2 H), 3.76 (s, 3 H), 7.01 (s, 1 H), 7.09-
7.29 (m, 6 H), 7.41 (d, J = 8.2 Hz, 2 H), 8.11 (d, J =
8.8 Hz, 2 H), 9.76 (br t, 1 H, NH); Anal. Calcd. for
C34H3,N5O6SØ3 H2O: C, 64.50; H, 5.89; N, 11.06. Found:
C, 64.45; H, 6.05; N, 10.87.
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Example 6
1-~N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl)
propyl]}carboxamido-5-methoxycarbonyl-4-methyl-
6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxo
pyrimidine.
a. 4-(4-Methoxyphenyl)-4-phenylpiperidine. 4-Hydroxy-
4-phenylpiperidine (5.00 g, 28.2 mmol) was added to a
suspension of AlCl3 (18.8 g, 0.141 mol, 5.00 e~ in
anhydrous anisole (i00 mL). The mixture was stirred at
room temperature for 1 hours and then heated to 50 ~C
for 3.5 hours. It was cooled to room temperature and
poured cautiously into ice-water. The mixture was
basified to pH 11 by addition of 6 N aqueous NaOH, and
extracted with EtOAc (3 x 75 mL). The combined organic
extracts were applied directly to a flash
chromatography column, which was eluted with CH2Cl2/0.67
M NH3 in MeOH (4:1) to afford 1.683 g (22~) of light
yellow oil, which was characterized spectroscopically.
b. 3-[4-(4-Methoxyphenyl)-4-phenylpiperidin-1-
yl]propionitrile. Acrylonitrile (1.03 mL, 15.7 mmol,
2.50 eq) was added at 0 ~C to a solution of 4-(4-
methoxyphenyl)-4-phenylpiperidine (1.68 g, 6.28 mmol)
in EtOH (20 mL) and the resulting solution was stirred
for 1.5 hours at room temperature. After removal of
the solvent, the residue was purified by flash
chromatography (SiO2, EtOAc-CHCl3 1:3) to give 1.41 g
(70~) of colorless oil, which was characterized
spectroscopically.
c. 3-~4-(4-Methoxyphenyl)-4-phenylpiperidin-1-
yl]propylamine. To a stirred solution of 3-[4-(4-
methoxyphenyl)-4-phenylpiperidin-1-yl]pro
pionitrile (1.41 g, 4.40 mmol) in anhydrous THF (10 mL)
under argon was added a solution of BH3 in TH~ (1.0 M,
11.0 m~, 2.5 eq) at room temperature. The mixture was
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refluxed for 4.5 hours and then cooled to room
temperature. Aqueous HCl ~6 N, 15 mL) was added and
stirring was continued for 2 h at 55-60 ~C. The
mixture was basified to pH 9 by addition of 6 N a~.
NaOH and extracted with CH2Cl2 (3 x 75 mL). The
combined organic solutions were dried (MgSO4) and
concentrated. The residue was dissolved in CH2Cl2 (10
mL) and treated with HCl in ether (1.0 M, 9.0 mL, 2.0
eq). The solvents were removed, ether (30 mL) was
added, the mixture was filtered, and the filter cake
was washed with ether (2 x 10 mL). Water (20 mL) was
added to the resulting white solid, the pH was adjusted
to 10 with 1 N NaOH, and the aqueous phase was
extracted with CH2Cl2 (3 x 40 mL). The combined organic
extracts were dried (MgSO4) and concentrated to give 610
mg (43%) of white solid, which was characterized
spectroscopically.
d. 1-{N-~3-~4-(4-Methoxyphenyl)-4-phenylpiperidin-l-yl)
propyll}carboxamido-5-methoxycarbonyl-4-methyl-6-
(4-nitrophenyl)-1,2,3,6-tetrahydro-2
-thio~Limidine.
To a stirred mixture of l,6-dihydro-S-methoxycarbonyl-2
-[~(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrop
henyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592
g, 1 mmol) and K2CO3 (0.276 g, 2 mmol) in anhydrous THF
(10 mL) at room temperature under argon atmosphere, a
solution of 3-[4-(4-methoxyphenyl)-4-phenyl
piperidin-1-yl]propylamine t0.390 g, 1.2 mmol, 1.2 eq)
in THF ~10 mL) was added and the stirring was continued
for 1 hour. Solvent was evaporated from the reaction
mixture and the residue was redissolved in CH2Cl2 (50
mL), washed with 5~ Na~CO3 (3 X 25 mL), brine (50 mL),
and dried (MgSO4). The CH2C12 solution was filtered and
cooled to S ~C. To this, ethanethiol (0.5 mL) and TFA
(0.5 mL) were added and the mixture was stirred and
allowed to warm to room temperature. After 3 hours,
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solvents were evaporated completely, the residue was
redissolved in EtOAc (10 mL), washed with 5g6 NaHCO3 (5
X 1 mL), and dried (MgSO4). Solvent was evaporated and
the residue was purified by column chromatography using
1:1 hexane/~:tOAc to 100% EtOAc as gradient eluent. The
oily product was crystallized from hexane and EtOAc
(0.41 g, 62~); m.p. 120-121 ~C; lH-NMR (CDCl3): ~ 1.60-
1.80 (m, 2 H), 2.31 (s, 3 H), 2.31-2.51 (m, 8 H), 3.32-
3.43 (m, 2 H), 3.75 (S, 3 H), 3.76 (S, 3 H), 6.77 ~d,
- J = 8.8 HZ, 2 H), 7.02 (S, 1 H), 7.12 (d, J = 8.6 HZ,
2 H), 7.20-7.27 (m, 6 H), 7.41 (d, J = 8.6 Hz, 2 H),
8.11 (d, J - 8.8 Hz, 2 H), 9.76 (br t, 1 H, NH); Anal.
Calcd. for C3sH39NsO6S: C, 63.91; H, 5. 98; N, ~0.65.
Found: C, 64.19; H, 6.22; N, 10.36.
Example 7
a. 4-Ethoxycarbonyl-4-phenylpiperidine. To a stirred
solution of H2SO4 (1. 62 g, 16.56 mmol) in EtOH (200 mL~,
4-phenyl-4-piperidine-carboxylic acid 4-methyl
benzenesulfonate (2S g, 66.23 mmol) was added and the
mixture was stirred and refluxed for 12 hours. Excess
ethanol was evaporated at reduced pressure and the
residue was poured into a mixture of ice and 6 N NaOH.
The pH was adjusted to 10-11 by adding more 6 N NaOH
and extracted with CH2Cl2 (3 X 100 mL). The combined
CH2Cl2 extracts were dried (MgSO4) and the solvent
evaporated to leave the desired product as a colorless
viscous oil, the lH-NMR showed it to be pure (14.68 g,
95~) and was used without any further purification.
b. 3-(4-Ethoxycarbonyl-4-phenylpiperidin-1-yl)
propylamine.
A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5
g, 0.131 mol), 3-bromopropylamine hydrobromide (42.93
g, 0.196 mol), potassium carbonate (36.14 g, 0.241
mole), and KI (10.8 g, 0.065 mol) in 1,4-dioxane (500
mL) was stirred and refluxed for 24 hours. Dioxane was
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evaporated at reduced pressure, the residue was treated
with ice-cold 6 N NaOH (400 mL) and extracted with
CH2Cl2 (4 X 120 mL). Solvent was evaporated from the
combined dried (K2CO3) CH2C12 extracts and the residue
was purified by column chromatography on silica gel
using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluen~
to afford the product as a viscous oil (24.2 g, 83.3~).
c. l-{N-[3-(4-EthoxycA~h~nyl-4-phenylpiperidin-l-yl)
propyl~}caL~-o~ -;do-5-methoxycarbonyl-4-methyl-6-
(4-nitrophenyl)-1,2,3,6-tetra-hydro-2-
thiGxG~y~imidine. This compound was prepared from
1~6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)me
thyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophen
yloxy)carbonyl]pyrimidine (0.592 g, 1 mmol), K2CO,
(0.276 g, 2 mmol), 3-[4-ethoxycarbonyl-4-phenyl
piperidin-l-yl]propylamine (0.350 g, 1.2 mmol, 1.2 eq),
ethanethiol (0.5 mL), and TFA (0.5 mL) using the
procedure described in Example 7 and purified by flash
column chromatography (0.295 g, 47~); m.p. 125-126 ~C
H-NM~ (CDC13): ~ 1.13 (t, J = 7 Hz, 3 H), 1.62-1.80 (m,
2 H), 1.87-2.0 (m, 2 H), 2.06-2.18 (m, 2 H), 2.31 (s,
3 H), 2.34-2.39 (m, 2 H), 2.50-2.55 (m, 2 H), 2.79-2.83
(m, 2 H), 3.30-3.51 (m, 2 H), 3.74 (s, 3 H), 4.07 (q,
J = 7 Hz, 2 H), 7.03 (s, 1 H), 7.18-7.36 (m, 6 H), 7.40
(d, J = 8.8 Hz, 2 H), 8.08 (d, J = ~.8 Hz, 2 H), 9.78
(br t, 1 H, NH)i Anal. Calcd. for C3lH3,NsO7S: C, 59.70;
H, 5.98; N, 11.23. Found: C, 59.55; H, 5.99; N, 11.43.
Examplo 8
1,6-Dihydro-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propy
l~}carboxamido-2-methoxy-5-methoxycarbonyl-4-methyl-
6-(4-nitrophonyl)pyrimidine. To a stirred mixture of
1~6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl
-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyri
midine (0.940 g, 2 mmol) and K2CO3 (0.552 g, 4 mmol) in
anhydrous THF (20 mL) at room temperature under argon
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atmosphere, a solution of 3[4,4-diphenylpiperidin-1-yl]
propylamine (0.882 g, 3 mmol, 1.5 eq) in THF (5 mL) was
added and the stirring was continued for 1 hour.
Solvent was evaporated from the reaction mlxture, the
residue was redissolved in CH2C12 (50 mL), washed with
5% NaHCO3 (3 X 25 mL), brine (50 mL), and dried (MgSO4).
Solvent was e~aporated and the residue was purified by
flash chromatography on silica gel using 10% methanol
in EtOAc as the eluent to give the desired product as
an oil, which on trituration with hexane and drops of
EtOAc became a white powder (1.10 g, 88%); m.p. 95-96
~C; 1H-NMR (CDCl3): ~ 1.61-1.71 Im, 2 H), 2.26-2.33 (m,
2 H), 2.38 (S, 3 H), 2.39-2.50 (m, 8 H), 3.20-3.41 (m,
2 H), 3.65 (S, 3 ~I), 3.89 ~S, 3 H), 6.65 (S, 1 H), 6.84
(br t, 1 H, NH), 7.08-7.29 (m, 10 H), 7.40 (d, J = 8.7
Hz, 2 H), 8.03 (d, J = 8.6 Hz, 2 H); Anal. Calcd. for
C3sH39N5O6Ø75 CH2Cl2: C, 62.28; H, 5.92; N, 10.16.
Found: C, 62.23; H, 5.76; N, 10.12.
Example 9
5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-t3-
(4,4-diphenyl-piperidin-1-yl)propyl]~carboxamido-
2-oxo-1,2,3,6-tetrahydropyrimid-ine.
a
1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-~4-
nitro-phenyl)pyrimidine.
A mixture of methyl 2-~ (4-nitrophen-yl)methylene}-3-
oxobutyrate (12.46 g, 0. 05 mol), O-methylisourea
hydrogen sulfate (10.32 g, 0.06 mol), and NaOAc ~9.84
g, 0.06 mol) in DMF (50 mL) was stirred and heated at
70-75 ~C for 4 hours. Tne mixture was cooled and poured
into ice-water ~300 mL). The precipitate formed was
filtered, washed with water, and dried. The crude
3 5 product was purified by flash column chromatography on
silica gel using 10~ through 30~ EtOAc in hexane as the
gradient eluent (9.8 g, 64%). The lH-NMR analysis of
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the product showed it to be a 19:1 mixture of the
amine/imine tautomers which was used as such in the
next step. lH-NMR (CDCl3): ~ 2.32, 2.38 (2 s, 3 H),
3.59, 3.70 (2 5, 3 H), 3.70, 3.85 ~2 s, 3 H), 5.40,
5.66 (s, d, J = 3 Hz, 1 H), 5.50, 6.08 (s, d, J = 3 Hz,
1 ~), 7.43, 7.45 (2 d, J = 9 Hz, 2 H), 8.10, 8.11 (2 d,
J = 9 Hz, 2 H).
b.1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-
(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl~
pyrimidine.
To a well-stirred mixture of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-6-(4-nitrophenyl)pyrimidine
(5.7 g, 0.0187 mol), NaHC03 ~6.27 g, 0.074 mol), CH.Cl~
(200 mL), and water (50 mL) at 0-5 ~C, 4-nitrophenyl
chloroformate (3.76 g, 0.0186 mol) was added in 5 min
and the mixture was allowed to warm to room
temperature. After 10 hours, the TLC analysis of the
reaction mixture showed the presence of a small amount
of starting pyrimidine, therefore, more 4-nitrophenyl
chloroformate (0.65 g, 0.0032 mol) was added and the
stirring continued for an additional 4 hours. The two
layers were separated, the CH2C12 layer was washed with
saturated aqueous NaHCO~ solution (3 X 50 mL), dried
(MgS04), and the solvent evaporated. The residue was
recrystallized from CH2C12 and hexane to give the
product as white crystals (12.8 g, 89%); lH-NMR (CDCl3):
~ 2.48 (s, 3 H), 3.69 ~s, 3 H), 3.94 (s, 3 H), 6.34 (s,
1 H), 7.36 (d, J = 9.1 Hz, 2 H), 7.46 (d, J = 8.7 Hz,
2 H), 8.14 (d, J = 8.7 Hz, 2 H), 8.26 (d, J = 9.1 Hz,
2 H); m.p. 168-169 ~C. Anal. Calcd. for C21H1~N4O9: C,
53.62; H, 3.86; N, 11.91. Found: C, 53.69; H, 3.92; N,
11.85.
c. 5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-
1-{N-t3-(4,4-di-phenylpiperidin-1-yl)propyl~}
carboxamido-2-oxo-1,2,3,6-tetrahydro-pyrimidine.
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To a stirred solution of 1,6-dihydro-2-methoxy-6-
methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-~N-[3-
(4,4-diphenylpiperidin-1-yl)propyl]~carboxamidopyrimi
dine (0.208 g, 0.33 mmol) in THF (10 mL) at 5~C under
argon, 3 N HCl (6 mL) was added and the mixture was
allowed to warm to room temperature. After 2 hours,
solvents were evaporated completely, the residue was
treated with 40 mL of 10~ NaHCO3, the product was
extracted with CH2C12 (2 X 15 mL) and the combined
extracts were dried (MgSO4). Solvent was evaporated and
the residue was crystallized from hexane and EtOAc
(0.20 g, 97~); m.p. 197-198 ~C; lH-NM~ ~CDCl3): ~ 1.63-
1.67 ~m, 2 H), 2.23-2.28 ~m, 2 H), 2.34 ~s, 3 H), 2.37-
2.42 (m, 8 H), 3.20-3.41 (m, 2 H), 3.69 (s, 3 H), 6.75
(s, 1 H), 7.08-7.26 (m, 11 H), 7.46 (d, J = 8.7 Hz, 2
H), 8.08 (d, J = 8.7 Hz, 2 H), 8.77 (~r t, 1 H, NH);
Anal. Calcd. for C34H37N5O6: C, 66.76; H, 6.10; N, 11.45.
Found: C, 66.48; H, 5.97; N, 11.25.
Example 10
1-{N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl)
propyl}~carboxamido-5-methoxycarbonyl-4-methyl-6
-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine.
To a stirred mixture of 1,6-dihydro-2-meth-
oxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)
-l-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.47 g,
mmol) and K2CO3 (0.552 g, 4 mmol) in anhydrous THF (10
mL) at room temperature under argon atmosphere, a
solution of 3-[4-(4-methoxyphenyl)-4-phenyl
piperidin-1-yl]propyl-amine (0.390 g, 1.2 mmol, 1.2 eq)
in THF (10 mL) was added and the stirring was continued
for 2 hours. The solid was removed by filtration and
the solution was cooled to 0-5 ~C. 6N HCl (2 mL) was
added to the solution and stirring was continued.
After 3 hours, solvents were evaporated completely, the
residue was redissolved in CH2Cl2 (20 mL), washed with
10~ NaHCO3 (2 X 10 mL), and dried (MgSO4). Solvent was
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evaporated and the residue was purified by column
chromatography using l:1 hexane/EtOAc to 100% EtOAc as
gradient eluent. The oily product was crystallized
from hexane and EtOAc (0.55 g, 86%); m.p. 100-102 ~C;
lH-NMR (CDCl3): ~ 1.65-1.80 (m, 2 H), 2.26-2.31 (m, 2
H), 2.35 (s, 3 H), 2.39-2.44 (m, 6 H), 3.18-3.40 (m, 2
H), 3.69 (s, 3 H), 3.73 (s, 3 H), 6.75 (s, 1 H), ~7.60
(d, J = 8.7 Hz, 2 H), 6.84 (br s, 1 H, NH), 7.10 (d, J
8.7 Hz, 2 H), 7.18-7.26 (m, 5 H), 7.46 (d, J = 8.6
Hz, 2 H), 8.08 (d, J = 8.6 Hz, 2 H), 8.78 (br t, 1 H,
NH); Anal. Calcd. for C3sH39NsO7Ø~ 2 CH2Cl2Ø12 EtOAc:
C, 64.54; H, 6.12; N, 10.57. Found: C, 64.44; H, 6.12;
N, 10.28.
Example 11
1-{N-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-
yl)propyl~}carboxamido-5-methoxycarbonyl-4-methyl-
6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine
(Scheme 2).
To a stirred mixture of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-
[(4-nitrophenyloxy)carbonyl]pyrimidine (0.47 g,
mmol), K2CO3 (0.276 g, 2 mmol) in anhydrous THF (10 mL)
at room temperature under argon atmosphere, a solution
of 3-[4-methoxycarbonyl-4-phenylpiperidin-l-yl]
propylamine (0.332 g, 1.2 mmol, 1.2 eq) in THF (10 mL)
was added and the stirring was continued for 2 hours.
The solid was removed by filtration and the soiution
was cooled to 0-5 ~C. To this, 6 N HCl (2 mL) was added
and the stirring continued. After 3 hours, solvents
were evaporated completely, the residue was redissolved
in CH2Cl2 (20 mL), washed with 10% NaHCO3 (2 X 10 mL),
and dried (MgSO4). Solvent was evaporated and the
residue was purified by column chromatography using 1:1
hexane/EtOAc to 100% EtOAc as gradient eluent. The
oily product was crystallized from hexane and EtOAc
(0.55 g, 86%); m.p. lB0-181 ~C; ~H-NMR (CDCl3): ~ 1.60-
,
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1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m, 2 H),
2.28-2.33 (m, 2 H), 2.35 (s, 3 H), 2.48-2.50 (m, 2 H),
3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 3.68 (s, 3 H), 6.75
(s, 1 H), 7.20-7.34 (m, 6 H), 7.46 (d, J = 8.8 Hz, 2
H), 8.07 (d, ~ = 8.8 Hz, 2 H), 8.78 (br t, 1 ~, NH);
Anal. Calcd. for C3~H3sNsO8: C, 60.70; H, 5.94; N, 11.80.
Found: C, 60.71; H, 5.99; N, 11.43.
Examples lla ~ 11 b
(+)-1-{N-~3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)
propyl]}~Arho~mido-5-methoxycarbonyl-4-methyl-6-
(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine and
(-)-1-{N-t3-(4-Methoxyc~h~nyl-4-phenyl-piperidin-1-yl)
propyl]}carboxamido-5-methoxy~rhnnyl-4-methyl-6-(4-
nitrophenyl)-2-oxo-1,2,3,6-tetrahydhv~yLi~dine (Scheme
3).
a. (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methyl-6-(4-nitro-phenyl)-1-{N-[(2-phenyl)ethyl]}
carboxam;dopyrimidine and (+)-1,6-Dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-
phenyl)ethyl]}carboxamidopyrimidine.
To a stirred solution of (+)-1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitr
ophenyloxy)carbonyl]pyrimidine (2.66 g, 5.6 mmol) in
anhydrous THF (80 mL) at room temperature under argon
atmosphere, a solution of (S)-(-)-a-methylbenzylamine
(0.82 g, 6.78 mmol, 1.2 eq) in THF (5 mL) was added and
the stirring was continued for 6 hours. Solvent was
evaporated from the reaction mixture, the residue was
redissolved in CH2Cl2 (50 mL), washed with 5~ NaHCO3 (3
X 25 mL), brine (50 mL), and dried ~MgSO4). Solvent was
evaporated and the residue was purified by flash
chromatography on silica gel using 5% to 30~ EtOAc in
hexane as the gradient eluent. The first major product
to elute was (~ 6-dihydro-2-methoxy-5-methoxy
carbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)
.
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ethyl~}carboxamidopyrimidine and this compound was
crystallized from isopropyl ether (0.85 g, 33.6~); m.p.
119-120 ~C; [~]D = -329.32 (CH2Cl2, 10.3 g/100 mL); ~H-
NMR (CDCl3): ~ 1.47 (d, J = 7 Hz, 3 H), 2.40 (s, 3 H),
3.61 (s, 3 H), 3.95 (s, 3 H), 4.96 (~uint, J = 6.5 Hz,
2 H), 6.66 (s, 1 H), 6.82 (d, J = 6.8 Hz, 1 H, NH),
7.22-7.36 (m, 5 H), 7.43 (d, J = 8.6 Hz, 2 H), 8.09 (d,
J = 8.6 Hz, 2 H); Anal. Calcd. for C23H24N4O6: C, 61.06;
H, 5.35; N, 12.38. Found: C, 60.85; H, 5.13; N, 12.42.
The second major compound to elute was (+)-
1l6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6
(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamido
pyrimidine and this compound was crystallized from
isopropyl ether (0.92 g, 36.4~); m.p. 138-140 ~C; [a] D
= +171.81 (CH2Cl2, 11.31 g/100 mL); ~H-NMR (CDCl3):~ 1.47
(d, J = 7 Hz, 3 H), 2.42 (s, 3 H), 3.644 (s, 3 H),
3.917 (s, 3 H), 4.989 (quint, J = 6.5 Hz, 2 H), 6.70
(s, 1 H), 6.81 (d, J - 6.8 Hz, 1 H, NH), 7.22-7.35 (m,
5 H), 7.36 (d, J = 8.6 Hz, 2 H), 8.04 (d, J = 8.6 Hz,
2 H); Anal. Calcd. for C23H24N4O6: C, 61.06; H, 5.35; N,
12.38. Found: C, 60.95; H, 5.20; N, 12.38.
b. (+)-1-{N-~3-(4-~ethoxycarbonyl-4-phenyl
piperidin-1-yl)propyl~}c~rho~mido-5-methoxyc~ho~yl-4-
methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydro
pyrimidine.
A solution of (+)-1,6-dihydro-2-methoxy-S-methoxy
carbonyl-4-methyl-6-(4-nitrophenyl)-1-(N-[(2-phenyl)
ethyl]}carboxamidopyrimidine (0.226 g, 0.5 mmol) and
1,8-diazabicyclo[5.4.0]-unde-7-ene (DBU) (0.076 g, 0.5
mmol) in CH2Cl2 (10 mL) was stirred and refluxed for 4
hours and the solvent evaporated. The product was
purified by column chromatography using 30% EtOAc in
hexane as the eluent. The product was found to be a
mixture of the amine-imine tautomers (0.120 g, 78.7%);
[~] D = +14-5 (CH2C12, 6 g/100 mL).
, . ,, . _
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To a well-stirred solution of (+)-ll6-dihydro-5-methoxy
carbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine
(0.12 g, 0.393 mmol) and pyridine (0.5 mL) ln CH~Cl2 (10
mL) at 0-5 ~C, 4-nitrophenyl chloroformate (0.095 g,
0.472 mmol) was added in 5 min and the mixture was
allowed to warm to room temperature. After 2 h,
saturated aqueous NaHCO3 solution (10 mL) was added and
the stirring continued for 30 min. The two layers were
separated, the CH2Cl2 layer was washed with saturated
aqueous NaHCO3 solution (3 X 5 mL), dried (Na2SO4), and
the solvent evaporated. The residue was redissolved in
THF ~10 mL) and mixed with K2CO3 (0.11 g, 0.8 mmol). To
this, a solution of 3-[4-methoxycarbonyl-4-phenyl
piperidin-l-yl]propylamine (0.138 g, 0.5 mmol) in THF
(5 mL) was added and the mixture was stirred for 2
hours. The solid was removed by filtration and the
solution was cooled to 0-5 ~C. To this, 6 N HCl' (0.5
mL) was added and the stirring continued. After 3
hours, solvents were evaporated completely, the residue
was redissolved in CH2C12 ~20 mL), washed with 10~
NaHCO3 (4 X 5 mL), and dried (MgSO4). Solvent was
evaporated and the residue was purified by column
chromatography using 1:1 hexane/EtOAc to 100~ EtOAc as
gradient eluent. The oily product was crystallized
from hexane and EtOAc (0.19 g, 82~); m.p. 138-~40 ~C;
[~]D = +lOB (CH2Cl2, 6.65 g/100 mL); lH-NMR (CDCl3):~
1.60-1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m,
2 H), 2.28-2.33 (m, 2 H), 2.35 (s, 3 H), 2.48-2.50 (m,
2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 3.68 (s, 3 H),
6.75 (s, 1 H), 7.20-7.34 (~, 5 H), 7.46 (d, J = 8.8 Hz,
2 H), 7.60 (br s, 1 H, N H), 8.07 (d, J = 8.8 Hz, 2 H),
8.78 (br t, 1 H, NH); Anal. Calcd. for C30H35NsO~Ø2
CH2Cl2Ø2 EtOAc: C, 59.27; H, 5.94; N, 11.15. Found:
C, 59.07; H, 5.76; N, 10.99.
c. (~ {N-t3-(4-Methoxycarhonyl-4-phenyl
piperidin-l-y~)propyl]}carbox~mido-5-methoxy
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carbonyl - 4 -methyl - 6 - ( 4 - ni trop~enyl ) - 2 - oxo -
1, 2, 3, 6 - tetrahydropyrimidine .
A solution of (-)-1,6-dihydro-2-methoxy-5-methoxy
car~onyl-4-methyl-6-(4-nitrophenyl)-1-¦N-[t2-phenyl)
ethyl]}carboxamidopyrimidine (0.35 g, 0.774 mmol) and
1~8-diazabicyclo[5.4.o]-unde-7-ene (DBU) (0.117 g,
0.774 mmol) in CH2Cl2 (10 mL) was stirred and refluxed
for 8 hours and the solvent evaporated. The product
was purified by column chromatography using 30~ EtOAc
in hexane as the eluent. The product, (-)-
1~6-dihydro-5-methoxycar~onyl-2-methoxy-4-methyl-6-
(4-nitrophenyl)pyrimidine, was found to be a mixture of
the amine-imine tautomers (0.170 g, 72~). To a well-
stirred solution of (-)-l~6-dihydro-5-methoxy
carbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine
(0.152 g, 0.5 mmol) and pyridine (0.5 mL) in CH2Cl2 (10
mL) at 0-5 ~C, 4-nitrophenyl chloroformate (0.121 g, 0.6
mmol) was added in 5 min and the mixture was allowed to
warm to room temperature. After 2 hours, saturated
aqueous NaHCO3 solution ~10 mL~ was added and the
stirring continued for 30 min. The two layers were
separated, the CH2Cl2 layer was washed with saturated
aqueous NaHCO3 solution (3 X 5 mL), dried (Na2SO4), and
the solvent evaporated. The residue was redissolved in
THF (10 mL) and mixed with K2CO3 (0.165 g, 1.2 mmol).
To this, a solution of 3-[4-methoxycarbonyl-
4-phenylpiperidin-1-yl]propylamine (0.166 g, 0.6 mmol)
in THF (5 mL) was added and the mixture was stirred for
2 hours. The solid was removed by filtration and the
solution was cooled to 0-5 ~C. To this, 6 N HCl (0.5
mL) was added and the stirring continued. After 3
hours, solvents were evaporated completely, the residue
was redissolved in CH2Cl2 (20 mL), washed with 10~
NaHCO3 (4 X 5 mL), and dried ~MgSO4). Solvent was
evaporated and the residue was purified by column
chromatography using 1:1 hexane/EtOAc to 100~ EtOAc as
gradient eluent. The oily product was crystallized
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from hexane and EtOAc (0.19 g, 64~); m.p. 138-140 ~C;
[~] D = -106 (CH2Cl2, 3.95 g/100 mL); lH-NMR (CDC13):~
1.60-1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m,
2 H~, 2.28-2.33 (m, 2 H), 2.35 (s, 3 H), 2.48-2.50 (m,
2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 3.68 (s, 3 H),
6.75 (s, 1 H), 7.20-7.34 (m, 6 H), 7.46 (d, J = 8.8 ~z,
2 H), 8.07 (d, J = 8.8 Hz, 2 H), 8.78 (br t, 1 H, NH);
Anal. Calcd. for C30H3sNso8~o~4 CH2C12: C, 58.18; H, 5.75;
N, 11.16. Found: C, 58.25; H, 5.67; N, 10.98.
Example 12
5-Methoxycarbonyl-1-{N-~3-(4-methoxycarbonyl-
4-phenylpiperidin-1-yl)propyl]}carh~Y~ido-4-methyl-6
-~3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetra
l.y~y~imidine.
To a stirred solution of 5-benzyloxycarbonyl-1-{N-~3-
(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}
carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-o
xo-1,2,3,6-tetrahydropyrimidine (0.320 g, 0.48 mmol) in
methanol (20 mL) and HCOOH (1 mL) at 0-5 ~C, 10~ Pd-C
(0.26 g) was added in portions and the cooling bath was
removed. TLC analysis of the reaction mixture at
frequent intervals showed the completion of the
reaction after 2 hours. The catalyst was removed by
filtration and the solvent was evaporated to leave
1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)
propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxy
phenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylic
acid as a white solid (0.275 g, 99~). The product was
used in the next step without any further purification
and characterization. A mixture of 1-{N-[3-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)propyl])
carboxamido-4-methyl-6-(3,4-methylenedioxy
phenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5-
carboxylic acid (0.2 g, 0.346 mmol), 1-(3-dimethylamino
propyl)-3-ethylcarbodiimide hydrochloride (0.382 g, 2
mmol), and 4-(N,N-dimethylamino)pyridine (0.488 g, 4
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mmol), in methanol (20 mL) was stirred and refluxed for
5 h and the solvent evaporated. The residue was
redissolved in CH2Cl2 (15 mL), washed with saturated
aqueous ammonium chloride solution ~3 X 10 mL), and
dried (Na2SO4). Evaporation of the solvent left the
pure product as white powder (0.202 g, 99~); m.p. 139-
141 ~C; lH-NMR (CDCl3):~ 1.62-1.80 (m, 2 H), 1.95-2.20
(m, 4 H), 2.35 (s, 3 H), 2.30-2.55 (m, 4 H), 2.76-2.90
(m, 2 H), 3.21-3.40 (m, 2 H), 3.61 (s, 3 H), 3.67 (s,
3 H), 5.89 (s, 2 H), 6.61-6.82 (m, 3 H), 6.63 (s, 1 H),
7.21-7.35 (m, 6 H), 8.79 (br t, 1 H, NH); Anal. Calcd.
for C3lH36N4O8Ø3 EtOAc: C, 62.47; H, 6.25; N, 9.05.
Found: C, 62.64; H, 6.25; N, 8.87.
Example 13
(+)-5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonyl-
4-phenylpiperidin-1-yl)propyl~}carh~m;do-6-(4-nitro
phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine (Scheme 4).
a. 2-Cyanoethyl 3-{(4-nitrophenyl)methylene~-4-
oxopentanoate.
A mixture of ethyl propionylacetate (25 g, 0.173 mol)
and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was
stirred and heated at 200-205 ~C for 2 h and the ethanol
formed was remo~ed by distillation. The residue was
subjected to high vacuum distillation and the fraction
distilling at 120-125 ~C at 0.4 mm of Hg was collected
to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%).
A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol),
2-cyanoethyl propionylacetate ~17.0 g, 0.1005 mol),
piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid
(0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 m~) was
stirred at room temperature for 24 h. The white solid,
2-cyanoethyl 3-~(4-nitrophenyl)methylene}-4-oxo
pentanoate, formed was filtered, washed with 2-propanol
(2 X 50 mL) and dried (28.34 g, 97~); m.p. 98-100 ~C.
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b. 5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-
ethyl-6-(4-nitrophenyl)pyrimidine.
A mixture of 2-cyanoethyl 3-{(4-nitrophenyl)methylene}
-4-oxopentanoate (5.00 g, 16.54 mmol), O-methylisourea
hydrogen sulfate (3.422 g, 19.85 mmol), and NaHCO3 (2.78
g, 33.08 mol) in EtOH (70 mL) was stirred and heated at
85-90 ~C for 5 h. The solid was removed by filtration
and ethanol was evaporated from the filtrate. The
residue was redissolved in EtOAc (300 mL), washed with
water (2 X 100 mL), dried (Na2SO4), and the solvent
evaporated. The crude product was purified by flash
column chromatography on silica gel using CHCl3/methanol
(30:1) as the eluent, to leave the product as a white
solid ~2.95 g, 50~). The lH-NMR analysis of the product
showed it to be a 5:1 mixture of the amine/imine
tautomers and was used as such in the next step.
c. 5-(2-CyanoethoxycArho~yl)-4-ethyl-1,6-d~hydro-2-
methoxy-6-(4-nitrophenyl)-1-~(4-nitrophenyloxy)
carbonyl]pyrimidine.
To a well-stirred solution of 5-(2-cyanoethoxy
carbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-
(4-nitrophenyl)pyrimidine (2.64 g, 7.36 mmol) and
pyridine ~1.19 mL, 14.72 mmol) in CH2Cl2 (100 mL) at 0-5
~C, 4-nitrophenyl chloroformate (1.485 g, 7.36 mmol) was
added in 5 min and the mixture was allowed to warm to
room temperature. After 16 h, saturated aqueous NaHCO
solution ~25 mL) was added and the stirring continued
for 30 min. The two layers were separated, the CH2Cl
layer was washed with saturated aqueous NaHCO3 solution
(3 X 50 mL), dried (Na2SO4), and the solvent evaporated.
The crude product was purified by flash column
chromatography on silica gel using CHCl3/EtOAc (25:1) as
the eluent to give the product as a viscous oil (1.70
g, 44~ H-NMR (CDCl3): ~ 1.24 (t, J = 7 Hz, 3 H),
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2.61-2.68 (m, 2 H), 2.88-2.92 (m, 2 H), 3.97 (s, 3 H),
4.32 (t, J = 7 Hz, 2 H), 6.34 (s, 1 H), 7.37 (d, J =
9.2 Hz, 2 H), 7.50 (d, J c 8.7 Hz, 2 H), 8.18 (d, J =
8.7 Hz, 2 H), 8.28 (d, J = 9.2 Hz, 2 H).
d. S-(2-Cyanoethoxycar~onyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}
carboxamidopyrimidine.
To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4-
ethyl-1,6-dihydro-2-methoxy-6(4-nitrophenyl)-1-
[(4-nitrophenyloxy)car~onyl]pyrimidine (17.5 g, 33.43
mmol) in anhydrous TH~ (200 mL) at room temperature
under argon atmosphere, (R)-(~)-a-methylbenzylamine
(4.86 g, 40.11 mmol) was added and the stirring was
continued for 16 h. Solvent was evaporated from the
reaction mixture and the residue was purified by flash
chromatography on silica gel using toluene/EtOAc (20:3)
as the eluent. The ~irst major product to elute was
(+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2
-methoxy-6-(4-nitrophenyl)-1-{N-I(2-phenyl)ethyl]}
carboxamidopyrimidine and obtained as a viscous oil
(6.11 g, 36.2%); [~]D = +299.5 (c = 1.95, CHCl3); 'H-NMR
(CDCl3): ~ 1.18 (t, J = 7 Hz, 3 H), 1.47 (d, J = 7 Hz ,
3 H), 2.61 (t, 2 H), 2.7-2.92 (m, 2 H), 3.98 (s, 3 H),
4.20-4.32 (m, 2 H), 4.96 (quint, J = 6.5 Hz, 2 H), 6.66
(s, 1 H), 6.82 (d, J = 6.8 Hz, 1 H, NH), 7.22-7.36 (m,
5 H), 7.45 (d, J = 8.6 Hz, 2 H), 8.11 (d, J = 8.6 Hz,
2 H). The second major compound to elute was (-) -5- (2-
cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(4-nitrophenyl)-1- {N- [ (2-phenyl)ethyl]}
carboxamidopyrimidine and obtained as a viscous oil
(5.92 g, 35~); [~]D = -105.1 (c = 3.9, CHCl3); 'H-NMR
(CDCl3): ~ 1.20 (t, J = 7 Hz, 3 H), 1.48 (d, J = 7 Hz,
3 H), 2.62 (t, 2 H), 2.82 (q, 2 H), 3.94 (s, 3 H),
4.20-4.32 (m, 2 H), 4.96 (quint, J = 6.5 Hz, 2 H), 6.69
- (s, 1 H), 6.84 (d, J = 6.8 Hz, 1 H, NH), 7.22-7.36 (m,
5 H), 7.39 (d, J = 8.6 Hz, 2 H), 8.06 (d, J = 8.6 Hz,
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2 H).
e.(+)-5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-
methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.
To a stirred solution of (+)-5-(2-
cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-
(4-nitrophenyl)-1-~N-[(2-phenyl)ethyl]}carboxamido
pyrimidine (2.62 g, 5.182 mmol) in toluene (40 mL) was
added 1~8-diazabicyclo[5~4~o]-undec-7-ene (0.237,1.55
mmol) at room temperature and the resulting solution
was heated at 90 ~C for 3.5 minutes. The solvent was
e~aporated and the residue was purified by flash column
chromatography on silica gel using 9:1 CHCl3/EtOAc as
the eluent, to give 1.32 g (71~)of (+)-5-(2-
cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-
(4-nitrophenyl)pyrimidinei [~]D = +4.0 (c = 3.25,
CHCl3).
f.(+)-5-~2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)
carbonyl~pyrimidine.
To a well-stirred solution of 5-(2-cyanoethoxycarbonyl)
-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)
pyrimidine (1.62 g, 4.52 mmol) and 4-(N,N-
dimethylamino)pyridine (0.663 g, 5.43 mmol) in CH2Cl2
(50 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (1.094 g,
5.43 mmol) was added in 5 minutes and the mixture was
allowed to warm to room temperature. After 3 hours the
solvent evaporated and the product was purified by
flash column chromatography on silica gel using
CHCl3/EtOAc (25:1) as the eluent to give the product as
a white solid (2.25 g, 95~ H-NMR (CDCl~ 1.24 (t,
J = 7 Hz, 3 H), 2.61-2.68 (m, 2 H), 2.88-2.92 (m, 2 H),
3.97 (s, 3 H), 4.32 (t, J = 7 Hz, 2 H), 6.34 (s, 1 H),
7.37 (d, J = 9.2 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H),
B.18 (d, J = 8.7 Hz, 2 H), 8.28 (d, J = 9.2 Hz, 2 H);
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[~] D = +317. 2 (c = 3.9, CHCl3).
g.(+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-l-{N-r3-(4
methoxycarbonyl-4-phenylpiperidin-1-yl)propyll}
c~r~oYamido-6-(4-nitrophenyl)-2-oxo-1,2.3,6-tetrhydro
pyrimidine.
To a stirred mixture of (+) -5- (2-cyanoethoxycar}:onyl)
-4-ethyl-1, 6-dihydro-2-methoxy-6- (4-nitrophenyl)
-1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (3.60 g,
6.878 mmol) in anhydrous THF ~100 mL) at room
temperature under argon atmosphere, a solution of 3- [4-
methoxycarbonyl - 4 -phenylpiperidin -1 -yl ] propylamine
(2.47 g, 8.94 mmol, 1.3 eq) in THF (10 mL) was added
and the stirring was continued for 12 hours. The
mixture was cooled to 0 ~C and aqueous 6N hydrochloric
acid ( lO mL) . The mixture was allowed to warm to room
temperature and the stirring was continued for 5 h.
Solvent was e~raporated from the reaction mixture, the
residue was purified by flash chromatography on silica
gel using ethyl acetate ( 800 mL~ followed by
chloroform-methanol-2M ammonia in methanol ~90/8/4) as
the eluent, to obtain the desired product as a white
powder (4.40 g, 98.5~ -NMR (CDC13): ~ 1.23 (t, LJ =
7 . 5 Hz, 3 H), 2 . 0-2 . 1 (m, 2 H), 2 . 40-2 . 95 (m, 12 H),
3.25-3.50 (m, 4 H), 3.6~ (s, 3 H), 4.27-4.32 (m, 2 H),
6 .64 (s, 1 H), 7.20-7.33 ~m, 5 H), 7 .49 (d, J = 7. 8 Hz,
2 H), 8.08 (d, J = 7.B ~Z, 2 H), 8.70-8.90 (m, 2 H);
[~¦D = +112.1 ~C = 2 . 15 , CHC13 ); This product was used
in the next step without any additional analysis.
h.(+)-5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonyl-
4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitro
phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine.
To a stirred solution of 5- ~2-cyanoethoxycarbonyl) -4-
ethyl~ N- [3- (4-methoxycarbonyl-4-phenyl
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piperidin-1-yl)propyl]}carboxamido-6-~4-nitrophenyl)-2-
oxo-l~2~3~6-tetrhydropyrimidine (4.40 g, 6.8 mmol) in
acetone (50 mL) at 0 ~C, sodium hydroxide solution (1 N,
27.2 mL, 4 eq.) was added drop wise and the stirring
was continued until the disappearance of the starting
material (1 hour). Most of the acetone from the
mixture was evaporated under reduced pressure while
keeping the temperature at 0 ~C and the residue was
adjusted to pH 7.0 by the addition of lN hydrochloric
acid. The white precipitate of (+)-4-ethyl-1-~N-[3-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]~
carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydro
pyrimidine-5-carboxylic acid formed was filtered and
dried under vacuum (3.59 g, 89%). lH-NMR (CDCl3):
1.07 (t, J = 7.5 Hz, 3 H), 1.55-1.70 (m, 2 H), 1.72-
1.84 (m, 2 H), 1.84-2.15 (m, 2 ~), 2.20-2.40 (m, 4 H),
2.70-2.90 (m, 2 H), 3.10-3.40 (m, 4 H), 3.51 (s, 3 H),
6.54 (s, 1 H), 7.18-7.38 (m, 6 H), 7.41 (d, J = 7.8 Hz,
2 H), 8.15 (d, J = 7.8 Hz, 2 H), 8.79 (br t, 1 H, N H),
10.05 (br S, 1 H, COOH); This product was used in the
next step without any additional analysis.
A mixture of (+)-4-ethyl-1-~N-[3-(4-methoxycarbonyl-
4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitro
phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine-5-carboxylic
acid (0.350 g, 0.59 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (0.2264 g, 1.181 mmol,
2eq.), and 4-(N,N-dimethylamino)pyridine (0.1443 g,
1.181 mmol, 2 eq) in anhydrous dichloromethane was
stirred at room temperature for 2 h. To this, 40
aqueous ammonia (0.6 mL) was added and the stirring was
continued for 12 h. The mixture was diluted with 100
mL of dichloromethane and washed with saturated aqueous
ammonium chloride solution (3 X 20 mL). Solvent was
evaporated from the dried ( magnesium sulfate)
dichloromethane solution and the residue was purified
by column chromatography on silica gel using
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chloroform-methanol-2M ~mmonia in methanol (500/16/8)
as the eluent, to obtain the desired product as a white
powder (0.24 g, 69~)i m.p. 107-109 ~CjlH-NMR (CDCl3):
1.20 (t, J = 7.5 Hz, 3 H), 1.66-1.72 (m, 2 H), 1.79-
2.00 (m, 3 H), 2.00-2.20 (m, 2 H), 2.29-2.35 (m, 2 H),
2.42-2.60 (m, 2 H), 2.62-2.82 (m, 3 H), 3.20-3.40 (m,
2 H), 3.60 (8, 3 H), 5.70 (br m, 2 H, N~I2), 6.59 (s, 1
H), 7.20-7.39 (m, 6 H), 7.52 (d, J = 7.8 Hz, 2 H), 8.13
(d, ~ = 7.8 Hz, 2 H), 8.82 (t, 1 H) i [~]D = +115.71 (c
= 1.4, CHC1 3); Anal. Calcd. for C30H36N6O7Ø~ H2O: C,
59.36; H, 6.24; N, 13.84. Found: C, 59.47; H, 6.07;
N, 13.64.
Example 14
(+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl-
1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)
propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine
(Scheme 5).
a. Benzyl 3-~(3,4-difluorophenyl)methylene]-4-
oxopentanoate. A solution of benzyl propionylacetate
(36.3 g, 176 mmol), 3,4-difluorobenzaldehyde (25.0 g,
176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic
acid (0.49 mL, 9.0 mmol) were refluxed with removal of
water using Dean-Stark apparatus for 5h. The solvent
was removed in vacuo and the residue was dissolved in
EtOAc. It was washed with water (100 mL) followed by
brine (100 mL) and dried over anhydrous Na2SO4. Solvent
was evaporated to get pale yellow syrup (60.2 g). It
was used in the next step without further purification.
- b. 5-~Benzyloxyca-ho~yl)-1,6-dihydro-2-methoxy-4-ethyl-
6-(3,4-difluorophenyl)pyrimidine. A suspension of
benzyl 3-~(3,4-difluorophenyl)methylene]-4-
oxopentanoate (16.0 g, 48.0 mmol), O-methylisourea
hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO~ (16.3 g,
. _ .
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130.2 mmol) in DMF (190 mL) was stirred at 70~C for 20h.
After cooling to room temperature, the mixture was
filtered and the filtrate was diluted with EtOAc (300
mL) and then washed with water (4X100 mL), brine (200
mL) and dried over Na2SO4. After removal of solvent, the
residue was purified by column chromatography (SiO~,
EtOAc/Hexane, 10%-30~) to get 5-(benzyloxycarbonyl)-
1,6-dihydro-2-methoxy-4-methyl-6-(3,4-
difluorophenyl)pyrimidine as a colorless oil (10.6 g,
58~). The NMR analysis showed it to be a mixture of
amine/imine tautomers and was used as is in the next
step.
c. 5-(Benzyloxyc~rhonyl)-4-ethyl-1,6-dihydro-2-methoxy-
6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy~carbonyl]
pyrimidine. To a well stirred solution of 5-(benzyloxy
carbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluoro
phenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethyl
aminopyridine (6.99 g, 57.25 mmol) in CH2Cl2 (200 mL)
was added a powder of 4-nitrophenyl chloroformate 11.54
g, 57.25 mmol) at room temperature. The reaction
mixture was stirred for 12 hours and then the solvent
was removed in vacuo. The residue was purified by
chromatography (SiO2, EtOAc/Hexane 10-30~) to get 5-
(benzyloxycarbonyl)-4~ethyl-1,6-dihydro-2-methoxy-6-
( 3 , 4 - d i f l u o r o p h e n y l ) - 1 - [ ( 4 -
nitrophenyloxy)carbonyl~pyrimidine as a colorless
viscous oil(12.6 g, 50~).1H NM~ (CDCl3): ~ 1.24 (t,
J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14
(ABq~ ~A=5.08~ ~= 5.20, J= 12.3 Hz, 2H), 6.28 (s, 3H),
7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d,
J=9.2 Hz, 2H).
d. 5-~Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-e2-
phenyl)ethyl]}c~QY~mido-2-methoxy-6-(3,4-difluoro
phenyl)pyrimidine. To a stirred mixture of 5-
(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-
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~3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine (12.6 g, 22.86 mmol) in THF (150 mL) was
added a solution of R-(+)-a-methyl benzylamine (3.53
mL, 27.44 mmol) at room temperature. The stirring was
continued for 12 hours. Solvent was removed in vacuo.
The yellow residue was dissolved in chloroform (200 mL)
and was washed with 10~ K2CO3 solution (2x30 mL). The
organic layer was dried over Na2SO4, filtered and
solvent was removed in ~acuo. The resulting mixture of
diastereomers was separated by column chromatography
over silica gel with 9:1 Pet. ether:Ether to 4:1 Pet.
ether:Ether. First major product to elute was (+)-5-
(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-l-{N-[2-
phenyl)ethyl]~carboxamido-2-methoxy-6-(3,4-
diflurophenyl)pyrimidine. Colorless oil, Rf= 0.31(4:1
Pet ether:ether), wt. = 3.8 g (60~), [~]~ = +267.05 (c =
0.76, CHCl3) lH NMR: ~i 1.22 (t, ~=7.5 Hz, 3H), 1.52 (d,
J=6.9 Hz, 3H),2.88 (q, J=6.0 Hz, 2H), 3.99 (s, 3H),
4.99 (m, lH), 5.09 (ABq~ ~A=5.00, ~B= 5.19, J= 12.6 Hz,
2H), 6.66 (s, lH), 6.99-7.36 (m, 13H).; Second major
product to elute was (-)-5-(benzyloxycarbonyl)-4-ethyl-
1,6-dihydro-1-{N-[2-phenyl)ethyl])carboxamido-2-
methoxy-6-(3,4-diflurophenyl)pyrimidine.Colorlessoil.
~f= 0.22(4:1 Pet ether:ether), wt.= 3.2 g (51.2~), [~]D
= -146.89 (c = 0.38, CHCl3), lH NMR: ~ 1.22 (t, J=7.2
Hz, 3H), 1.49 (d, J=6.6 Hz, 3H),2.88 (q, J=6.0 Hz, 2H),
3 94 (s 3H), 5 03 (m, lH), 5.11 (ABq~ ~A=5.02, ~B -
5.19, J= 12.6 Hz, 2H), 6.68 (s, lH), 6.91-7.34 (m,
13H).
e. (+)-5-~Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-
ethyl-6-~3,4-diflurophenyl)pyrimidine. To a stirred
solution of (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-
dihydro~ N- [2-phenyl)ethyl]}carboxamido-2-methoxy-6-
(3,4-diflurophenyl)pyrimidine (l.B3 mmol, 1.0 g) in
toluene (10 mL) was added 1,8-diazabicyclo[5,4,0]-
undec-7-ene (0.81 mmol,0.12 mL) at room temperature and
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the resulting solution was heated to reflux for 5h and
then stirred for 12h at room temperature. The solvent
was evaporated and the residue was purified by flash
column chromatography on silica gel with 3:1
EtOAc/Hexanes as the eluting system. 0. 56 g of the (+)-
5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4- ethyl-6-
(3,4-diflurophenyl)pyrimidine was obtained (77%).
f. (+)-5-lLenzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(3,4-diflurophenyl)-1-t(4-nitrophenyloxy)
carbonyl~pyrimidine. To a well stirred solution of (+)-
5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-
(3,4-diflurophenyl)pyrimidine (17.0 g, 44.04 mmol) and
4-dimethylaminopyridine (6.99 g, 57.25 mmol) in CH2Cl2
(200 mL) was added a powder of 4-nitrophenyl
chloroformate 11.54 g, 57.25 mmol) at room temperature.
The reaction mixture was stirred for 12 hours and then
the solvent was removed in vacuo. The residue was
purified by chromatography (Sio2, EtOAc/Hexane 10-30~)
toget(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy)
carbonyl]pyrimidine as a colorless viscous oil(19.3 g,
76%).
g. (~) -5- (Benzyloxycarbonyl) -6- (3,4-difluorophenyl) -4-
ethyl-1-{N- [3- (4-methoxycarbonyl-4-phenyl
piperidin- 1 -yl ) propyl ] } carboxamido - 2 - oxo -
1,2,3,6-tetrhydropyrimidine. To a stirred mixture of
(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)
carbonyl]pyrimidine (0.55 g, 1.12 mmol) in THF (5 mL)
was added a solution of 3-[4-methoxycarbonyl-4-
phenylpiperidin-1-yl]propylamine (0.31 g, 1.12 mmol) in
THF (5 mL) at room temperature. The stirring was
continued for 12 hours. A solution of 10% HCl in water
(2 mL) was added and stirred for 2 h. The solvent was
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then removed in vacuo and the residue was extracted
with ethyl acetate (3 X 10 mL). It was washed with 10~
aq. KOH solution, dried over Na2SO4 and solvent was
removed in vacuo to obtain (+)-5-(benzyloxycarbonyl)-
6-(3,4-difluorophenyl)-4-ethyl~ N-~3-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)propyll}
carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine as a
white foamy compound (0.73 g, 96.6%~ the purity of
which was characterized as its HCl salt. It was used in
the next step without further purification. Anal.
Calcd. for C37H4lClF2N4O6Ø5CHCl3:C, 58.43; H, 5.43; N,
7.27. Found: C, 58.11, H; 5.85; N, 7.64.
h. 6-(3,4-Difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxy
carbonyl-4-phenylpiperidin-1-yl)propyl~}carboxamido-
1,2,3,6-tet hy~o-2-oxopyrimidine-5-carboxylicacid.To
a suspension of 10~ Pd-C (0.14 g, 20~ by wt.) in MeOH
(3 mL) was added the solution of (+)-5-
(benzyloxycarbonyl)-6-t3,4-difluorophenyl)-4-ethyl-
l-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-l-yl)
propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine
at room temperature with constant stirring. A balloon
filled with H2 was attached and the reaction mixture was
stirred for 48 hours. The black suspension was filtered
through a pad of celite and the filtrate was
concentrated in vacuo. The residue was purified by
column chromatography (SiO2, 10% MeOH in EtOAc) to
obtain (+)-6-(3,4-difluorophenyl)-4-ethyl-l-~N-[3-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)
propyl])carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-
5-carboxylic acid as a white solid. M.P. 184-186 ~C;
[~]D = +142.2 ~c = 0.25, CHCl3) The purity was checked
by combustion analysis as a HCl salt. Anal. Calcd. for
C30H3sClF2N4O6Ø3CHCl3:C, 55.40; H, 5.42; N, 8.53. Found:
C, 55.34; H; 5.80; N, 8.13.
i. (~)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl-
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1-{N-[3-~4-methoxycarbonyl-4-phenylpiperidin-1-yl)
propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydro
pyrimidine.
To a solution of (+)-6-(3,4-difluorophenyl)-4-ethyl-
l-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-l-yl)
propyl]~carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-
5-carboxylic acid (0.22 g, 0.375 mmol) in CH2Cl2 ~3 mL)
was added 4-N,N-dimethylamino pyridine (0.14 g, 1.12
mmol)andl-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.21 g, 1.12 mmol) under argon and the
resulting solution was stirred at room temperature for
2h. Three drops of saturated NH40H was then added and
the solution was stirred for 4~ h. The solution was
washed with water (5 ml) and dried over Na2SO4. The
solvent was removed in ~acuo and the residue was
purified by-column chromatography (SiO2, 10~ MeOH in
CHCl3)toobtain5-carboxamido-6-(3,4-difluorophenyl)-4-
e t h y l - 1 - { N - [3 - (4 - m e t h o x y c a r b o n y l -
4-phenylpiperidin-1-yl)propyl]~carboxamido-2-oxo-
1,2,3,6-tetrhydropyrimidine as a beige solid ~0.1 g,
45~). Characterized as HCl salt. M.P. 136-138~C,, [~]D
= +111.44 (c = 0.18, MeOH): ~ 1.21 (t, J=7.5 Hz, 3H),
1.60-1.75 (m, 2H), l.g2-2.1 (m, 8H), 2.33 (t, J=6.6 Hz,
2H), 2.44-2.52 (m, 2~), 2.53-2.84 (m, 4H), 3.27-3.32
(m, 2H), 3.60 (s, 3H), 5.60 (br s,2H), 6.47 (s, lH),
7.05-7.33 (m, 8H), 8.80 (br t, lH), Anal. Calcd. for
C30H35ClF2N4O6.1.0 CHCl3:C, 50.35; H, 5.04; N, 9.47.
Found: C, 50.40; H; 5.33; N, 9.13.
Example 15
6-(3,4-Difluoropheny~)-5-methoxycarbonyl-4-methyl-2-
oxo-1-{N- [4- (2 -pyridyl) -p ip eridine-1-
yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidine
dihydrochloride ~Scheme 7).
a. 1-Benzyl-4-cyano-4-(2-pyridyl)piperidine. To a
mixture of N,N-bis-(2-chloroethyl)benzylamine
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(E.Szarvasi, Eur. J. Med. Chem. Chim. Ther. 11(2), 115-
124, 1976) (60 g, 22 mmol), 2-pyridylacetonitrile (2.51
ml, 22 mmol) and tetrabutylammonium hydrogen sulfate
(0.26 g, 0.7 mmol) in toluene (10 ml), sodium hydroxide
solution (2.43 g in 4.86 ml H2O) was added over a 20
minute period. The reaction mixture was heated at 65
~C for 4 hours. The reaction mixture was cooled to room
temperature, 10 ml of water was added and the solution
partitioned between ethyl acetate (45 ml) and water.
The organic layer was dried over sodium sulfate,
filtered and concentrated. Purification of the crude
product by column chromatography (hexane:EtOAc,2:3)
gave 6.2 g (B7%) of the title compound as a red solid;
lH-NMR (CDCl3): ~ 2.05 (d, J = 13.1 Hz, 2 H), 2.30 (t,
J = 13.2 Hz, 2 H), 2.4B (t, J = 13.2 Hz, 2 H), 2.97 (d,
J = 12.1 Hz, 2 H), 3.57 (s, 2 H), 7.19-7.27 (m, 6 H),
7.30 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H),
8.58 (d, J - 4.6 Hz,lH).
b. 1-Benzyl-4-carboxamido-4-~2-pyridyl)piperidine. To
1-benzyl-4-cyano-4-(2-pyridyl)piperidine (4.5 g, 14.3
mmol), 10 ml of conc.H2SO4 was added and the solution
was stirred at room temperature for 24 hours. It was
cooled to 0 ~C, diluted with ice pieces and poured into
crushed ice. The mixture was then carefully
neutralized with 50 ~ NaOH solution. The reaction
mixture was repeatedly extracted with chloroform (3 x
25 ml), dried over sodium sulfate, filtered and
concentrated to gi~e 4.5 g (95%)of the crude product
which was used as such for the subsequent step; 1H-NMR
(CDCl3): ~ Z.21-2.28 (m, 2 H), 2.47 (s, 6 H), 3.41 (s,
2 H), 5.23 (s, 1 H), 6.40 (s, 1 H), 7.12-7.29 (m, 6 H),
7.33 (d, J - 7.6 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1 H),
8.55 (d, J = 4.6 Hz, 1 H).
c. 1-Benzyl-4-(2-pyridyl)-piperidine. To l-benzyl-4-
carboxamido-4-(2-pyridyl)piperidine (4.5 g, 13.5 mmol)
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in anhydrous methanol (100 ml), HCl gas was bubbled
through the solution at 0 ~C for 15 minutes. The
reaction mixture was then refluxed for 24 hours. It
was cooled to room temperature, concentrated,
neutralized with 50 ~ NaOH and repeatedly extracted
with chloroform ~3 x 25 ml). The combined organic
layer was then dried over sodium sulfate, filtered and
concentrated. Flash chromatography
(hexane:ethylacetate, 1:4) of the crude product yielded
1.72 g (50%) of the product as a syrup; 'H-NMR (CDCl3):
1.8-1.94 (m, 4 H), 2.11 (t , J = 11.4 Hz , 2 H), 2.70 -
2.72 (m, 1 H) ,3.02 (d, J = 11.4 Hz, 2 H), 3.54 (s, 2
H), 7.07-7.36 (m, 7 H), 7.58 (t, J = 7.6 Hz, 1 H), 8.52
(d, J = 4.6 Hz, 1 H).
d.3-~4-~2-Pyridyl)-piperidine-l-yl]propylamine(Scheme
6) . To 1-Benzyl-4- (2-pyridyl) -piperidine (3.26 g, 12.9
mmol) in dry methanol (25 ml), 1096 palladium hydroxide
(1.9 g) was added and the solution was hydrogenated at
200 psi for 24 hours. The solution was filtered over
celite, concentrated to give 2.1 g (99%) of 4- (2-
pyridyl)-piperidine which was used as such for the
subsequent step. A mixture of 3-bromopropylamine
hydrobromide (20 g, 91.3 mmol), potassium carbonate
~37.85 g, 273.9 mmol) and di- tert-butyldicarbonate
(21.90 g, 100 mmol) in methanol was stirred at room
temperature for 24 hours. The reaction mixture was
concentrated and partitioned between 250 ml EtOAc and
50 ml water, dried over sodium sulfate, filtered and
concentrated. Purification of the crude product by
column chromatography (Hexane: EtOAc, 4.5: 0.5) gave
17.5 g (80%) of the product as a pale yellow oil . To
a stirred solution of the 4- (2-pyridyl) -piperidine
(1.86 g, 11.4 mmol) in dioxane ( 20 ml), N- (tert-
butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol)
and potassium carbonate (3.16 g, 22.9 mmol) were added
and the solution refluxed for 24 hours. The reaction
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mixture was cooled to room temperature, concentrated
and partitioned between 40 ml chloroform and 5 ml
water. The organic layer was dried over sodium
sulfate, filtered and concentrated. The crude product
was purified by column chromatography (ethyl acetate:
methanol, 4:1) to yield 1.86 g (49 %) of the required
product as a colorless oil; 1H-NM~ (CDC13): ~ 1.45 (s,
9 H),1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80
(m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, lH), 7.13-7.17
(m, 1 H), 7.33 (d, J = 7.93 Hz, 1 H).7.63 (t, ~ = 7.6
Hz, 1 H), 8.54 (d, J = 4.6 Hz, 1 H). To N-(tert-
butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-
yl]propylamine (0.15g, 0.45 mmol) in 5 ml of
dichloromethane, 1 ml of trifluoroacetic acid was added
and the solution stirred at room temperature for 1
hour. The solution was concentrated, neutralized with
10 ~ KOH solution and extracted into 25 ml of
dichloromethane. The organic layer was dried over
sodium sulfate, filtered and concentrated to give 0.098
g (100~) of3-[4-(2-pyridyl)-piperidin-1-yl]propylamine
which was used as such for the subsequent step (step
h).
e. Methyl 2-{(3,4-difluorophenyl)methylene}-3-
oxobutyrate. A mixture of 3,4-difluorobenzaldehyde
(14.2 g, 0.1 mol), methyl acetoacetate (12.2 g, 0.10~
mol), piperidine (0.430 g, 5 mmol), and acetic acid
(0.30 g, 5 mmol) in benzene (150 mL) was stirred and
refluxed with a Dean-Stark trap for 8 hours. Benzene
was evaporated, the residue was dissolved in ethyl
acetate (200 mL) and washed with brine (50 mL),
saturated potassium bisulfate solution (50 mL), and
saturated sodium bicarbonate solution in sequence. The
ethyl acetate solution was dried (magnesium sulfate),
solvent removed under reduced pressure and the residue
was purified by column chromatography (SiO2,
EtOAc/hexane, 10~-15%). The product, methyl 2-~(3,4-
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difluorophenyl)methylene}-3-oxobutyrate, was obtained
as a yellow oil ~0.98 g, 98.3~) and was used in the
next step without any further characterization.
f . 6- ~3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl-4-methylpyrimidine. A mixture of
methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate
(8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate
(9.4 g, 55 mmol), and NaHCO3 (12.3 g, 0.146 mol) in DMF
(30 mL) was stirred and heated at 70 ~C for 16 hours.
The mixture was cooled, diluted with EtOAc (300 mL) and
washed with water (5 X 300 mL), brine (300 mL), and
dried (MgSO4). Solvent was evaporated and the crude
product was purified by flash column chromatography on
silica gel using 10~ through 20% EtOAc in hexane as the
gradient eluent, to leave the product as an oil (3.82
g, 30.2~ H-NMR (CDC13):~ 2.32,2.39 (2 s, 3 H), 3.58,
3.64 (2 s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.55 ( s, 1 H),
6.13-7.8 (m, 4 H).
g. 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)car~o
nyl]pyrimidine.
To a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g,
9.52 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52
mmol) in CH2Cl2 (50 mL),at 0-5 ~C, 4-nitrophenyl
chloroformate (1.82 g, 9.04 mmol) was added and the
mixture was allowed to warm to room temperature. After
12 hours solvent was evaporated and the residue was
purified by flash column chromatography (Sio2,
EtOAc/hexane, 10%-15%)to obtain the product as white
crystals (3.72, 84.7%); m.p. 172-174 ~C; 1H-NMR
(CDCl3):~ 2.51 (s, 3 H), 3.72 (s, 3 H), 3.97 (s, 3 H),
6.26 (s, 1 H), 7.0-7.3 (m, 3 H), 7.38 (d, J = 9.3 Hz,
2 H), 8.32 (d, J = 9.3 Hz, 2 H).
-
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h. 6-(3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-2-
oxo-l-{N-t4-(2-pyridyl)-piperidine-1-yl]propyl}
carboxamido-1,2,3,6-tetrahydropyrimidine
dihydrochloride. To 6-(3,4-difluorophenyl)-1,6-
dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-
nitrophenoxy)carbonylpyrimidine (0.04 g,0.086 mmol~ ln
10 ml of dry dichloromethane, 3-[4- (2-pyridyl)-
piperidine-1-yl]propylamine (0.038 g, 0.17 mmol) was
added and the solution was stirred at room temperature
for 24 hours. The reaction mixture was stirred for
another 1 hour after addition of 2 ml of 6N HCl. After
neutralization with 10% aqueous KOH solution, the
reaction mixture was extracted into dichloromethane (3
x 10 ml). The organic layer was dried over sodium
sulfate, filtered and concentrated. The crude product
was purified by flash chromatography ( Et~Ac: MeOH,
4.5:0.5) to give 0.040 g (8996) as a syrup ; lH-NMR
(CDCl3): ~ 1.73-2.11 (m, 7 H), 2.41 (s, 6 H), 2.69 (m,
1 H), 3.04 (d, J = 12.1 Hz, 2 H) , 3.31-3.48 (m, 2 H),
3.71 ( s, 3 H3, 6.70 (s, 1 H), 7.24-7.27 (m, 5 H), 7.61
( t, J = 8.0 Hz, 2 H), 8.51 (d, J = 4.6 Hz, 1 H), 8.89
(t, J = 5.1 Hz, 2 H).
To the free base (0.04g, 0.07 mmol) in 4 ml of
dichloromethane, 5 ml of lN HCl in ether was added, and
the solution concentrated under reduced pressure.
Recrystallization from ether gave 0.046 g (98%) of 6-
(3,4-difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-
l-~N-[4-(2-pyridyl)-piperidine-l-yl~propyl)carboxamido-
1,2,3,6-tetrahydropyrimidine dihydrochloride as a white
solid; m.p. 170-174 ~C; Anal. Calcd. for
C27H33C12F2N5O4.1.0 H2O: C, 52-43; H,5.70, N 11.30. Found:
C, 52.16; H 5.35; N 11.10.
Example 16
6-(3,4-Benzofurazan-5-yl)-5-methoxycarbonyl-4-methyl-2-
oxo-1-{N-t4-(2-pyridyl)-piperidin-1-yllpropyl}carbox
.
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amido-1,2,3,6-tetrahydropyrimidine dihydrochloride
(Scheme B).
5-Methylbenzfuroxan. 4-Methyl-2-nitroaniline (100
g, 0.650 mol~ was suspended in saturated alcoholic
sodium hydroxide solution (1.50 l). To this suspension
was added with cooling (5 ~C) commercial aqueous sodium
hypochlorite till the red color disappeared. The
fluffy yellow precipitate formed was filtered, washed
with cold water and recrystallized from ethanol to get
5-Methylbenzfuroxan (88.2 g, 89 % yield) as a pale
solid.
5-Methylbenzofurazan. To 5-Methylbenzfuroxan (88.2
g, 0.59. mol) in refluxing EtOH (75 ml) was added
dropwise P(OEt)3 (150 ml ). When addition was complete,
refluxing was continued for 1 more hour. The solvent
was removed by rotary evaporation and the residue
shaken with water (200 mL) and allowed to stand
overnight at (0-5 ~C). The brown solid so obtained was
filtered, washed with water and chromatograghed on
silica gel to yield 5-Methylbenzofurazan (70 g, 87 ~)
as white needle.
5-Dibromomethylbenzofurazan. 5-Methylbenzofurazan
(70 g, 0.52 mol), NBS (325 g), and benzoyl peroxide
(0.5 g) were refluxed with stirring in carbon
tetrachloride (1.5 ~) with exclusion of moisture for 30
hours. The reaction mixture was washed with water
(2X0.5L), dried (NaSO4), and the solvent was removed in
vacuo. The residue was chromatographed (silica, EtOAc-
hexane, 1:150) to give 122 g (80~) of the title
compound. The resulting white solid was used in the
next step without any further characterization.
5-Formylbenzofurazan. To a refluxing mixture of the
dibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1
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L) was added AgNO3 (163 g) in 2 L of water. Refluxing
was continued for 2 hours. The mixture was cooled and
the AgBr was removed by filtration through Celite, and
the solvent was concentrated to a small volume. The
resulting solution was extracted with toiuene (10 X
100 mL), dried (MgSO4), and the solvent was removed in
vacuo. The residue was chromatographed on silica
(EtOAc-hexane, 8:1000) to give 48.2 g of the title
aldehyde (78~) as a white solid.
a.Methyl2-{(benzofuran-5-yl)methylene}-3-oxobutyrate.
A mixture of 5-Formylbenzofurazan (0.6 g, 4.1 mmol),
methyl acetoacetate (0.52 g, 4.5 mmol), piperidine
(0.019 g, 0.225 mmol), and acetic acid (0.014 g, 0.225
mmol) in benzene (30 mL) was stirred and refluxed with
a Dean-Stark trap for 8 h. Benzene was evaporated, the
residue was dissolved in ethyl acetate (80 mL) and
washed with brine (50 mL), saturated potassium
bisulfate solution (50 mL), and saturated sodium
bicarbonate solution in sequence. The ethyl acetate
solution was dried (magnesium sulfate), solvent removed
under reduced pressure and the residue was purified by
column chromatography (SiO2, EtOAc/hexane, 10~-15%).
The product, methyl 2-~(benzofuran-5-yl)methylene)-3-
oxobutyrate, was obtained as an oil (0.98 g, 98.3~) and
was used in the next step without any further
characterization.
b. 6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl-4-methylpyrimidine. A mixture of
methyl 2-{(benzofuran-5-yl)methylene~-3-oxobutyrate
(1.02 g, 4.1 mmol), O-methylisourea hydrogen sulfate
(1.06 g, 6.2 mmol), and NaHCO3 (1.3 g, 16.4 mmol) in DMF
(15 mL) was stirred and heated at 70 ~C for 16 h. The
mixture was cooled, diluted with EtOAc (50 mL) and
washed with water (5X 50 mL), brine (50 mL), and dried
.. ..
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(MgSO4). Solvent was evaporated and the crude product
was purified by flash column chromatography on silica
gel using 10~ through 20~ EtOAc in hexane as the
gradient eluent, to leave the product as an oil (0.52
g, 4396); lH-NMR (CDCl3):~ 2.38,2.42 (2 s, 3 H), 3.60,
3.66 (2 s, 3 H), 3.74, 3.82 (2 s, 3 H), 5.53, 5.68 (2
s, 1 H), 6.31, 6.32 (br s, 1 H), 7.0-7.8 (m, 3 H).
c. 6-~enzofurazan-5-yl)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbo
nyl~pyrimidine.
To a solution of 6-(benzofuran-5-yl)-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methylpyrimidine (0.485 g,
1.6 mmol) and 4-dimethylaminopyridine (0.2 g, 1.6 mmol)
in CH2Cl2 (20 mL),at 0-5 ~C, was added 4-nitrophenyl
chloroformate (0.307 g, 1.52 mmol) and the mixture was
allowed to warm to room temperature. After 12 hours
solvent was evaporated and the residue was purified by
flash column chromatography (SiO2, EtOAc/hexane, 10~-
15~)to obtain the product as white crystals (0.665 g,
89~); m.p. 180-183 ~C; lH-NMR (CDCl3):~ 2.54 (s, 3 H),
3.75 (s, 3 H), 3.98 (s, 3 H), 6.37 (s, 1 H), 7.40 (d,
J = 9.3 Hz, 2 H), 7.52 (d, ~ = 9.0 Hz, 1 H), 7.68 (s,
1 H), 7.84 (d, J = 9.0 Hz, 1 H), 8.32 (d, ~ = 9.3 Hz,
2 H).
d . 6 - ( 3, 4 -Benzofurazan- 5 -yl ) - 5 -methoxycar}~onyl - 4 -
methyl-2-oxo-1-{N- [4- (2-pyridyl) -piperidin-1-yl]propyl}
carboxamido- 1, 2, 3, 6 - tetrahydropyrimidine
dihydrochloride. To 6-(benzofurazan-5-yl)-1,6-dihydro-
2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-
nitrophenoxy)carbonylpyrimidine (0.04 g,0.085 mmol) in
10 ml of dry dichloromethane, 3-[4-(2-pyridyl)-
piperidine-1-yl]propylamine (0.037 g, 0.17 mmol) was
added and the solution was stirred at room temperature
for 24 hours. The reaction mixture was stirred for
another 1 hour after addition of 2 ml of 6N HCl. After
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neutralization with 10~ aqueous KOH solution, the
reaction mixture was extracted into dichloromethane (3
x 10 ml). The organic layer was dried over sodium
sulfate, filtered and concentrated. The crude product
was purified by flash chromatography ( EtOAc: MeOH,
4.5:0.5) to give 0.040 g (89~) as a syrup; lH-NMR
(CDC13): ~ 1.74-2.10 (m, 7 H), 2.46 (s, 6 H), 2.70-2.72
(m, 1 H), 3.05 (d, J = 12.1 Hz , 2 H), 3.34 -3.48 (m, 2
H), 3.76 ( s, 3 H), 6.82 (s, 1 H), 7.11-7.32 (m, 3 H),
7.54-7.78 (m, 4 H), 8.53 (d, J = 4.6 Hz, 1 H), 8.89 (
t, J = 5.16 Hz, 2 H) .
To the free base ( 0.04g, 0.07 mmol) in 4 ml of
dichloromethane, 5 ml of lN HCl in ether was added, and
the solution concentrated under reduced pressure.
Recrystallization from ether gave 0.040 g (87~6) of 6-
(3,4-benzofurazan-5-yl) -5-methoxycarbonyl-4-methyl-2-
oxo-1- {N- [4- (2-pyridyl) -piperidine-l-yl] propyl}
carboxamido-1, 2, 3, 6-tetrahydropyrimidine
dihydrochloride as a white solid; m.p. 200-204 ~C; Anal.
Calcd. for C27H33Cl2N70s. 2.5 H2O: C, 49.77; H,5.88. Found:
C, 49.41; H 5.20.
Example 17
6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-
(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-
2,4-dimethylpyrimidine (Scheme 9).
a. 6-(3,4-D~fluorophenyl)-1,6-dihydro-2,4-dimethyl-
5-methoxycarbony}pyrimidine. To a solution of
acetamidine hydrochloride (1. 53 g, 16.2 mmol . ) in DMF
(10 mL) were added a solution of potassium tert-
butoxide (1.33 g, 11.8 mmol. ) in DMF (10 mL) and a
solution of methyl ~2- (3,4-difluorophenyl) methylene~ -
- 35 3-oxobutanoate (2.6 g, 10. 8 mmol . ) in DMF (10 mL) at
0~C. After the mixture was stirred for 0.5 hour at 0~C,
p-toluenesulfonic acid monohydrate (4.1 g, 21.5 mmol . )
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was added. The mixture was heated at 100-120~C for 2
hrs. The reaction mixture was cooled to room
temperature, quenched with a~ueous NaOH solution (2N,
60 mL), and extracted with ether. The organic layer was
dried over Na2SO4 and evaporated. The residue was flash
chromatographed over silica gel (eluent: ethyl acetate)
to give the product in 59~ yield (1.8 g) as a yellow
solid: lH NMR (300 MHz, CDC13) ~ 1.98 ~3H, s), 2.31 (3H,
s), 3.59 (3H, s), 5.47 (lH, s), 7.03-7.05 (3H, m).
(5-Chloropentyl) -6- (3, 4-difluorophenyl) -1, 6-
dihydro-2,4-dimethyl-5-methoxycarbony}pyrimidine. To a
suspension of NaH (90 mg, 60~ dispersion in mineral
oil, 2.25 mmol.) in THF (7 mL) was added a solution of
the above yellow solid (0.6 g, 2.14 mmol.) in THF (8
mL) at 0~C. After 2D min, 1-bromo-5-chloropentane (1 mL,
d 1.408, 7.59 mmol.) was added. The reaction mixture
was then refluxed overnight. After the removal of the
solvent, the residue was flash chromatographed over
silica gel (eluent: ethyl acetate) to give the product
in 75% yield (0.614 g) as a yellow oil: lH NMR (~00 MHz,
CDC13) ~ 1.42-1.75 (6H, m), 2.17 ~3H, s), 2.28 (3H, s),
3.05-3.45 (2H, m), 3.49 (2H, t, ~=5.88Hz), 3.63 (3H,
s), 5.23 (lH, s), 7.01-7.15 (3H, m).
c . 6 - ( 3, 4 -Dif luorophenyl ) -1, 6 - dihydro - 5 -
methoxycarbonyl-1- (5- (4-methoxycarbonyl-4-
phenylpiperidin-1-yl) -pentyl) -2, 4-dimethylpyrimidine .
A mixture of the above yellow oil (0.667 g, 1.73
mmol.), 4-methoxycarbonyl-4-phenyl piperidine (0.76 g,
3.47 mmol.), potassium carbonate (0.96 g, 6.95 mmol.),
sodium iodide (0.52 g, 3.47 mmol.) and 1,4-dioxane (15
mL) was refluxed overnight. The undissolved solid was
then filtered off and the solvent was evaporated. The
residue was flash chromatographed over silica gel
(eluent: 80:20 v/v ethyl acetate-2M ammonia in
methanol) to give the title compound in 78~ yield
.
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(0.768 g) as a yellow oil: CIMS, m/z 568 (MH~); iH NMR
(300 MHz, CDCl3) ~ 1.23-1.28 (2H, m), 1.43-1.51 (2H, m),
1.77-2.13 (8H, m), 2.16 (3H, s), 2.28 (3H, s), 2 47-
2.55 (2H, m), 2.74-2.81 (2H, m), 3.00-3.12 (lH, m),
3.22-3.38 (lH, m), 3.613 (3H, s), 3.615 (3H, s), 5.22
(lH, s), 6.99-7.35 (3H, m).
Treatment of the free base with 2 equivalents of lM HCl
in ether gave the HCl salt as a yellow foam: m.p. 170-
176~C. Anal. Calc. for C32H39F2N3O42HCl 2.3H2O: C, 56.35;
H, 6.74; N, 6.16; Found: C, 56.34; H, 6.62; N, 5.86.
Example 18
(+)-6-~3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-
2-oxo-1-{N-~3-(4-(2-pyridyl)-4-hydroxypiperidin-1-
yl)propyl~}carboxamido-1,2,3,6-tetrahydropyrimidine
dihydrochloride.
A solution of (+)-6-~3,4-difluorophenyl)-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)
carbonylpyrimidine (0.894 g, 2 mmol), 3-[4-(2-pyridyl~-
4-hydroxypiperidin-1-yl]propylamine (0.517 g, 2.2 mmol)
in tetrahydrofuran (100 mL) was stirred at room
temperature for 24 hours. The reaction mixture was
stirred for another 1 hour after addition of 2 ml of 6N
HCl. Solvent was evaporated at reduced pressure and
the residue was basified by treatment with 10% aqueous
KOH solution, extracted with dichloromethane (3 x 10
mL). The combined extracts were dried over potassium
carbonate, and solvent evaporated. The crude product
was purified by flash chromatography on silica gel
(dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to
give 1.20 g (97~) as a syrup. The free base was
dissolved in 20 mL anhydrous ether, cooled to 0-5 ~C and
treated with 10 mL of lN HCl in ether. The white powder
was filtered and dried to give 6-(3,4-difluorophenyl)-
5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4-~2-
pyridyl)-4-hydroxypiperidin-1-yl)propyl]}carboxamido-
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1~2~3t6-tetrahydropyrimidine dihydrochloride; m.p. 200-
206 ~C; [~] D = +91 (C = 1.15 g, in 100 mL of
chloroform). Anal. Calcd. for C27H33C12F2NsO4Ø4CHCl3: C,
48.18; H, 4.92; N, 10.18. Found: C, 48.34; H, 5.01; N,
10.08.
Example 19
(+)-1,2,3,6-Tetrahydro-l-{N-t4-(2-pyridyl)-piperidin-
l-yl]-(2-hydroxypropyl)}carboxamido-5-methoxycar~onyl
lo -2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine
dihydrochloride
a) 3 -[ 4-~2-Pyridyl)- piperidin-1-yl](2-hydroxypropyl)
phthalimide
A mixture of 4-(2-pyridyl)piperidine (3.25 g, 19.90
mmol) and 2,3-epoxypropylphthalimide (4.449 ~, 21.89
mmol) in DMF (20 mL) was stirred and heated at 70 ~C for
48 h. The solvent was evaporated under reduced
pressure and the residue was purified by column
chromatography on silica gel using chloroform-methanol-
2M ammonia in methanol (1000/28/14) as the eluent, to
obtain the desired product as a viscous oil (6.15 g,
84%).
b) 3-~4-(2-Pyridyl)-piperidin-l-yl]-2-hydroxy
propylamine
A mixture of 3 -[ 4-(2-pyridyl)- piperidin-1-yl](2-
hydroxypropyl)phthalimide (1.35 g, 3.68 mmol) and
hydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was
stirred and refluxed for 4.5 h. It was cooled,
filtered, and the solid was washed with methanol (30
mL). Evaporation of solvent from the filtrate gave the
product as a viscous oil (0.85 g, 98%).
c)(+)-1,2,3,6-Tetrahydro-1-{N-t4-(2-pyridyl)-piperidi
n-1-yl]-(2-hydroxypropyl)}carboxamido-5-methoxycarbon
yl-2-oxo-6-(3,4-difluorophenyl~-4-methylpyrimidine
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dihydrochloride
A solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6-
tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-
nitrophenoxy) carbonylpyrimidine (105 mg, 0.23 mmol),
3-[4-(2-pyridyl)piperidin-1-yl]-2-hydroxypropylamine
(50 mg, 0.23 mmol~ in tetrahydrofuran (20 mL) was
stirred at room temperature for 24 hours. Solvent was
evaporated at reduced pressure and the residue was
basified by treatment with 10% aqueous KOH solution,
extracted with dichloromethane (3 x 10 mL). The
com~ined extracts were dried over potassium carbonate,
and solvent evaporated. The crude product was purified
by fiash chromatography (dichloromethane:MeoH:2M
ammonia in MeOH,90:8:4) to give 120 mg (g7~) as a
syrup; The HCl salt was prepared by treatment with lN
HCl in ether; m.p. 215-220 ~C; [~]D = +41 (c = 1.15 g, in
100 mL of methanol). Anal. Calcd. for C27H33NsO6F2C12Ø8
MeOH: C, 52.00i H, 5.68; N, 10.90. Found: C, 52.08; H;
5.70; N, 10.53.
Example 20 and Example 21
(+)-1,2,3,6-Tetrahydro-1-{N-[3-~4-(2-pyridyl)-
piperidin-l-yl)-(2-fluoro)propyl]}carboxamido-5-metho
xycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrim
idine dihydrochloride
A mixture of (+)-1,2,3,6-tetrahydro-1-{N-I3-
(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroxy)propyl~ca
rboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophen
yl)-4-methylpyrimidine (0.50 g, 0.92 mmol),
diethylaminosulfur trifluoride (DAST, 0.222 g, 1.38
mmol, 1.5 eq.), and benzene (50 mL) was stirred at 70
~C under dry argon atmosphere for 24 h. The TLC analysis
of reaction mixture showed the complete disappearance
of the starting material. Solvent was evaporated under
- 35 reduced pressure and the residue was purified by column
chromatography on silica gel (20 g), using
chloroform/methanol/2 M ammonia in methanol (500tl6/8)
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as the eluent to give two products as a mixture of two
diastereomers. These diastereomers were purified by
chiral HPLC separation on Chiralpak A3, 4. 6 X 250 mm
column, using isocratic condition ~90% hexane and 10~
ethanol containing 0. 5~ DEA). The retention time for
the first product (example 26) was 12. 97 minutes and
for the second product (example 27) was 16.18 minutes.
The combined yield of these products is (65 mg + 65 mg~
24%. The HC1 salt was prepared by treatment with lN
HCl in ether; Example 20: m.p. 132-134 ~C; [~] D = +108
(c = 0.715 g, in 100 mL of chloroform). Anal. Calcd.
for C2~H32NsO4F3Cl2.2.0 H2O: C, 53.38; H, 5.60; N, 11.12.
Found: C, 53.28; H; S.89; N, 10.96. Example 21: m.p.
130-132 ~C; [~] D = +100 (C = O . 7 g, in 100 mL of
chloroform). Anal. Calcd. for C2~H32NsO4F3Cl2.1.5 H2O: C,
54.15; H, 5.52; N, 11.28. Found: C, 54.17; H; 5.57; N,
11 . 00 .
Note: Examples 14 and 15 are two diastereomeric
products derived from the (+)enantiomer at the
pyrimidine part and the two possible enantiomeric
compounds with respect to the fluoromethylene chiral
center.
Example 22
(I)-5-Carboxamido-6-(2,4-difluorophenyl)-4-ethyl-
1-{N-~3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
a) 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthal;mide.
A mixture of 4-cyano-4-phenylpiperidine hydrochloride
(lll g, 0.5 mol), 3-~romopropylphthalimide (135.39 g,
0.505 mol), potassium carbonate (276.42 g, 2 mol), and
potassium iodide (5.4 g) in DMF (1 L) was stirred and
heated at lO0-110 ~C for 8 h. About 80~ of the solvent
was evaporated at reduced pressure, the residue was
diluted with dichloromethane (1 L) and washed with
brine (3 X 300 mL) and dried (Na2SOq). Solvent was
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evaporated from the dichloromethane solution and the
residue was treated with isopropanol (400 mL) and
cooled. The pale yellow crystalline product formed was
filtered, washed with ice-cold isopropanol and dried
(168.6 g, 90~); M.p. 96-98 ~C.
b) 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine.
To a solution of 3-(4-cyano-4-phenylpiperidin-l-yl)
propylphthalimide (112 g, 0.3 mol) in methanol (1. 5
L), hydrazine ~30 mL) was added and the mixture was
stirred and refluxed for 20 h. It was cooled, the
white solid formed was filtered and washed with more
methanol (200 mL). Solvent was evaporated from the
filtrate and residue was dried under vacuum for 4 h.
Chloroform (500 mL) was added to this, stirred for 1 h
and filtered. The white solid was washed with more
chloroform (200 mL), the solvent was evaporated from
the combined filtrates to leave the product as an oil
(70 g, 96%).
c) Benzyl 2-[(2,4-difluorophenyl)methylene]-3-
oxopentanoate. A solution of benzyl propionylacetate
(157 g, 0.758 mol), 2,4-difluorobenzaldehyde (107.65 g,
0.758 mol), and piperidinium acetate (5.49 g, 38 mmol)
in benzene (1 L) were stirred at room temperature for
96 h. The mixture was washed with water (2 X 100 mL),
dried (magnesium sulfate) and the solvent evaporated
under reduced pressure to get the product as a pale
yellow syrup (251.2 g). It was used in the next step
without further purification.
d) 5-(Benzyloxyc~rhonyl)-1,6-dihydro-2-methoxy-4-ethyl-
6-(2,4-difluorophenyl)pyrimidine.
A suspension of benzyl 2-[(2,4-difluorophenyl)
methylene]-3-oxopentanoate (80.0 g, 0.241 mol), O-
methylisourea hemisulfate (63.8 g, 0.362 mol, 1.5 eq.),
NaHCO3 (60.48 g, 0.72 mol) in ethanol (800 mL) was
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stirred at 60-70 ~C for 20 h. After cooling to room
temperature, the mixture was filtered, and the solid
was washed with ethanol (200 mL). The solvent was
evaporated from the combined filtrates and the residue
was purified by column chromatography (SiO2,
EtOAc/Hexane, 10~-30%) to get 5-(benzyloxycarbonyl)-
1l6-dihydro-2-methoxy-4-ethyl-6-(2~4-difluorophenyl)
pyrimidine as a pale yellow oil (39 g, 42~). The lH-NMR
analysis showed it to be a mixture of amine/imine
tautomers and was used as is in the next step.
e) 5-(~enzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-
6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine.
To a well stirred solution of 5-(benzyloxycarbonyl)-
1~6-dihydro-2-methoxy-4-ethyl-6-(2~4-difluorophenyl)
pyrimidine (22.5 g, 59.3 mmol) and 4-(N,N-dimethyl
amino)pyridine (9.3 g, 75.8 mmol) in CH2C12 (200 mL) was
added a powder of 4-nitrophenyl chloroformate (15.3 g,
75.8 mmol) at 0 ~C. The reaction mixture was stirred
for 12 h at room temperature and then water (50 mL) was
added. The pH of the aqueous layer was adjusted to 10-
ll by the addition of 6 N sodium hydroxide. The
dichloromethane layer was separated and dried (Na2SO4).
Solvent was evaporated in vacuo and the residue was
purified by column chromatography (SiO2, dichloromethane
/hexane, 20%-50%) to give the product as a viscous oil
(32.0 g, 98%).
f) 5- (Benzyloxycarbonyl) -4-ethyl-1, 6-dihydro-1-{N- [2-
phenyl) ethyl] }carboxamido- 2 -methoxy- 6 - ( 2, 4 -
di f luorophenyl ) pyrimidine .
To a stirred solution of 5-(benzyloxycarbonyl)-4-ethyl-
1~6-dihydro-2-methoxy-6-(2~4-difluoropheny~ -[(4
nitrophenyloxy)carbonyl]pyrimidine (32 g, 58.11 mmol)
in dichloromethane (200 mL) was added R-(+)-~-
methylbenzylamine (9.16, 75.6 mmol) at room temperature
~ . .
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and the stirring was continued for 12 h. The mixture
was diluted with more dichloromethane (200 mL) and
washed with 0.5 N NaOH solution (2 x 60 mL). The
organic layer was dried over Na2SO4, filtered and
solvent was evaporated. The resulting mixture of
diastereomers was separated by column
chromatography(SiO2, 3~ EtOAc in toluene). The first
major product to elute was (+)-5-(benzyloxycarbonyl)-4-
ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-
methoxy-6-(2,4-difluorophenyl~pyrimidine (12.15 g,
38~). [~] D = +214 (c = 1.5 g in 100 mL CHCl3); The
second major product to elute was the other
diastereomer and no effort was made to isolate it.
g) (I)-5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-
ethyl-6-(2,4-difluorophenyl)pyrimidine.
To a stirred solution of (+)-5-(benzyloxycarbonyl)-4-
ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-
methoxy-6-(2,4-difluorophenyl)pyrimidine (11.15 g,
20.41 mmol) in toluene (250 mL) was added 1,8-
diazabicyclo~5,4,0]-undec-7-ene (4.04 g, 26.53 mmol)
and the mixture was stirred at room temperature for 14
h. The solvent was evaporated and the residue was
purified by flash column chromatography on silica gel
with 3:1 EtOAc/hexane as eluent to give (+)-5-
(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-
(2,4-difluorophenyl)pyrimidine as a viscous oil (6.15
g, 78~).
h) (I)-5-~Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)
carbonyl~pyrimidine.
To a well stirred solution of (+)-5-(benzyloxycarbonyl)
-l~6-dihydro-2-methoxy-4-ethyl-6-(2~4-difluorophenyl)
- 35 pyrimidine (4.1 g, 10.62 mmol) and 4-(N,N-
dimethylamino)pyridine (1.69 g, 13.80 mmol) in CH2Cl2
(200 mL) was added a powder of 4-nitrophenyl
~, . _ . . ,
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chloroformate ~2.78 g, 13.80 mmol) at room temperature.
The reaction mixture was stirred for 12 h and washed
with 0.5 N NaOH solution (2 X 50 mL). The organic layer
was separated and dried (Na2SO4;. The solvent was
evaporated and ~he residue was purified by column
chromatography on silica gel using
dichloromethane/hexane (20~-50~) as the eluent to glve
(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
met ho x y- 6- (2, 4 - dif luo rop he n y l) - 1 - [(4 -
nitrophenyloxy)carbonyl~pyrimidine (5.37 g, 92%) as a
viscous oil.
i) (+)-5-(Benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4-
ethyl-l-{N-~3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-5-(benzyloxycarbonyl)-4-ethyl-l~6-
dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-
nitrophenyloxy)carbonyl]pyrimidine (6.50 g, 11.81 mmol)
and3-[4-cyano-4-phenylpiperidin-1-yl]propylamine (3.60
g, ~5.36 mmol) in THF (500 mL) was stirred at room
temperature for 18 h. It was cooled to O ~C and 10% HCl
in water (2 mL) was added and stirred for 2 h. The
mixture was washed with 0.5 N aq. NaOH solution (30
mL), dried over Na2SO4 and the solvent evaporated. The
residue was purified by column chromatography on SiO2
using CHCl3/MeOH/2M NH3 in MeOH (100/2/1) as eluent to
obtain (+)-5-(benzyloxycarbonyl)-6-(2,4-
difluorophenyl)-4-ethyl-1-(N- [3-(4-cyano-
4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-
1~2~3~6-tetrahydropyrimidine as a white foamy solid
(7.05 g, 93~).
;) 6-~2,4-Difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-
4-phenylpiper~din-1-yl)propyl]}carboxamido-
1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid.
To a suspension of 10~ Pd-C (2.1 g) in MeOH (100 mL)
_,, ~
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and H2O (20 mL) was added a solution of (+)-5-
(benzy~oxycarbonyl)-6-(2,4-dlfluorophenyl)-4-ethyl-
l-~N-[3-(4-cyano-4-phenylpiperidin-l-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine( 7. 55g,
11.2 mL) in methanol (100 mL) and the mixture was
hydrogenated at 80 psi for 14 h. The black suspension
was filtered through a pad of celite and washed
thoroughly with MeOH (2.0 L) and methanol/chloroform
(1:2, 200 mL). Solvent was evaporated from the
combined filtrate to leave the product (+)-6-(2,4-
difluorophenyl)-4-ethyl-1-{N- [3-(4-cyano-
4-phenylpiperidin-1-yl)propyl]}carboxamido-
1l2~3l6-tetrahydro-2-oxopyrimidine-5-carboxylicacidas
a white solid (6.06 g, 98~). It was used in the next
step without further purification.
k) (+)-5-CarhnYa~;do-6-(2,4-difluorophenyl)-4-ethyl-
1-{N-t3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-6-(2,4-difluorophenyl)-4-ethyl-
l-~N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-
carboxylic acid (6.30 g, 11~18 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcar~odiimide hydrochloride
(4.29 g, 22.36 mmol, 2 eq.), and 4-(N,N-
dimethylamino)pyridine (3.41 g, 27.95 mmol, 2.5 eq) in
anhydrous dichloromethane (400 mL) was stirred at room
temperature for 2 h. To this, 40~ aqueous ammonia (6.13
g, 5 eq) was added and the stirring was continued for
12 h. The mixture was diluted with 200 mL of
dichloromethane and washed with saturated aqueous
ammonium chloride solution (3 X 200 mL). Solvent was
evaporated from the dried (sodium sulfate)
dichloromethane solution and the residue was purified
by column chromatography on silica gel using
chloroform-methanol-2M ammonia in methanol (100/2/l) as
the eluent, to obtain the desired product as a white
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powder (5.45 g, 87%); m.p. 210-211 ~C; Part of the
compound (300 mg) was dissolved in dichloromethane (3
mL), cooled to 0-5 ~C and treated with lN HCl in ether
~10 mL) followed by anhydrous ether (20 mL). The white
powder formed was filtered, washed with ether (100 mL)
and dried (320 mg, 100g~); m.p. 196-97 ~C; [~Y] D = +126 (c
0.505 g, in 100 mL of 1:1 chloroform/MeOH).Anal.
Calcd. for C29H33N6O3F2Cl: C, 59.27; H, 5.78; N, 14.24.
Found: C, 59.33; H; 5.67i N, 14.32.
Example 23
(+) - S - Carboxamido - 6 - (3, 4 - di f luorophenyl ) - 4 -
methoxymethyl-1-{N- [3- (4 (2-pyridyl)piperidin-1-yl)
propyl~}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine
dihydrochloride.
a) 2-Cyanoethyl 4-methoxyacetoacetate.
A mixture of methyl 4-methoxyacetoacetate ~50 g, 0.342
mol) and 3-hydroxypropionitrile (31.61 g, 0.444 mol)
was heated to 160-180 ~C in a distillation set-up. It
was kept at that temperature for 2 h until the
distillation of the methanol stopped. The residual
yellow oil of 2-cyanoethyl 4-methoxyacetoacetate (56.4
g, go~) was used as is without any further
purification.
b) 2-Cyanoethyl 2- [(3,4-difluorophenyl)methylene] -3-
oxo-4-methoxybutyrate.
A solution of 2-cyanoethyl 4-methoxyacetoacetate (17.8
g, 0.125 mol), 3,4-difluorobenzaldehyde (25.5 g, 6.26
mmol), acetic acid (0.376 g, 6.26 mmol), and piperidine
(0.533 g, 6.26 mmol) in benzene (500 mL) were added
molecular sieves (200 g) and the mixture was stirred at
room temperature for 24 h. Then the solvent was
evaporated under reduced pressure and the residue was
purif ied by column chromatography using
chloroform/ethyl acetate (100:5) to get the product as
an oil (29 g, 75~).
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c) 5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-
methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
A suspension of 2-cyanoethyl 2-[(3,4-
difluorophenyl)methylene]-3-oxo-4-methoxybutyrate ~29
g, 0.094 mol), O-methylisourea hemisulfate (21 g, 0.121
mol, 1.3 eq.), dimethylaminopyridine (29.67 g, 0.243
mol, 2.5 eq.) in ethanol (400 mL) was stirred at 50-55
~C for 6 h. The solvent was evaporated from the
combined filtrates and the residue was purified by
10 column chromatography (Sio2~ EtOAc/hexane, 10%-30%) to
get 5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-
methoxymethyl-6-(3,4-difluorophenyl)pyrimidine as a
pale yellow oil (10.5 g, 31%). The lH-NMR analysis
showed it to be a mixture of amine/imine tautomers and
15 was used as is in the next step.
d) 5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-
dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-~(4-
nitrophenyloxy)carbonyl]pyrimidine.
20 To a well stirred solution of 5-(2-cyanoethoxy
carbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-
dif1uorophenyl)pyrimidine (10.5 g, 28.74 mmol) and 4-
(N,N-dimethylamino)pyridine (6.95 g, 34.49 mmol) in
CH2Cl2 (100 mL) was added a powder of 4-nitrophenyl
chloroformate (4.21 g, 34.49 mmol) at 0 ~C. The
reaction mixture was stirred for 12 h at room
temperature and then the solvent was evaporated. The
residue was purified by column chromatography (SiO2,
~ dichloromethane/hexane, 20%-50%) to give the product as
a viscous oil (6.5 g, 43%).
e) 5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-
dihydro-l-{N-~2-phenyl)ethyl]}carboxamido-2-methoxy-6-
(3,4-difluorophenyl)pyrimidine.
~ 35 To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4-
methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-
difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl~
-
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pyrimidine (6.5 g, 12.25 mmol) in dichloromethane ~150
mL) was added ~-(+)-~-methylbenzylamine (1.78 g, 14.7
mmol) at room temperature and the stirring was
continued for 12 h. Solvent was evaporated and the
residue was purified by column chromatography (SiO2, 10-
20~ EtOAc in hexane). The first major product to elute
was (+)-5-(2-cyanoethoxycarbonyl)-4- methoxmethyl-1,6-
dihydro-l-~N-[2-phenyl)ethyl])carboxamido-2-methoxy-6-
(3,4-difluorophenyl)pyrimidine (2.54 g, 44-5~)-[~]D =
10 +177.8 (c = 9.2 g in 100 mL CHC13); The second major
product to elute was the other diastereomer and no
effort was made to isolate it.
f) (I)-5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-
15 4-ethyl-6-(3,4-difluorophenyl)pyrimidine.
To a stirred solution of (+)-5-(2-cyanoethoxycarbonyl)-
4-methoxymethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}
car~oxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine
(2.80 g, 5.46 mmol) in toluene (80 m~) was added 1,8-
20 diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol)
and the mixture was stirred at 75 ~C for 1 h. The
solvent was evaporated and the residue was purified ~y
flash column chromatography on silica gel with 3:1
EtOAc/hexane as eluent to give (+)-5-(2-
25 cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-
methoxymethyl-6-(3,4-difluorophenyl)pyrimidine as a
viscous oil (0.82 g, 40.5%).
g) (~)-5-~2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-
30 dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-
nitrophenyloxy)carbonyl]pyrimidine.
To a well stirred solution of ~+)-5-(2-
cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-
methoxymethyl-6-(3,4-difluorophenyl)pyrimidine(0.82g,
35 2.24 mmol) and 4-(N,N-dimethylamino)pyridine (0.329 g,
2.69 mmol) in CH2Cl2 (200 mL~ was added a powder of 4-
nitrophenyl chloroformate (0.543 g, 2.69 mmol) at room
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temperature. The solvent was evaporated and the
residue was purified by column chromatography on silica
gel using dichloromethane/hexane ~20~-50~) as the
eluent to give (+)-5-(2-cyanoethoxycarbonyl)-4-
methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-
difluorophenyl)-1-[~4-nitrophenyloxy)carbonyl]
- pyrimidine (0.80 g, 67%) as a viscous oil.
h ) ( + ) - 5 - ( 2 - Cyanoe thoxyc arbonyl ) - 6 - ( 3, 4 -
difluorophenyl) -4 -methoxymethyl-1- {N- [3 - (4 - (2 -
pyridyl) piperidin-1-yl) propyl] }carboxamido-2 -oxo-
1, 2, 3, 6 - tetral~yd~y ~ imidine .
A mixture of (+)-5-(2-cyanoethoxycarbonyl)-4-
methoxymethyl-1,6-dihydro-2-methoxy-6-~3,4-
difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl~
pyrimidine (0.44 g, 0.83 mmol) and 3-[4-(2-
pyridyl)piperidin-1-yl]propylamine (0.218 g, 0.996
mmol) in THF (15 mL) was stirred at room temperature
for 12 h. It was cooled to 0 ~C and 10~ HCl in water (2
mL) was added and stirred for 2 h. Solvent was
evaporated and the residue was purified by column
chromatography on SiO2 using CHCl3/MeOH/2M NH3 in MeOH
(100/2/1) as eluent to obtain (+)-5-(2-
cyanoethoxycarbonyl)-6-(3,4-difluorophenyl)-4-
methoxymethyl-1-~N-[3-(4-(2-pyridyl)piperidin-1-yl)
propyl]~carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine
as a white foamy solid (0.41 g, 83~).
i) 6-(3,4-Difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-
(2-pyridyl)piperidin-1-yl)propyl~}carboxamido-
1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid.
To a stirred solution of (+)-S-(2-cyanoethoxycarbonyl)-
6-~3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-
pyridyl)piperidin-1-yl)propyl]~car~oxamido-2-oxo-
~ 1~2~3~6-tetrahydropyrimidine (0.34 g, 0.57 mmol) in
acetone ~5 mL) at 0 ~C, sodium hydroxide solution (1 N,
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1.71 mL) was added drop wise and the stirring was
continued until the disappearance of the starting
material (1 hour). Most of the acetone from the
mixture was evaporated under reduced pressure while
keeping the temperature at 0 ~C and the residue was
adjusted to pH 7.0 by the addition of lN hydrochloric
acid. The white precipitate of 6-(3,4-
difluorophenyl)-4-methoxymethyl-1-~N-[3-(4- (2-
pyridyl)piperidin-l-yl)propyl])carboxamido-
lo 1~2~3~6-tetrahydro-2-oxopyrimidine-5-carboxylic acid
formed was filtered and dried under vacuum (0.30 g,
g6~) .
j) (I)-5-Carboxamido-6-(3,4-difluorophenyl)-4-
methoxymethyl-1-{N-~3-(4-~2-pyridyl)piperidin-1-yl)
propyl]}carbox~;do-2-oxo-1,2,3,6-tetr~,~ ~y imidine.
A mixture of (+)-6-(3,4-difluorophenyl)-4-
methoxymethyl-l-~N-[3-(4-(2-pyridyl)piperidin-1-yl)
propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-
5-carboxylic acid (0.30 g, 0.55 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.212 g, 1.1 mmol, 2 eq.), and 4-(N,N-
dimethylamino)pyridine (0.134 g, 1.1 mmol, 2 eq) in
anhydrous dichloromethane (20 mL) was stirred at room
temperature for 2 h. To this, 40~ aqueous ammonia (0.64
g, 10 eq) was added and the stirring was continued for
12 h. The mixture was diluted with 20 mL of
dichloromethane and washed with saturated aqueous
ammonium chloride solution (3 X 200 mL). Solvent was
evaporated from the dried ~sodium sulfate)
dichloromethane solution and the residue was purified
by column chromatography on silica gel using
chloroform-methanol-2M ammonia in methanol (100/2/1) as
the eluent, to obtain the desired product as a white
powder (0.232 g, 78~)i The HCl salt of this compound
was prepared by treatment with 1 N HCl in ether. m.p.
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95-97 ~C; [~] D = +139 (c = 2.1 g, in lOo mL of
chloroform). ~nal. Calcd. for C27H34N6O4F2C12.2.2 H2O: C,
49.50; H, 5.91; N, 12.83. Found: C, 49.50; H, 5.89; N,
12.43.
Example 24
(+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4-
methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)
propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-6-~3,4-difluorophenyl)-4-
methoxymethyl~ N-[3-(4-(2-pyridyl)piperidin-1-yl)
propyl]~carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-
5-carboxylic acid (0.30 g, 0.55 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.212 g, 1.1 mmol, 2 eq.), and 4-(N,N-dimethylamino)
pyridine (0.134 g, 1.1 mmol, 2 eq) in methanol (20 mL)
was stirred at room temperature for 20 h. Solvent was
evaporated and the residue was dissolved in 20 mL of
dichloromethane and washed with saturated a~ueous
ammonium chloride solution (3 X 200 mL). Solvent was
evaporated from the dried (sodium sulfate)
dichloromethane solution and the residue was purified
by column chromatography on silica gel using
chloroform-methanol-2M ammonia in methanol (100/2/1) as
the eluent, to obtain the desired product as a white
powder (278 mg, 91%); The HCl salt of this compound was
prepared by treatment with 1 N HCl in ether. m.p. 180-
184 ~C; [~]D = +122 (c = 1.25 g, in 100 mL of methanol).
Anal. Calcd. for C28H3sNsosF2cl2~l.o H2O: C, 51.86; H,
5.75; N, 10.80. Found: C, 52.14; H, 5.72; N, 10.53.
Example 25
(+)-1,2,3,6-Tetrahydro-l-{N-t3-(4-(2-pyridyl)-
piperidine-1-yl)-(2-oxo)propyll}carboxamido-5-methoxy
car~onyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethyl
pyrimidine dihydrochloride
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a) Methyl 2-[(3,4-difluorophenyl) methylene~-3-oxo-4-
methoxy~utyrate.
A solution of methyl 4-methoxyacetoacetate (84 . 32 g,
0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577
mmol), and piperidinium acetate (5 . 86 g, 0 . 068 mol) in
benzene (1.5 L) were added molecular sieves (400 g) and
the mixture was stirred at room temperature for 48 h.
The molecular sieves were removed by filtration and the
solvent was evaporated ~rom the f iltrate under reduced
pressure. The residue was purified by column
chromatography on silica gel using chloroform/ethyl
acetate ( 100: 3 ) to get the product as an oil ( 67 g,
47g~) -
b) 5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4-
methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
A suspension of methyl 2-[(3, 4-difluorophenyl)
methylene] -3-oxo-4-methoxybutyrate (7 . 50 g, 27 . 75
mmol), O-methylisourea hemisulfate (7.17 g, 41.63 mmol,
1.5 eq.), sodium bicarbonate (6.99 g, 83.25 mmol, 3
eq. ) in ethanol (400 mL) was stirred at 50-55 ~C for 6
h . The solvent was evaporated f rom the combined
f iltrates and the residue was purif ied by column
chromatography (SiO2, EtOAc/hexane, 10g6-30~) to get 5-
methoxycarbonyl-1, 6-dihydro-2-methoxy-4-methoxymethyl-
6- (3,4-difluorophenyl)pyrimidine as a pale yellow oil
(4 . 3 g, 47~? . The lH-NMR analysis showed it to be a
mixture of amine/imine tautomers and was used as is in
the next step.
c) 5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-
methoxy-6-(3,4-difluorophenyl)-1-l(4-nitrophenyloxy)
carbonyl]pyrimidine.
To a well stirred solution of 5-methoxycarbonyl-1, 6-
dihydro-2-methoxy-4-methoxymethyl-6 - (3, 4-
difluorophenyl)pyrimidine (4.3 g, 13.18 mmol) and 4-
(N,N-dimethylamino)pyridine (2.09 g, 17.13 mmol) in
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CH2Cl2 (100 mL) was added a powder of 4-nitrophenyl
chloroformate (3.45 g, 17.13 mmol) at 0 ~C. The
reaction mixture was stirred for 12 h at room
temperature and the solid formed was removed by
filtration. Solvent was evaporated from the filtrate
and the residue was purified by column chromatography
- (SiO2, dichloromethane/heY~ne, 20~-50%) to give the
product as a viscous oil (3.85 g, 59~).
d) 5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-1-{N-
[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-
difluorophenyl)pyrimidine.
To a stirred solution of 5-methoxycarbonyl-4-
methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-
difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine (3.82 g, 7.77 mmol) in THF (140 mL) was
added R-(+)-~-methylbenzylamine (1.13 g, 9.33 mmol, 1.2
eq.) at room temperature and the stirring was continued
for 12 h. Solvent was evaporated and the residue was
purified by column chromatography (SiO2, 10-20~ ~tOAc in
hexane). The first major product to elute was (+)-5-
methoxycarbonyl-4-methoxmethyl-1,6-dihydro-1-{N-[2-
phenyl)ethyl])carboxamido-2-methoxy-6-(3,4-
difluorophenyl)pyrimidine (1.74 g, 44-5%)-~]D = +205.5
(c = 5.1 g in 100 mL CHCl3); The second major product to
elute was the other diastereomer and no effort was made
to isolate it.
e) (+)-5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4-
methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
To a stirred solution of ~+)-5-methoxycarbonyl-4-
methoxymethyl-1,6-dihydro~ N-I2-phenyl)ethyl])
carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine
(1.74 g, 3.67 mmol) in toluene (40 mL) was added 1,8-
diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol)
and the mixture was stirred at 70-80 ~C for 1.5 h. The
solvent was e~aporated and the residue was purified by
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- 1 0 6 -
flash column chromatography on silica gel with 9 :1
CHC13/EtOAc as eluent to give ( + ) - 5 -methoxycarbonyl - i, 6 -
dihydro-2 -methoxy-4 -methoxymethyl - 6 - ( 3, 4 -
difluorophenyl)pyrimidine as a viscous oil (1.11 g,
92 . 5~) .
f) (+)-5-Methoxyc~rhrnyl-4-methoxymethyl-1,6-dihydro-2-
methoxy-6-(3,4-difluorophenyl)-1-~(4-nitrophenyloxy)
carbonyl]pyrimidine.
To a well stirred solution of (+)-5-methoxycarbonyl-
1, 6 -dihydro- 2 -methoxy- 4 -methoxymethyl - 6 - ( 3, 4 -
dif luorophenyl ) pyrimidine ( 1 . ll g, 3 . 4 mmol ) and 4 -
(N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol) in
CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl
chloroformate (0.891 g, 4.42 mmol) at room temperature.
The solvent was evaporated and the residue was purified
by column chromatography on silica gel using CHCl3/EtOAc
( 2 0 ~ - 5 0 ~6 ) as the e luent to give ( + ) - 5 - methoxycarbonyl -
4-methoxymethyl-1, 6-dihydro-2-methoxy-6- (3, 4-
difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl]
pyrimidine (1.30 g, 78g6) as a viscous oil. [~]D = +262.2
(c = 2 . 3 g in 100 mL CHCl3) .
g) (+)-1,2,3,6-Tetrahydro-l-{N-13-(4-~2-pyridyl)-
piperidine-1-yl)-(2-hydroxy)propyl]}carboxamido-5-met
hoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxyme
thylpyrimidine.
A solution of (+) -6- (3, 4-difluorophenyl) -1, 6-dihydro-2-
methoxy- 5 -methoxycarbonyl -4 -methoxymethyl - l - ( 4 -
nitrophenoxy)carbonylpyrimidine (0.450 g, 0.91 mmol),
3 - [4 - ( 2 -pyridyl ) piperidin- l -yl] - 2 -hydroxypropylamine
(0.280 g, 1.19 mmol) in tetrahydrofuran (100 mL) was
stirred at room temperature for 24 hours. The reaction
mixture was stirred for another 1 hour after addition
3 5 of 2 ml of 6N HCl . Solvent was e~aporated at reduced
pressure and the residue was basif ied by treatment with
10~ aqueous KOH solution, extracted with
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dichloromethane (3 x 10 mL). The combined extracts
were dried over potassium carbonate, and solvent
evaporated. The crude product was purified by flash
chromatography (dichloromethane:MeOH:2M am~nonia in
MeOH,90:8:4) to give 0.514 ~ (989~) as a syrup.
h) (+)-1,2,3,6-Tetrahydro-1-{N- ~3- (4-(2-pyridyl) -
piperidine-l-yl)- (2-oxo)propyl~ }carboxamido-5-methoxy
carbonyl-2-oxo-6- ~3,4-d~fluorophenyl) -4-methoxymethyl
pyrimidine dihydrochloride
To a stirred solution of DMSO (0.174 g, 2.23 mmol) in
dichloromethane (5 mL) at -78 ~C, oxalyl chloride (0.135
g, 1.07 mmol) in dichloromethane (5 mL) was added and
the mixture was stirred for 3 min. To this, a solution
of (l)-1,2,3,6-tetrahydro-1-{N- [3-(4-(2-pyridyl)-
piperidine-1-yl)- (2-hydroxy)propyl])carboxamido-5-met
hoxycarbonyl-2-oxo-6- (3,4-difluorophenyl)-4-methoxyme
thylpyrimidine (0.51 g, 0.889 mmol) in dichloromethane
(5 mL) was added and the stirring was continued for 15
min. It was warmed to room temperature and added 5 mL
of water. The pH of the mixture was adjusted to 10-11
by adding lN NaOH and the dichloromethane layer was
separated. The aqueous layer was extracted with more
dichloromethane (3 X 10 mL). The combined
dichloromethane extracts were dried (magnesium
sulfate), solvents evaporated, and the residue was
purif ied by f lash chromatography
(dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to
give 0.32 g (63%) of the product as a syrup. [~]~, = +122
(c = 0.55 g in 100 mL CHCl3); Anal. Calcd. for
C29H33NsO6F2Cl2.2.5 H2O: C, 48.77; H, 5.55; N, 10.16.
Found: C, 48.71i H, 5.72; N, 9.87.
Example 26 and Example 27
Syn and anti i~omers of (1)-1,2,3,6-tetrahydro-1-{N-[3-
(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroYim;no)propyl
] }carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluoro
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phenyl)-4-methoxymethylpyrimidine dihydrochloride
A solution of ~+)-1,2,3,6-tetrahydro~ N-[3-
(4-(2-pyridyl)-piperidin-1-yl)-(2-oxo)propyl]}carboxa
mido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4
-methoxymethylpyrimidine (0.14 g, 0.22 mmol),
hydroxylamine hydrochloride (19.6 mg, 0.28 mmol), and
sodium acetate (74.8 mg, 0.55 mmol) in methanol (5 mL)
was stirred at room temperature for 24 h. Solvent was
evaporated at reduced pressure, the residue was mixed
with dichloromethane (30 mL) and washed with water.
The dichloromethane solution was dried (sodium sulfate)
and the solvent evaporated. The residue was purified
by column chromatography on silica gel
tchloroform:MeOH:2M ammonia in MeOH,90:8:4). The first
product to elute was Example 26, syn isomer with
respect to oxime hydroxyl and piperidine ~30 mg); [O~] D
+94.1 (c = 0.528 g in 100 mL CHCl3); The HCl salt was
prepared by treatment with lN HCl in et}ler; m.p. 90-92
~C; Anal. Calcd. for C28H34N6O6F2C12.1.5 H2OØ6 CH2Cl2: C,
47.65; H, 5.35; N, 11.26. Found: C, 47.67; H; 5.56; N,
11.36.
The second product to elute was example 33, anti isomer
with respect to oxime hydroxyl and piperidine (70 mg);
[CY~D = +104 (c = 0.3 g in 100 mL CHCl3)i The HCl salt
was prepared by treatment with lN HCl in ether; m.p.
103-105 ~C; Anal. Calcd. for C28H34N6O6F2Cl2.2.2 H2OØ22
CH2Cl2: C, 47.74; H, 5.51; N, 11.84. Found: C, 48.01;
H, 5.72; N, 11.57.
Example~ 28
(+) -1, 2,3, 6-Tetrahydro-l-{N- [3- (4- (2-pyridyl) -
piperidine-1-yl)-(2-methoximino)propyl]}carboxamido-5
-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-metho
xymethylpyrimidine dihydrochloride
A solution of (+)-1,2,3,6-tetrahydro-1-{N-[3-
(4-(2-pyridyl)-piperidine-l-yl)-(2-oxo)propyll}carbox
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- 1 0 9 -
amido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl~-
4-methoxymethylpyrimidine (30 mg, 0.047 mmol), O-
methoxylamine hydrochloride (7.78 mg, 0.093 mmol), and
sodium acetate (32 mg, 0.24 mmol) in methanol (5 mL)
was stirred at room temperature for 24 h. Solvent was
evaporated at reduced pressure, the residue was mixed
with dichloromethane (30 mL) and washed with water.
The dichloromethane solution was dried (sodium sulfate)
and the solvent e-~aporated. The residue was purified
by column chromatography on silica gel
(chloroform:MeOH:2M ammonia in MeOH,90:8:4). Only one
isomeric product was detected by this purification (20
mg, 71~); [~x] D = +98 (c = 0.4 g in 100 mL CHCl3); The
HCl salt was prepared by treatment with lN HCl in
ether; m.p. 109-112 ~C; Anal. Calcd. for
C29H36N6O6F2C12.2.3H2OØ46 CH2C12: C, 46.93; ~, 5.55; N,
11.15. Found: C, 47.08; H, 5.66; N, 10.88.
Example 29
( + ) - 1 , 2 , 3 , 6 - T e t r a h y d r o - 1 - { N - [ 3
(4- (2-car~oxamidophenyl)-piperazin-1-yl)-propyl] }carb
oxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-me
thylpyrimidine dihydrochloride
a) 3-{(3,4,5-Trifluorophenyl)methylene}-2,4-
pentan~lione.
A mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2
mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), piperidine
(0.430 g, 5 mmol)in benzene (150 mL) was stirred and
refluxed with a Dean-Stark trap for 8 hours. Benzene
was evaporated, the yellow oily residue, 2-~(3,4,5-
trifluorophenyl)methylene}-2,4-pentanedione, was used
in the next step without any further purification.
b) 6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxy-
5-acetyl-4-methylpyrimldine.
A mixture of 2-{(3,4,5-trifluorophenyl)methylene}-2,4-
,
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- 1 1 0 -
pentanedione ~26.2 mmol), O-methylisourea hydrogen
sulfate (3.22 g, 39.3 mmol), and NaHCO3 (6.6 g, 78.6
mmol) in EtOH (400 mL) was stirred and heated at 95-100
~C for 6 hours. The mixture was filtered, the solid
residue was washed with ethanol ~100 mL). Solvent was
evaporated from the combined filtrate and the crude
product was purified by flash column chromatography on
silica gel using 10% through 25~ EtOAc in hexane as the
gradient eluent, to leave the product as an oil (2.80
g, 36~).
c) 6-~3,4,5-Trif~uorophenyl)-1,6-dihydro-2-methoxy-
5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine
To a solution of 6-(3,4,5-trifluorophenyl)-
1l6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine (2.8
g, 9.38 mmol) and pyridine (10 mL) in CH2Cl2 (200 mL) at
0-5 ~C, 4-nitrophenyl chloroformate (1.886 g, 9.38 mmol)
was added and the mixture was allowed to warm to room
temperature. After 12 hours solvent was evaporated and
the residue was purified by flash column chromatography
(SiO2, dichloromethane/EtOAc, 10~-15~)to obtain the
product as a white powder (4.0 g, 92~).
d) 6-(3,4,5-Trifluorophenyl)-1,2,3,6-tetrahydro-2-oxo-
5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim
idine.
To a well-stirred solution of 6-(3,4,5-
trifluorophenyl)-1,6-dihydro-2-methoxy-
5-acetyl-4-methyl-1-~(4-nitrophenyloxy)carbonyl]pyrim
idine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5 ~C, 6N
aqueous HCl (4 m~) was added and the mixture was
allowed to warm to room temperature. After 2 h, sol~ent
was evaporated and the product dried under vacuum. The
product was obtained as a pure single component and no
need for further purification (3.88 g, 100~).
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- 111 -
e) (I) - 1, 2, 3, 6- T e tr a h y d r o- 1 - { N - ~3 -
(4-(2-carboxamidophenyl)-piperazin-1-yl)-propyl]}carb
oxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-me
thylpyrimidine dihydrochloride
A mixture of 6-(3,4,~-difluorophenyl)-1,2,3,6-tetra
hydro-2-oxo-5-acetyl-4-methyl-1-[~4-nitrophenyloxy)
carbonyl]pyrimidine (44.9 mg, 0.1 mmol) and 3-
[4-(2-carboxamidophenyl)-piperazin-1-yl]-propylamine
~26.2 mg, 0.1 mmol) in THF (10 mL) was stirred at room
temperature for 10 h and the solvent evaporated. It
was redissolved in dichloromethane ~10 mL), washed with
ice-cold 0.5 N NaOH (2 X 5 mL), dried and solvent
evaporated. The residue was purified by preparative
thin layer chromatography on silica gel using
chloroform-methanol-2M ammonia in methanol (100/2/1) as
the eluent to afford the product as a white powder (60
mg, 93~); The HCl salt was prepared by treatment with
lN HCl in ether to give the product as a
dihydrochloride salt. Anal. Calcd. for C2~H33N6O4Cl2F30.4
H2O: C, 51.52; H, 5.22; N, 12.88. Found: C, 51.70; H,
5.25; N, 12.53.
Example 30
1,2,3,6-Tetrahydro-l-{N-[3-(4-(4-~luorobenzoyl)
piperidin-1-yl)ethyl]}carhoxa~;do-5-methoxycarbonyl-4
-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine
hydrochloride
a) 6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-
methoxycarbonyl-4-methyl-1-(4-nitrop~n~Yy)
carbonylpyrimidine.
A well stirred solution of 6-(3l4-difluorophenyl)-l~6-
dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-
nitrophenoxy)carbonylpyrimidine (10 g) in THF (200 mL)
at room temperature, aqueous 6N hydrochloric acid (10
mL) was added and the stirring was continued for 3 h.
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-112-
Solvent was evaporated and the residue was dried under
vacuum to obtain the product as a white powder (9.7 g,
100~); m.p. 185-186 ~C.
b) 6-(3,4-Difluorophenyl)-1,2,3,6-tet~ahydro-2-oxo-5-
methoxycarbonyl-4-methyl-1-(2-bromoethylamino
~hQ~yl)pyr~idine.
A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-
2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)
carbonylpyrimidine (0.5 g, 1.118 mmol), 2-
bromoethylamine hydrobromide ~0.458 g, 2.237 mmol), and
potassium carbonate ~2.0 g) in THF/water (50 mL/5 mL)
were stirred at room temperature for lh. Then most of
the solvent was evaporated at reduced pressure. The
residue was partitioned between dichloromethane and
water (100 mL and 100 mL). The dichloromethane layer
was separated, washed with ice-cold 0.5 N NaOH (2 X 50
mL) and dried (sodium sulfate). Evaporation of the
solvent gave the product as a single product (0.48 g,
100~) as a white powder; m.p. 159-160 ~C.
c ) 1 , 2 , 3 , 6 - T e t r a h y d r o - 1 - { N - [ 2 -
(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl~}carboxamido
-5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-
~u~ imidine hydrochloride
A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-
2-oxo-5-methoxycarbonyl-4-methyl-1-~2-bromoethylamino
carbonyl)pyrimidine (43 mg, 0.1 mmol), 4-(4-
fluorobenzoyl)piperidine p-toluene sulfonate (57 mg,
0.15 mmol), potassium carbonate (300 mg), and potassium
iodide (30 mg) in THF(10 mL) was stirred at room
temperature for 20 h. The solid material was removed
by filtration, the solvent from the filtrate was
evaporated, and the residue was purified by preparative
thin layer chromatography on silica gel using
chloroform-methanol-2M ~mmQni a in methanol (100/2/1) as
.
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-113-
the eluent to afford the product as a viscous oil which
was converted to the HC1 salt by treatment with lN HCl
in ether; m.p. 159-160 ~C; Anal. Calcd. for
C29H29N4O5F3.1HClØ8Et2O: C, 57.27; H, 5.85; N, 8.56.
Found: C, 57.31; H; 5.75; N, 8.79.
Example 31
1,2,3,6-Tetrahydro-l-{N-~3-(4-(4-fluorophenyl)-4-
hydroxypiperidin-l-yl)propyl]}carboxamido-5-methoxyca
rbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine
hydrochloride
a) 6-(3,4-D~fluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-
methoxyca~hQ~yl-4-methyl-1-t3-bromopropylamino
c~r~nyl) pyri~ 9-
A mixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-
2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)
carbony~pyrimidine (1.0 g, 2.237 mmol), 3-
bromopropylamine hydrobromide (0.979 g, 4.474 mmol),
and potassium carbonate (4.0 g) in THF/water (100 mL/10
mL) were stirred at room temperature for lh. Then most
of the solvent was evaporated at reduced pressure. The
residue was partitioned between dichloromethane and
water (100 mL and 100 mL). The dichloromethane layer
was separated, washed with ice-cold 0.5 N NaOH (2 X 50
mL) and dried (sodium sulfate). Evaporation of the
solvent ga~e the product as a single product (0.98 g,
100~) as a white powder and confirmed by lH-NMR.
b) 1,2,3,6-Tetrahydro-1-{N-t3-(4-~4-fluorophenyl)-4-
hydroxypiperidin-1-yl)propyl~}carboxamido-5-methoxyca
rbonyl-4-methyl-6-(3,4-difluorophenyl)-2-ox~ imidine
hydrochloride
A mixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-
2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylamino
3~ carbonyl)pyrimidine (44.6 mg, 0.1 mmol), 4-(4-
fluorophenyl)-4-hydroxypiperidine (28.7 mg, 0.15 mmol),
potassium carbonate (300 mg), and potassium iodide (30
mg) in THF(10 mL) was stirred at room temperature for
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20 h. The solid material were removed ~y filtration,
the solvent from the filtrate was evaporated, and the
residue was purified by preparative thin layer
chromatography on silica gel using chloroform-methanol-
2M ammonia in methanol (100/2/1) as the eluent to
afford the product as a viscous oil which was converted
to the HCl salt by treatment with lN HCl in ether; m.p.
160-164 ~C; Anal. Calcd. for C29H29N4O5F3.lHClØ8Et2O: C,
57.27; H, 5.85; N, 8.56. Found: C, 57.31; H; 5.75; N,
8.79.
Example 32
a) (-) -S- (Elenzylo~cycarbonyl) -4-ethyl-1, 6-dihydro-2-
methoxy- 6 - ( 3, 4 - di f luorophenyl ) -1 -me thoxy -
carbonyll pyrimidine .
To a well stirred solution of (-)-5-
(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-
(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-
(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in
CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL,
2.66 mmol) at room temperature. The solvent was
removed in vacuo and the residue was purified by column
chromatography on silica gel with 3:1 Petroleum
ether/EtOAC as the eluting system to obtain 0.45 g (78%
yield) of (-)-5-(benzyloxycarbonyl)-4-ethyl-1,6-
dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxy-
carbonyl]pyrimidine as a colorless oil.
b) ( - ) -1, 2, 3, 6-Tetrahydro-4-ethyl-2 -oxo-6 - (3, 4-
difluorophenyl) -1- ~methoxycarbonyl] pyrimidine - 5 -
carboxylic acid.
To a solution of (-)-5-(benzyloxycarbonyl)-4-ethyl-
1, 6-dihydro-2-methoxy-6-(3,4 -difluorophenyl) -1-
[methoxycarbonyl]pyrimidine (0.45 g, 1.18 mmol) in 20
mL of MeOH was added 0.05 g of 10% Pd on carbon and the
resulting suspension was hydrogenated under 100 psi for
12 h. The catalyst was then filtered through a pad of
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-115-
celite and was washed thoroughly with MeOH. A~l the
MeOH washings were collected and the solvent was
removed in vacuo to obtain 0.42 g (99% yield) of (-)-
1~2~3~6-tetrahydro-4-ethyl-2-oxo-6-(3~4-
difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-
carboxylic acid as a white solid which was used in the
- next reaction without further purification.
c) (-)1,2,3,6-Tetrahydro-5-{N-~3-(4-methoxyc~hnnyl)-4-
phenyl-piperidin-1-yl]propyl}-carboxamido-1-
methoxycarbonyl-4-ethyl-6-(3,4-difl~orophenyl)-2-oxo-
pyrimidine.
To a solution of (-)-1,2,3,6-tetrahydro-4-ethyl-2-oxo-
6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-
carboxylic acid (1.18 mmol, 0.4 g) and 3-[4-
methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine
(1.23 mmol, 0.34 g) in 20 mL CH2C12 was added 4-(N,N-
dimethylamino)-pyridine (1.16 mmol, 0.15 g), followed
by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.84
mmol, 0.54 g) and the resulting solution was stirred at
room temperature under argon for 2 days. The solution
was then transferred into a separatory funnel,
extracted with CH2C12, washed with sat. NH4Cl solution
(2 X 20 mL) and then with brine (20 mL). The organic
layer was separated and dried over Na2SO4, filtered and
the solvent was evaporated in vacuo to obtain an off-
white solid. It was purified by column chromatography
on silica gel with 10~ MeOH in EtOAc as the solvent
system to obtain (-)1,2,3,6-tetrahydro-5-{N-[3-(4-
methoxycarbonyl)-4-phenyl-piperidin-l-yl]propyl}-
carboxamido-l-methoxycarbonyl-4-ethyl-6-(3,4-
difluorophenyl)-2-oxo-pyrimidine as a white solid (0.55
g, 79~ yield). M.P. 53-55~C; I~ID = -48.5 (c = 0.43,
CHCl3). It was characterized as HC1 salt. Anal. Calcd.
For C31H3~N4O6F2ClØ4 CHCl3: C, 55.23; H, 5.52; N, 8.20.
Found: C, 55.29; H, 5.35; N, 7.99.
._ ~ . ,
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Example 33
(+)-1-3-{[4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-
tetrahydro-4H-furo[3,4-d]-pyr~midine-3-c~h~yl]smino}-
propyl-4-phenyl-piperidine-5-carboxylic acid methyl
ester.
a) (I)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-
methoxy-carbonyl-4-bromomethyl-1-[(4-nitrophenyl-
oxy)carbonyl]pyrimidine.
To a well stirred solution of (+) -6-(3, 4-
difluorophenyl)-1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-1-[~4-nitrophenyloxy)
carbonyl]pyrimidine tl.5 mmol, 0.66 g~ in 5 mL of
chloroform was added a solution of bromine (1.5 mmol,
0.09 mL) in 3 mL of chloroform at 0~C and the solution
was allowed to attain room temperature over 1.5 h. The
solvent was removed in vacuo and the residue was again
dissolved in CHCl3 ~20 mL) and washed with brine. The
organic layer was separated, dried over Na2S04, filtered
and the solvent was removed in vacuo to get 0.81 g of
(+) -6- (3, 4-difluorophenyl)-1, 2,3, 6-tetrahydro-2-oxo-5-
methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)
carbonyl]pyrimidine as a yellow foam. It was used in
the next step without any purification.
b) (+) -4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,4,5,6,7-
hexahydro-cyclopentapyrimidine-3-carboxylic acid-4-
nitrophenyl ester.
(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-methoxy-
carbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)
carbonyl]pyrimidine (1.5 mmol, 0.81 g) was heated in
oil bath for 3 h (bath temperature 130~C). The brown
residue thus obtained was washed with CHCl3 and (+)-4-
(3, 4-difluoro-phenyl)-2,5-dioxo-1,2,4,5,6,7-hexahydro-
cyclopenta pyrimidine-3-carboxylic acid-4-nitrophenyl
ester was obtained as a pale brown solid which was used
in the next step without further purification (crude
wt. O.S1 g).
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-117-
c)(~ 3-{[4-~3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-
tetrahydro-4H-furo[3,4-d]-pyrimidine-3-cArho~yl]a~ino}-
propyl-4-phenyl-piperidine-5-carboxylic acid methyl
ester.
A solution of (+)-4-(3,4-difluorophenyl)-2,5-dioxo-
1~2~4~5~6l7-hexahydro-cyclopenta pyrimidine-3-
carboxylic acid-4-nitrophenyl ester ((0.30 mmol, 0.13
g) and 3-[4-methoxycarbonyl-4-phenylpiperidin-l-
yl)propylamine (0.32 mmol, 0.09 g) in 10 m~ of
anhydrous THF was stirred overnight at room
temperature. The solvent was remo~ed in vacuo and the
residue was purified by column chromatography ~CH2Cl2
followed by 9:1 CH2Cl2/MeOH) to obtain (+)-1-3-~[4-(3,4-
difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-
furo[3,4-d]-pyrimidine-3-carbonyl]amino~-propyl-4-
phenyl-piperidine-5-carboxylic acid methyl ester as a
pale yellow solid (0.12 g, 70%). [~]D = 128.1 (c =
0.525, CHCl3). It was characterized as HCl salt. M.P.
142-145~C; Anal. Calcd. For C29H31N4O6F2C1Ø23 CHCl3: C,
55.55; H, 4.98; N, 8.87. Found: C, 55.25; H, 5.03; N,
8.52.
Example 34
(-)-1-3-{t4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-
tetrahydro-4H-furo[3,4-d]-pyr~ ;ne-3-c~rhnnyl]amino}-
propyl-4-phenyl-piperidine-5-carboxylic acid methyl
ester. In a similar way, (-)-1-3-{[4-~3,4-
difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-
furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-
phenyl-piperidine-5-carboxylic acid methyl ester was
prepared starting with (-)-6-(3,4-difluorophenyl)-1,6-
dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-
nitrophenyloxy)carbonyl]pyrimidine (overall yield 27~).
M.P. 162-165 ~C [~]D = -121.3 (c = 0.52, CHCl3).
Example 35
~ 1 , 2 , 3 , 6 - T e t r a h y d r o - 1 - { N - t4 - ( 2 -
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W097/42956 PCT~S97/08335
c~ phenyl)piperaz~n-lyl]propyl}-carh~Y~;do-4-
methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine
a)1-(2-Carboxami~p~nyl)piperazine
Concentrated sulfuric acid (15 mL) was added to ~-(2-
cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a
round bottom flask and the resulting slurry was stirred
at room temperature for 48 h. The reaction mixture was
poured on crushed ice very slowly and then basified (pH
9) with 50~ solution of NaOH. The aqueous layer was
extracted several times with EtOAc, dried over K2CO3,
filtered and the solvent was evaporated. 1-(2-
carboxamidophenyl)piperazine was obtained as an off-
white solid (1.2 g, 73~). It was used in the next step
without further purification. Mass spectrum 206 (M +
l, 100~); Combustion analysis was obtained on its
hydrochloride salt. Anal. Calcd. for Cl~Hl,N3OClØ3
CHC13: C, 43.23; H, 5.55; N, 13.30. Found: C, 43.58; H,
5.70; N, 12.79.
b) (+) - 1,2,3, 6 -Te trahy d ro-1 -{~- [4 - (2 -
~hoy~midophenyl)piperazin-lyl]propyl}-carboxamido-4-
methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of (+)-6-(3~4-difluorophenyl)-l~2~3~6
tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-
bromopropylaminocarbonyl)pyrimidine (0.435 g, 1.0 mmol)
and 1-(2-carboxamidophenyl)piperazine (0.4 g, 2.0 mmol)
in 25 mL of anhydrous acetone was added powdered K2CO~
(0.69 g, 5.0 mmol) and KI (0.17 g, 1.0 mmol) and the
resulting suspension was heated to reflux for 10 h.
TLC indicated complete formation of the product (~f =
0.4, 3:0.5 EtOAc/MeOH). The solvent was evaporated and
the residue was dissolved in water (10 mL). The
aqueous layer was extracted in EtOAc (3 X 30 mL), the
separated organic extract was dried over Na2SO4 and the
~ solvent was removed in vacuo. The residue thus
obtained was purified by column chromatography on
.. . . ..
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- 119 -
silica gel with ÉtOAc/MeOH (5:1) as the eluting system.
(+)-l~2~3~6-tetrahydro-l-{N-[4-(2-carboxamido
phenyl)piperazin-lyl]propyl}-carboxamido-4-methyl-6-
(3,4-difluorophenyl)-2-oxo-pyrimidine was obtained as
light yellow powder (0.48 g, 84~ yield). The product
was analyzed as its dihydrochloride salt. M.P. 190-193
~Ci [~]D = 98.8 (c = 0.31, MeOH); Anal calcd. for
C2BH34N6F20sCl20.35 EtOAc: C, 52.16; H, 5.50; N, 12.46.
Found: C, 51.84; H, 5.67; N, 12.05.
Example 36
1,2,3,6-Tetrahydro-l{N-[4-(N-benzimidazolyl)-piperidin-
l-yl]propyl}-carboxamido-4-methyl-6-(3,4-
difluorophenyl)-2-oxo-pyrimidine.
15 To a solution of 6-(3,4-difluorophenyl)-1,2,3,6-
tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-
bromopropylaminocarbonyl)pyrimidine (43 mg, 0.1 mmol)
in 10 mL of anhydrous acetone was added 4-(N-
benzimidazolyl)-piperidine (32.6 mg, 0.15 mmol)
20 followed by NaHCO3 (41 mg, 0.3 mmol) and KI (16 mg, 0.1
mmol). The resulting suspension was heated to reflux
for 10 h and then cooled to room temperature. The
solvent was removed in vacuo and the residue was
purified by flash column chromatography on silica gel
25 with EtOAc followed by 10% MeOH in EtOAc to obtain
1~2~3l6-tetrahydro-l{N-[4-(N-benzimidazolyl)-piperidin-
l-yl]propyl~-carboxamido-4-methyl-6-(3,4-
difluorophenyl)-2-oxo-pyrimidine as an oil (15 mg, 26~
yield). The product thus obtained was then dissolved
30 in 2 mL of chloro~orm and 0.5 mL of HCl in Et20 ~1 M)
was added at room temperature. The solvent was removed
in vacuo and the HCl salt was characterized by
combustion analysis. M.P. 168-172 ~C. Anal calcd. for
C29H33N6F205Cl:0.75 CHCl3: C, 50.43; H, 4.90; N, 11.86.
35 Found: C, 50.84; H, 5.44; N, 11.46.
.
Example 37
(-)-6-(Benzoll, 2,5iQYa~;~701-5-yl) -1-carboxamido-4-et
. . .
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hyl-5-{N-t3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl
)propyl]}carboxamido-2- oxo-1,2,3,6-tetrahydro
pyrimidine.
a) 5-Methylbenzfuroxan.
4-~ethyl-2-nitroaniline (100 g, 0.650 mol) was
suspended in saturated alcoholic sodium hydroxide
solution (1.50 l). To this suspension was added with
cooling (5 ~C) commercial aqueous sodium hypochlorite
until the red color disappeared. The fluffy yellow
precipitate formed was filtered, washed with cold water
and recrystallized from ethanol to get 5-
methylbenzfuroxan (88.2 g, 89 ~ yield) as a pale solid.
b) 5-Methylbenzofurazan.
To 5-methylbenzfuroxan (88.2 g, 0.59 mol) in refluxing
EtOH ~75 ml) was added dropwise P(OEt)3 ~150 ml). When
addition was complete, refluxing was continued for l
more hour. The solvent was removed by rotary
evaporation and the residue shaken with water (200 ml)
and allowed to stand overnight at (0-5~C). The brown
solid so obtained was filtered , washed with water and
chromatographed on silica gel to yield 5-
methylbenzofurazan (70 g, 87 ~) as white needles.
c) 5-Dibromomethylbenzofurazan.
5-Methylbenzofurazan (70 g, 0.52 mol), NBS (325 g), and
benzoyl peroxide (0.5 g) were refluxed with stirring in
carbon tetrachloride (1.5 l) with exclusion of moisture
for 2 days. The reaction mixture was washed with water
(2 X 0.5 l), brine, dried (Na2SO4), and the solvent
removed in vacuo. The residue was chromatographed on
silica (hexane/ EtOAc = 150/1) to get 122 g (80~) of
the title compound as a pink solid. 5-
Triblo,,lul,~cthylbenzofurazan (17 g, 9~) was also isolated
as a pink solid.
d) 5-Formylbenzofurazan.
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To a refluxing mixture of 5-dibromo methylbenzofurazan
(122 g, 418 mmol) in EtOH ~1 1) was added AgNOl (163 g)
in 2 l of water. When addition was complete,
refluxing was continued for 2 hours. The mixture was
cooled and the Ag~r formed was removed by filtration.
The resulting solution was concentrated to a small
volume and extracted with toluene (10 X 300 ml). The
extract was concentrated and the residue collected was
chromatographed on silica gel (3 kg), ~EtOAc / hexane
= 8/1000 ) to get the title compound (48.2 g, 78~) as
a white solid.
e) 2-Cyanoethyl 3-benzo[1,2,5~oxadiazol-5-yl-2-
propionyl-acrylate.
A mixture of 5-formylbenzofurazan (25.0 g, 168.s
mmol), 2-cyanoethyl 3-oxo-pentanoate (31.4 g, 203
mm~l), and piperidinium acetate (1.22 g, 8.40 mmol) in
benzene (1.5 l ) was refluxed with a Dean-Stark trap
for 24 hours. Benzene was evaporated, and the residue
was chromatographed on silica (200 g) (EtOAc / CHCl3 =
5 / 100) to get the title compound (32.36, 62.1
yield) as a orange oil.
f)2-Cyanoethyl 6-benzo~1,2,5]oxadiazol-5-yl-4-ethyl-2-
methoxy-1,6-dih~lG~r~imidine-5-carboYylate.
A mixture of 2-cyano-ethyl 3-benzo[1,2,5]oxadiazol-5-
yl-2-propionyl-acrylate (19 g, 63.48 mmol), o-
methylisourea hydrogen sulfate (15.3 g, 88.9 mmol~,
and 4-dimethylaminopyridine (21.3 g, 175 mmol) in THF
(200 ml) was stirred at 65 ~C for 6 hours. The solvent
was evaporated and the residue was chromatographed on
silica gel (-300 g) (hexane / EtOAc = 2 / 1) to get 8
g of the title compound as an orange oily solid. This
reaction was repeated for many times and the yields
were between 5% and 38%.
g)6-~enzo[1,2,5]oYA~;A~ol-5-yl-4-ethyl-2-methoxy-6~I-
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pyrimidine-1,5-dicarboxylic acid 5-(2-cyan-ethyl) ester
1-(4-nitro-phenyl) ester.
To a solution of 2-cyanoethyl 6-benzo
[1, 2, 5] oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-
dihydropyrimidine-5-carboxylate (3.62 g, 10.19 mmol)
and 4-dimethylaminopyridine ~1.49 g, 12.2 mmol) in
CH2Cl2 (75 ml), at 0 ~C, was added 4-
nitrophenylchloroformate (2.46 g, 12.22 mmol). The
reaction mixture was slowly warmed to r.t. at which it
was stirred for 20 hours. Then, the solvent was
evaporated and the residue was purified by flash column
chromatography (~60 g of SiO2, CHC13 / EtOAc = 100 / 3)
to get the title compound (1.96 g, 37 % yield) as a
yellow solid.
h)2-Cyanoethyl ester 6-benzoll,2,5]oxadiazol-5-yl-4-
ethyl-2-methoxy-1-(1-phenyl- ethyl carbamoyl)-1,6-
dihydro-pyrimidine-5-carboxylate.
A solution of 6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-
methoxy-6H-pyrimidine-1,5-dicarboxylic acid 5-(2-
cyanoethyl) ester l-(4-nitrophenyl) ester ( 2.2 g, 4.22
mmol ) and (R)-(+)-~- methylbenzylamine (1.36 ml, 10.6
mmol) in CH2Cl2 (30 ml) was stirred at room temperature
for 10 hours. The solvent was evaporated, and the
residue was chromatographed on silica gel (100 g) (CHC13
/ EtOAc = 30 / 1) to get the two diasteromers of the
title compound (}.03 g in total, 49%).
i) (-)-2-Cyanoethyl 6-benzo~1,2,5]oxadiazol-5-yl-4-
ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate.
A mixture of (-)-2-cyanoethyl ester 6-
benzo~l,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1-(1-
phenyl- ethyl carbamoyl)-1,6-dihydro-pyrimidine-5-
carboxylate (557 mg, 1.11 mmol) and 1,8-
diazabicyclo[5,4,0]undec-7-ene (82.5 ml, 0.55 mmol) in
benzene (15 ml) was stirred at 50 ~C for 1 hour. The
solvent was evaporated, and the residue was
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chromatographed on silica gel (~30 g) (CHC13 / EtOAc /
2 N NH3 in MeOH = 40 / 10 / 1) to get the title compound
(270 mg, 68.5 % yield) as a yellow solid. No rotation
was observed for this compound.
j) (-)-6-Benzo[1,2,5~QYa~ia~ol-5-yl-4-ethyl-2-methoxy-
6H-pyrimidine-1,5-dicarboxylic acid 5-~2-cyanoethyl)
ester 1-(4-nitro-phenyl) ester.
To a solution of (-)-2-cyanoethyl 6-
benzo[l,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-
dihydropyrimidine-5-carboxylate (220 mg, 0.62 mmol) and
4-dimethylaminopyridine (99 mg, 0.81 mmol) in CH2Cl2 (12
ml), at 0 ~C, was added 4-nitrophenylchloroformate
(164 mg, 0.81 mmol). The reaction mixture was slowly
warmed to r.t. at which it was stirred for 24 hours.
The solvent was evaporated and the residue was purified
by flash column chromatography (-30 g of SiO2, CHCl3 /
EtOAc = 38/1) to get the title compound (301 mg, 93
yield) as a yellow solid.
k)(-)-6-(Be~zo[1, 2,5]n~ 3;Azol-5-yl) -l-carho~ido-4-
ethyl-5-{N-~3-(4-methoxycarbonyl-4-phenylpiperidin-1-
yl)propyl~}
carboxamido-2- oxo-1,6-dihydropyrimidine.
To (-)-6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-
6H-pyrimidine-1,5-dicarboxylic acid 5-(2-cyanoethyl)
ester 1-(4-nitrophenyl) ester (100 mg, 0.19 mmol) in
dry THF (10 ml) ~o~ia (gas) was introduced with a
balloon at room temperature. It was stirred at room
temperature for 14 hours. TLC and l~ NMR of the
reaction mixture showed that the reaction was complete.
NaOH (1 N, 3 ml) was added at room temperature. After
it was stirred for 6 hours, HCl solution (6 N, 4 ml)
was added. It was stirred at room temperature for 14
hours. The solvent was evaporated to get a white solid
which was used directly in the next step.
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A mixture of the crude product from the above step, 4-
dimethyl aminopyridine (61mg, 0.5 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(96 mg, 0.5 mmol) in CH2C12 (15 ml) was stirred at room
temperature for 4 hours. Methyl 1-(3-amino-propyl)-4-
phenyl-piperidine-4-carboxylate (140 mg, 0.5 mmol) was
added. The reaction mixture was stirred at room
temperature for 16 hours. The solvent was evaporated
and the residue was chromatographed on silica gel (5 g)
(CHCl3 / MeOH / 2 N NEI3 in MeH = 250 / 2 / 1) to get the
title compound as a white solid (10.8 mg, 10 ~ yield
over 3 steps). [~] D = -303.9- Hydrochloride of the
title compound was made with HCl in ether. M.P. of the
salt: 140-143~C. Calculated for C30H3sN7O6 + l.OHCl + 0.6
ether: C, 58.03 ~; H, 6.31 ~; N, 14.62 ~. Found: C,
58.07 ~; H, 6.08 %; N,14.66 %.
Example 38
6-(3,4-Difluoro-phenyl)-1-t3-(3',6'-dihydro-~2,4']bip
yridinyl-1'-yl)-propylcarbamoyl]-4-methyl-5-
methoxycarbonyl-2-oxo-1,2,3,6-tetrahydropyrimidine
hydrochloride.
a) 1-(3-Aminopropyl)-4-[pyrid-2-yl~pyridinium bromide
hydrobromide.
A solution of 2,4'-dipyridyl (5.0 g, 32.0 mmol) and 3-
bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF
(50.0 mL) and acetonitrile (50.0 mL) was heated at 90-
95~C for l h. After cooling, the white solid that came
out was filtered, washed with Et20 and dried. The
mother liquor was concentrated to remove Et20 and then
heated to 90-95~C for 4 h. The solvent was evaporated
and the white residue was triturated with Et20 (lOO.o
mL) and filtered. The combined weight of the salt was
11.6 g (97~).
b) 3-(3',6'-Dihydro-2'-H-l2,4']bipyridinyl-1'-yl)-
propylamine.
.
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To a solution of 1-(3-aminopropyl)-4-[pyrid-2-
yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol)
n 20.0 mL MeOH was added NaBH4 (0.101 g, 2.62 mmol) in
small portions. The reaction mixture was stirred for
30 min and then quenched with 6M HCl solution. The
solution was concentrated to 20.0 mL and basified with
50% NaOH solution to pH 12. Extracted witn CHCl3 (5 x
30.0 mL), dried over MgSOq and the solvent was removed
togive3-~3~6~-dihydro-2~-H-[2~4~bipyridinyl-l~-yl)-
propylamine as an oil ~0.37 g, 96~ yield). It is used
in the next step immediately without purification.
c)6-(3,4-Difluoro-phenyl~ t3-(3',6'-dihydro-[2,4'~b
ipyridinyl-1'-yl)-propylcarbamoyl~-4-methyl-5-
methoxycarbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine
hydrochloride.
A solution of 6-(3,4-difluorophenyl)-4-methyl-5-
methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-
2-oxo-1,2,3,6- tetrahydro-pyrimidine (20 mg, 0.045
mmol) and 3-(3', 6'-dihydro-2'H-[2,4']bipyridyl-1-
yl)propylamine (9.7 mg, 0.045 mmol) in CH2Cl2 (10 ml)
was stirred at room temperature for 3 days. The
solvent was removed in vacuum. The residue was
separated on preparative TLC (CHCl3 / MeOH = 100 / 15)
to get the title compound (21mg, 89 ~~ yield) as a
yellow solid. Hydrochloride salt was made with HCl in
ether. M.P. of the salt: 242-244~C. Calcd for
C27H29N5OqF2 ~ 2.0 HCl ~ 1.05 CHC13 + 1.05 ether: C, 48.32
%; H, 5.35 ~; N, 8.74 ~. Found: C, 48.10 ~; H,
5.13 %; N, 8.72 ~.
Example 39
6-(3,4-Difluorophenyl)-1-(3-imidazol-1-yl-propylcarba
moyl)-4-methyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine-5-
carboxylic acid methyl ester.
A solution of 6-~3,4-difluorophenyl)-4-methyl-5-
methoxycarbonyl-l-(4-nitrophenoxy)carbonyl-2-oxo-
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1~2~3~6-tetrahydro-pyrimidine (100 mg, 0.22 mmol) and
l-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) in CH2Cl~
(10 ml) was stirred at room temperature for 3 hours.
The solvent was removed in vacuum. The residue was
separated on preparative TLC (CHCl3 / MeOH = 100 / 15)
to get the title compound (80 mg, 84 % yield) as a
white solid. Hydrochloride of title compound was made
with HCl in ether. Calcd for C20HzlNsO4F2 + 0.3 H.O: C,
54.74 ~; H, 4.99 ~i N, 15.89 %. Found: C, 54.92 ~;H,
4.65 %; N, 15.77 %. M.P. of the salt: 221-224~C.
E x a m p l e 4 o
6-(3,4-Difluorophenyl)-1-{N-~3-(2-phenylimidazol-l-yl
)propyl]}carboxamido-4-methyl-5-methoxycarbonyl-2-oxo
-1,2,3,6-tetrahydropyrimidine hydrochloride.
A mixture of 6-~3,4-difluorophenyl)-1,2,3,6-tetrahydro-
2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylamino
carbonyl)pyrimidine (100 mg, 0.22 mmol), 2-
phenylimidazole (32.3 mg, 0.22 mmol), and CsC03 (358
mg, 1.1 mmol) in DMF (10 ml) was stirred at room
temperature for 2 days. The solid was filtered out.
The solution was concentrated and separated on
preparative TLC (EtOAc / hexane = 3 / 1) to get the
title compound (41 mg, 37 % yield) as a white oily
solid. Hydrochloride of title compound was made with
HCl in ether. M.P. of the salt: 278-282 ~C.
Calculated for C26H25NsO4F2 + 2.0 HCl + 0.25 H2O: C, 52.23
%; H, 4.60 %; N, 11.60 %. Found: C, 52.21 ~; H,
4.69 %; N, ll.11 %.
Example 41 and Example 42
(+)-, and (-)-3,6-Dihydro-l-{N-~4-(2-pyridyl)-
piperidine-1-yl] propyl}car~oxamido-5- methoxy
carbonyl-2-oxo-6-(3,4,5- trifluorophenyl)-4-methyl
pyrimidine dihydrochloride.
.
a) Methyl2-acetyl-3-(3,4,5-trifluoro-phenyl)-acrylate.
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A mixture of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3
mmol), methyl acetoacetate ( 0.81 ml, 7.5 mmol), and
piperidinium acetate (45 mg, 0.31 mmol) in benzene ~lQ
ml) was refluxed with a Dean-Stark trap for 12 hours.
The solvent was e~aporated, and the residue was
chromatographed on silica gel (~50 g) (EtOAc / hexane
= 1 / 6) to get the title compound (825 mg, 51 ~ yield)
as a mixture of cis and trans isomers (yellow oil).
b) Methyl 2-methoxy-4-methyl-6-(3,4,5-trifluoro-
phenyl)-1,6-dihydro-pyrimidane-5-carboxylate.
A mixture of methyl 2-acetyl-3-(3,4,5-trifluoro-
phenyl)-acrylate (670 mg, 2.60 mmol), O-methylisourea
hydrogen hemisulfate (448 mg, 3.63 mmol), and 4-
dimethylaminopyridine (407 mg, 3.63 mmol) in ethanol
(20 ml) was stirred at 65 ~C for 2 days. The solid
formed was filtered out. The filtrate was concentrated
and chromatographed on silica gel (30 g) (CH2Cl2 / EtOAc
= 9 / 1) to get the title compound (390 mg, 48 % yield)
as a pale yellow oil. Calculated for Cl4Hl3N2O3F3; C,
53.50 %; H, 4.20 ~; N, 8.90 ~. Found: C, 53.24 ~i H,
4.20 %; N, 8.60 ~.
c) 1,6-Dihydro-5-methoxycarbonyl-2-msthoxy-4-methyl-1-
(4-nitro phenyloxy)carbonyl -6-(3,4,5-trifluorophenyl)
-pyrimidine.
To a solution of methyl l,6-dihydro-2-methoxy-4-
methyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine-5-
carboxylate (385 mg, 1.23 mmol) and 4-
dimethylaminopyridine (195 mg, 1.60 mmol) in CH2Cl2 (15
ml), at room temperature, was added 4-nitrophenyl
chloroformate (322 mg, 1.60 mmol). The reaction
solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate
was concentrated and chromatographed on silica gel (~20
g) (CHCl3 / CH30H = 9 / 1) to get the titled compound
(206 mg, 35 ~ yield) as a white solid. Calculated for
.
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- 128 -
C2lH16N3O7F3 + 1.0 H2O: C, 50.71 %; H, 3.65 %; N, 8.45
9~. Found: C, 50.83~; H, 3.29 %; N, 8.33 ~.
d) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-
S {N-~4-(2-~yridyl)-piperidin-1-yl]-propyl}carbamoyl-6-
(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-5- methoxycarbonyl
-2-methoxy- (4-nitrophenyloxy) carbonyl-6-
(3,4,5-trifluorophenyl) - 4-methyl-pyrimidine ~25 mg,
0.05 mmol) and 3- [4- (2-pyridyl) -piperidin-1-yl] -
propylamine (16 mg, 0.078 mmol) was stirred at room
temperature for 12 hours. The solvent was evaporated
and the residue chromatographed on silica gel (~5 g)
(CHCl3 / EtOAc = 30 / 1 ) to get the title compound (16
mg, 57 ~ yield) as a pale solid.
e) 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-
2-oxo-1-{N-t4-(2-pyridyl)-piperidine-1-yl]-
propyl}carboxam~do-6-(3,4,5-trifluorophenyl)-
pyrimidine dihydrochloride.
1,6-Dihydro- 2 -methoxy-5-methoxycarbonyl-4-methyl-1- {N-
[4 - (2 -pyridyl ) -piperidin- 1 -yl] -propyl ~ carbamoyl - 6 -
(3,4,5-trifluoro-phenyl) -pyrimidine from the previous
step was dissolved in CH2C12 (5 ml) and concentrated HCl
solution (0.5 ml ) was added . The reaction mixture was
stirred at room temperature for 1 hour. NaOH solution
(1 N) was added to neutralized the reaction mixture .
It was extracted with CH2C12. The extractant was dried
( Na2SO4) and concentrated to get the title compound (16
mg, quantitative ) as a pale solid . Hydrochloride of
the title compound was made with HCl in ether.
Calculated for C2,H29NsO4F~ + 2.0 HCl + 4.0 THF ~ 0.8
CH2Cl2: C, 54.02 %; H, 6.69 %; N, 7.19 %. Found:
C, 54.00 %; H, 6.48 %; N, 7.42 %.
f) (+) -, and (-) -3,6-Dihydro-1-{N- t4- (2-pyridyl) -
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piperidine-l-yl] propyl}carboxamido-5- methoxy
carbonyl-2-oxo-6-~3,4,5- trifluorophenyl)-4-methyl
pyrimidine dihydrochloride.
The enantiomers were separated by chiral HPLC
separation (column: chiralpak AS) of the racemic
1,2,3,6-tetrahydro~ N-~4-(2-pyridyl)-piperidine-1-y
l]propyl}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4,s
-trifluorophenyl)-4-methylpyrimidine dihydrochloride
which was synthesized in the previous step. The (~)
isomer: [a~D = +80.4 (c = 0.2 g in 100 ml
dichloromethane): The (-) isomer: [a]D = -82.2
Hydrochloride salts of the title compounds was made
with HCl in ether.
Example 43
~ 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-
methoxymethyl-2-oxo-1-{N-~4-~2-pyridyl)-
p i p e r i d~ n e - 1 - y l] -p r o p y l } c a rb o x a m i d o -
6-(3,4,5-trifluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacetyl-3-(3,4,5-trifluoro-phenyl)-
acrylate.
A mixture of 3,4,5-trifluoro benzaldehyde (10 g, 62.5
mmol), methyl 4-methoxyacetoacetate (9.7 ml, 75.0
mmol), and piperidinium acetate (450 mg, 3.1 mmol) in
benzene (100 ml) was refluxed with a Dean-Stark trap
for 8 hours. The white solid formed ( some side
product) was filtered out. The solvent was evaporated,
and the residue was chromatographed on silica gel (- 1
Kg) (toluene / t-butyl methyl ether = 8 / 1) to get the
title compound (4.5 g, 25% yield) as a mixture of cis
and trans isomers (white solid).
b) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(3,4,5-
- trifluoro-phenyl)-acrylate (6.0 g, 20.8 mmol~, 0-
methylisourea hydrogen hemisulfate ~3.6 g, 29.2 mmol),
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and 4-dimethylaminopyridine ~3.6 g, 29.2 mmol) in
ethanol (20 ml) was stirred at 65 ~C for 12 hours. The
solid formed was filtered out. The filtrate was
concentrated and chromatographed on silica gel (~1 kg)
(hexane / ether = 2 / 1) to get the title compound (4.0
g, 56 ~ yield) as a pale colorless oily solid.
c ) 1, 6 -Dihydro- 2 -methoxy- S -methoxycarbonyl - 4 -
methoxymethyl - 1- ( 4 -ni trophenyloxy) carbonyl
- 6 - ( 3, 4, 5 - trif luorophenyl ) -pyrimidine .
To a solution of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-
phenyl)-pyrimidine (3.24 g, 9.41 mmol) and 4-
dimethylaminopyridine (1.38 g, 11.3 mmol) in CH2C12 ~20
ml), at room temperature, was added 4-nitrophenyl
chloroformate (2.28 g, 11.3 mmol). The reaction
solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate
was concentrated and chromatographed on silica gel
(hexane / ether = 1 / 1) to get the title compound
(3.70 g, 77 ~ yield) as a yellow solid.
d)(+)-, and (-)-1,6-Dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-1-[N-~2-methylbenzyl
)]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl~ 4-nitrophenyloxy)carbonyl-
6-(3,4,5-trifluorophenyl)-pyrimidine (3.80 g, 7.46
mmol) and (R)-(+)-~-methylbenzylamine (2.02 mg, 16.4
mmol) in CH2Cl2 was stirred at room temperature for 2
days. The solvent was evaporated and the residue
chromatographed on silica gel (toluene /t-butyl methyl
ether = 5 / 1) to get the title compound as yellow oil
solids. For the less polar isomer (1.81 g, 50
~yield): [~]D = +164.3. For the more polar isomer (1.79
g, 50 ~ yield): [~] D = -86.2.
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e)~ 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of (+)-1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-1-~N-(2-methylbenzyl
)]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine (1.81
g, 3.81 mmol) and 1,8-diazabicyclo~5,4,0]undec-7-ene
(0.28 ml, 1.90 mmol) in benzene (10 ml) was stirred at
room temperature for 4 days. The solvent was
evaporated, and the residue was chromatographed on
0 silica gel (~500 g) (hexane / ether = 2.5 / 1) to get
the title compound (1.2 g, 91 ~ yield) as a yellow oil.
No rotation was observed for this compound.
f ) ( + ) -1, 6 - D ihydro - 2 - me thoxy - 5 - me thoxyc a rb ony l - 4 -
methoxymethyl -1- ( 4 -ni trophenyloxy) carbonyl
- 6 - ( 3, 4, 5 - trif luorophenyl) -pyrimidine .
To a solution of 1,6-dihydro-2-methoxy-5-
methoxycar~onyl-4-methoxymethyl-6-(3,4,5-trifluoro-
phenyl)-pyrimidine (1.20 g, 3.49 mmol) and 4-
dimethylaminopyridine (0.51 g, 4.18 mmol) in CH2Cl2 (20
ml), at room temperature, was added 4-nitrophenyl
chloroformate (0.84 g, 11.3 mmol). The reaction
solution was stirred at room temperature for 12 hours.
The white solid formed was filtered out. Trials to
purify the crude product on silica gel only hydrolyzed
the desired product to the start materials. The crude
product was used in the next step without any further
purification.
g)(l)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-l-{N-14-(2-pyridyl)-piperidin-1-yl]-
propyl}carbamoyl-6-~3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of (+)-1,6-dihydro-2-methoxy-5-methoxy
carbonyl-4-methoxymethyl-1-~4-nitrophenyloxy)
carbonyl-6- ~3,4,5-trifluorophenyl)-pyrimidine and 3-
[4-(2-pyridyl)-piperidin-1-yl]-propylamine (215 mg,
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1.05 mmol) was stirred at room temperature for 12hours. The solvent was evaporated and the residue
chromatographed on prep. TLC (CHCl3 / MeOH = 100 / 15~
to get the title compound (115 mg, 22 ~ yield over 2
steps) as a yellow oil.
h) (+) -1, 2, 3, 6-Tetrahydro-5-methoxycarbonyl
-4-methoxymethyl-2-oxo-1- {N- [4- (2-pyridyl) -
piperidine -1 -yl~ -propyl } carboxamido -
6- (3, 4, 5-trifluorophenyl) -pyrimidine dihydrochloride .
1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-
propyl~carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine
from the previous step was dissolved in CH2Cl2 (5 ml)
and HCl solution (6 N,0.5 ml) was added. The reaction
mixture was stirred at room temperature for 4 hour.
KOH solution (1 N) was added to neutralize the reaction
mixture. It was extracted with CH2C12. The extractant
was dried ( Na2SO4) and concentrated to get the title
compound (106 mg, 94 % yield) as a pale oily solid.
[~] D = + 78.6 (c = 0.5 g in 100 ml dichloromethane).
Hydrochloride of the title compound was made with HCl
in ether. Calculated for C28H32NsOsF3 + 3.8 HCl+1.8
EtOAc: C, 48.44~; H, 5.80%; N, 8.02 ~. Found: C,
48.19 %; H, 5.38 ~; N, 8.32~.
Example 44
( - ) -1, 2, 3, 6-Tetrahydro-5-methoxycarbonyl-4-
me thoxyme thyl - 2 - oxo - 1 - { N - [ 4 - ( 2 - pyr i dyl ) -
piperidine -1 -yl] -propyl}carboxamido-
6 - ( 3, 4, 5 - tri f luorophenyl ) -pyrimidine dihydrochloride .
a) ( -) -1, 6-Dihydro-2-methoxy-5-methoxycarbonyl-4 -
methoxymethyl - 6 - ( 3, 4, 5 - tri f luoro -phenyl ) -pyrimidine .
A mixture of (-)-1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-1- [N-(2-
methylbenzyl)~carbamoyl-6-~3,4,5-trifluoro-phenyl)-
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pyrimidine (1.79 g, 3.B0 mmol) and 1,8-
diazabicyclo[5,4,01undec-7-ene (0.28 ml, 1.90 mmol) in
benzene (10 ml) was stirred at room temperature for 4
days. The solvent was evaporated, and the residue was
chromatographed on silica gel (~500 g) (hexane / ether
= 2.5 / 1) to get the title compound (0.92 g,70 ~) as
a yellow oil. No rotation was observed for this
compound.
b) (~) -1, 6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-1- (4-nitrophenyloxy) carbonyl
-6- ~3,4,5-trlfluorophenyl) -pyrimidine.
To a ~olution of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-
phenyl)-pyrimidine (0.92 g, 2.67 mmol) and 4-
dimethylaminopyridine ~0.46 g, 3.74 mmol) in CH,Cl2 (20
ml), at room temperature, was added 4-nitrophenyl
chloroformate (0.75 g, 3.74 mmol). The reaction
solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate
was concentrated and chromatographed on silica gel
(hexane / ether = 3 / 1) to get the title compound
(1.01 g, 79 % yield) as a yellow solid.
c) (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-1-{N-14-(2-pyridyl)-piperidin-1-yl]-
propyl}carbamoyl-6-(3,4,5-trifluorophenyl)-pyrimidine.
A m i x t u r e o f ( - ) -
1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-1-(4-nitrophenyloxy)carbonyl-
6-~3,4,5-trifluorophenyl)-pyrimidine (300 mg, 0.59
mmol) and 3-~4-(2-pyridyl)-piperidin-1-yll-propylamine
(160 mg, 0.77 mmol) was stirred a~ room temperature for
12 hours. The solvent was evaporated and the residue
chromatographed on prep. TLC (CHC13 / MeOH / 2 N NH3 in
MeOH = 20 / 2 / 1) to get the title compound (290 mg,
83 ~ yield) as a yellow oil.
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d) (-)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-
4-methoxymethyl-2-oxo-1-{N-[4-(2-pyridyl)-
piperidine-1-yl] -propyl}carboxamido-
6-(3,4,5-trifluorophenyl)-pyrimidine dihydrochloride.
(-)l~6-dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-l-{N-[4-(2-pyridyl)-piperidin-1-yl]-
propyl}carbamoyl-6- (3,4, 5-trifluoro-phenyl)-pyrimidine
(290 mg, 0.49 mmol) was dissolved in CH2Cl2 (5 ml) and
HCl solution (6 N, 2 ml) was added. The reaction
mixture was stirred at room temperature for 10 hour.
KOH solution (1 N) was added to neutralized the
reaction mixture. It was extracted with CH2Cl2. The
extractant was dried ( Na2SO4) and concentrated to get
the title compound (180 mg, 64 ~ yield) as a pale oily
solid. [CY]D = - 31.4 (c = 0.44 g in 100 ml
dichloromethane). Hydrochloride of the title compound
was made with HCl in ether. Calculated for C28H32NsO5F3
+ 2.0 HCl + 0.8 ether + 0.8 CH2Cl2: C, 50.59 %; H,
5.78 ~; N, 9.22 ~. Found: C, 50.86 ~; H, 5.82 ~;
N, 8.75 ~.
Example 45
1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-
2-oxo-1-{N-[4-(2-pyridyl)- piperidine-1-yl]-
propyl}cA~ do-6-(2,4,5-trifluorophenyl- pyrimidine
dihydrochloride.
a)Methyl2-acetyl-3-(2,4,5-trifluoro-phenyl)-acrylate.
A mixture of 2,4,5-trifluorobenzaldehyde (1.0 g, 6.3
mmol), methyl acetoacetate ( 0.81 ml, 7.4 mmol), and
piperidinium acetate(38 mg, 0.26 mmol) in benzene (10
ml) was stirred at room temperature for 2 days. The
solvent was evaporated, and the residue was
chromatographed on silica gel (-50 g) ( hexane / ether
= 5 / 1) to get the title compound (1.60 g,
quantitative ) as a mixture of cis and trans isomers
(colorless oil).
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b) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-
(2,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of methyl 2-acetyl-3-~2,4,5-trifluoro-
phenyl)-acrylate (1.60 g, 6.20 mmol), O-methylisourea
hydrogen hemisulfate (1.07 g, 8.68 mmol), and 4-
dimethylaminopyridine (1.06 g, 8.68 mmol) in ethanol
~10 ml) was stirred at 65 ~C for 2 days. The solid
formed was filtered out. The filtrate was concentrated
and chromatographed on silica gel (-50 g) (CH2Cl. /
EtOAc = 9 / 1) to get the title compound (982 mg, 50
yield) as a pale colorless oily solid.
c) 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-1-
(4-nitro phenyloxy)carbonyl -6-(2,4,~-trifluorophenyl)
-pyrimidine.
To a solution of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-6-(2,4,5-trifluoro-phenyl)-
pyrimidine (600 mg, 1.91 mmol) and 4-
dimethylaminopyridine (280 mg, 2.29 mmol) in CH2Cl2 (8
ml), at room temperature, was added 4-nitrophenyl
chloroformate (462 mg, 2.29 mmol). The reaction
solution was stirred at room temperature for 18 hours.
The white solid formed was filtered out. The filtrate
was concentrated and chromatographed on silica gel (~50
g) (hexane t ether = 4 / l) to get the title compound
(143 mg, 16 % yield) as a white solid.
d) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-
{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}c~bA~yl-6-
(2,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-5-methoxycarbonyl-2-
methoxy-4-methyl-1-(4-nitrophenyloxy)carbonyl-
6-(2,4,5-trifluorophenyl)-pyrimidine (70 mg, 0.146
mmol) and 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine
(46 mg, 0.220 mmol) was stirred at room temperature for
12 hours. The solvent was evaporated and the residue
separated on preparative TLC (CHC13 / MeOH / 2 N NH3 in
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MeOH = 20 / 2 / 1) to get the title compound (59 mg, 72
~6 yield ) as a yellow oil.
e) 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-
2-oxo-1-{N- [4- (2-pyridyl)- piperidine-1-yl] -
propyl}~h~Yamido-6-(2,4,5-trifluorophenyl- pyrimidine
dihydrochloride.
1~6-Dihydro-2-methoxy-5methoxycarbonyl-4-methyl-l-{N-
[4 - (2-pyridyl)-piperidin-1-yl] -propyl}carbamoyl-6-
(2,4,5-trif~uoro-phenyl)-pyrimidine (59 mg, 0.11 mmo')
was dissolved in THF (3 ml) and HCl solution (6 N, 2
ml) was added. The reaction mixture was stirred at
room temperature for 6 hour. KOH solution ~1 N) was
added to neutralized the reaction mixture. It was
extracted with CHzCl2. The extractant was dried (Na2SO4)
and concentrated to get the title compound (50 mg, 87
~ yield) as a white solid. Hydrochloride of the title
compound was made with HCl in ether. Calculated for
C27H3~NsOgF2 + 2.0 HCl + 1.0 C6Hl2 + 1.0 CHCl3: C, 49.68
~; H, 5.52 ~; N, 8.52 ~. Found: C, 49.22 ~; H,
6.11 9~; N, 8.59 ~. M.P. of the salt: 239-243 ~C.
Example 46
4- (3,4-Difluorophenyl)-3- [3-(3-hydroxy-3-phenyl-8-aza
bicyclo ~3.2.1] oct-8-yl)propylcarbamoyl] -6-methyl-2-ox
o-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid
methyl eE~ter
a) 8-Benzyl-3-phenyl-8-azabicyclo t3.2.1~ octan-3-ol:
N-benzyltropinone (14.4 g, 66.7 mmol) was added
dropwise (neat) to a solution of phenyl magnesium
bromide (100 mL, 0.1 M in THF). The addition was
continued as such a rate to maintain a gentle reflux.
Once the addition was complete, the reaction mixture
was heated at reflux temperature for 19 hours, cooled
to room temperature, poured over 200 mL of crushed ice,
saturated with Ammor-ium chloride, and extracted with 3
X 100 mL of ethyl acetate. The combined organic
.
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extracts were dried (K2CO3), solvent removed in Vacuo,
and the crude product was chromatographed on 500 g of
silica pac~ed with CHC13. The column was eluted with
CHCl3 (1 L), 5~EtOAc-CHCl3 (1 L), 10% (1 L), 20%, (1 L),
30% (1 L), 50~ (1 L), 100~ EtOAc (1 L), and 10~ MeOH-
EtOAc (2 ~), to give 11.8 g (40~) of the desired
product as a slightly yellow oily solid. Anal. Calc.
for C2DH23NIOl: C, 81.87; H, 7.90; N, 4.77. Found: C,
81.63; H, 8.01; N, 4.70.
b) 3-Phenyl-8-azabicyclo13.2.1~octan-3-ol:
A mixture of 5.10 g of 8-benzyl-3-phenyl-8-azabicyclo
13.2.1]octan-3-ol (17-4 mmol), 3.15 g of 10~ Pd/C in 50
mL of 95~ ethanol was hydrogenated in a pressurized
bomb (200 psi) at 60-70 ~C (bath temperature) for 16
hours. The reaction mixture was filtered through a pad
of Celite, and the solids were washed with 5 X 30 mL of
methanol. The combined organic extracts were
concentrated, and the crude product was chromatographed
on 300 g of silica packed with EtOAc-MeOH-isopropanol
(30:2:1). The column was eluted with EtOAc-MeOH-
isopropanol 25:2:1 (1 L), 20:2:1 (1 L), and 15:2-1 (1
L) to give 3.16 g (89~) of the desired product as a
slightly yellow oily solid. Anal. Calc. for C,3Hl7N1Ol:
C, 76.81; H, 8.43; N, 6.89. Found: C, 76.57; H, 8.53;
N, 6.80.
c)4-~3,4-Difluorophenyl)-3-[3-(3-hydroxy-3-phenyl-8-a
zabicyclo~3.2.1]oct-8-yl)propylcarbamoyl}-6-methyl-2-
oxo-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid
methyl ester.
A mixture of 243 mg of 3-phenyl-8-azabicyclo[3.2.l]
octan-3-ol (1.2 mmol), 640 mg of 1,2,3,6-tetra
hydro-1-~3- bromopropyl}carboxamido-5-methoxy
carbonyl-4-methyl-6-~3,4-difluorophenyl)-2-oxo
pyrimidine (1.44 mmol), 197 mg of K2CO3 (1.44 mmol),
catalytic amounts (a few crystals) of KI in 10 mL of
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ethanol were heated at reflux temperature for 4 hours.
The reaction mixture was cooled to room temperature,
and the crude product was purified with preparative TLC
(2000 microns, 10~ MeOH-EtOAc) to give 290 mg (43%) of
the desired product as a slightly yellow viscous oil.
Anal. Calc. For C30H34F2N4Os+ 1.0 Methanol: C, 61.99; H,
6.38; N, 9.33. Found: C, 62.12; H, 6.02; N, 9.58. The
hydrochloride salt was prepared by dissolving 150 mg o~
the free base in minimum EtOAc and excess lN HCl in
ether was added. The solvent was decanted and the
separated oil was triturated with ether to give the
hydrochloride as a slightly yellow powder: Anal. Calc.
for C30H34F2N4Os+ 1.0 HCl + 1.2 H2O: C, 57.50; H, 6.01; N,
8.94. Found: C, 57.76; H, 5.82; N, 8.50.
Example 47 and Example 48
1, 2, 3, 6-Tetrahydro-1- (N- (3 - (3 -imidazol-1-yl) propyl) am
ino ) propylcarboxamido - 5 -methoxycarbonyl - 2 - oxo - 6 - ( 3, 4 -
difluorophenyl)-4-methylpyrimidine dihydrochloride and
1, 2, 3, 6-Tetrahydro-1- (N- (3 - (2-indol-3-
yl) ) ethyl) amino) propylca ~ ; do-5-methoxycarbonyl-2
-oxo-6- (3,4-difluorophenyl) -4-methylpyrimidine
hydrochloride
In two separate reaction vessels, a mixture of 89 mg of
1~2~3~6-tetrahydro-l-{3-bromopropyl}carboxamido-5-met
hoxy carbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxo
pyrimidine t0.200 mmol), 0.200 mmol of the following
nucleophiles (25.0 mg of 1-(3-aminopropyl)imidazole, 25
mg of tryptamine), 89 mg of K2CO3, in 1 mL of
acetonitrile were heated at reflux temperature for 2-5
days, applied to the preparative-TLC and eluted with
CHCl3-MeOH-2N NH3 in MeOH (10:1:1) to give the title
compounds. The hydrochlorides were prepared by
dissolving the title compounds in minimum EtOAc, and
excess lN HCl in ether was added until no more
precipitate was apparent. The solids were filtered,
washed with ether, and dried under high vacuum.
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1,2,3,6-Tetrahydro-l- ~N- (3- (3-imidazol-l-yl)propyl)am
ino ) propylcarboxamido - 5 -methoxycarbonyl - 2 - oxo - 6 - ( 3, 4 -
difluorophenyl) -4-methylpyrimidine dihydrochloride ( 12
mg): Anal. Calc. for C23H2BF2N604 1 2.0 HCl + 0.6 ether
+ 0.3 CH2Cl2: C, 49.31; H, 5.76; N, 13.12. Found: C,
49.07; H, 5.78; N, 13.28.
1, 2, 3, 6-Tetrahydro-1- (N- (3- (2-indol-3 -
yl) ) ethyl) amino) propyl~rhQ~mido-5-methoxycarbonyl-2
- oxo - 6 - ( 3, 4 - dif luorophenyl ) - 4 -methylpyrimidine
1 0 hydrochloride
(23 mg); Anal. Calc. for C27H29F2NsO4+ 1.0 HCl + 3.7 THF:
C, 60.58; H, 7.25; N, 8.45. Found: C, 60.84; H, 7.21;
N, 8.48.
Example 49
6- (3,4-Difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-5-
( 3 - ( 4 -methoxycarbonyl - 4 -phenylpiperidin -1 -yl ) -
propyla~ n~a rbonyl ) - 2, 4 - dime thylpyrimidine
a) Benzyl 3-oxo-2- ~3,4-difluorobenzylidenyl)butanoate.
A mixture of 3,4-difluorobenzaldehyde (7.1 g, 50
mmol.), benzyl acetoacetate (12 .48 g, 65 mmol.), acetic
acid (0.15 g, 2.5 mmol.), piperidine (0.212 g, 2.5
mmol.) and benzene (300 mL) was refluxed under a dean-
stark trap overnight. After the removal of solvent, the
residue was then dissolved in ethyl acetate and washed
with saturated KHS04 ~ saturated NaHCO3, water and then
dried over Na2SO4. The solvent was evaporated, and the
residue was flash chromatographed over silica gel
(eluent: 1:1 v/v ethyl acetate-hexane) t~ give the
product in 87~ yield (13.7 g) as a yellow solid.
b) 5-Benzyloxycarbonyl-6- ~3, 4-difluorophenyl) -1, 6-
dihydro- 2, 4 - dimethylpyrimidine .
To a stirred solution of acetamidine hydrochloride
(1.42 g, 15 mmol.) in DMF (10 mL) were added a solution
of potassium tert-butoxide (1.23 g, 11 mmol.) in DMF
(lOmL) and a solution of the above yellow solid (3.16
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g, 10 mmol.) in DMF (10 mL) at 0~C. After the mixture
was stirred for 15 min at 0~C, p-toluenesulfonic acid
monohydrate (3.8 g, 20 mmol.) was added. The mixture
was heated at 100-110~C for 2 hrs. After cooling, it was
quenched with 2N aqueous NaOH solution and extracted
with ether. The organic layer was dried over Na2SO~ and
evaporated. The residue was flash chromatographed over
silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia
in methanol) to give the product in 42% yield (1.5 g)
as an off-white solid.
c) 5-Renzyloxycarbonyl-6- (3,4-difluorophenyl) -1, 6-
dihydro - l -methoxycarbonyl - 2, 4 - dimethylpyrimidine .
To a stirred slurry of NaH (59 mg, 60~ in mineral oil,
1.47mmol.) in THF ~5 mL) was added a solution of the
above off-white solid ~0.S g, 1.4 mmol.) in THF (10 mL)
at 0~C. After 5 min, methyl chloroformate (0.16 g, 1.7
mmol.) was added at 0~C. Stirring was continued at room
temperature for 30 min. The mixture was quenched with
brine and extracted with ethyl acetate. The organic
layer was dried over Na2SO4 and evaporated to give a
quantitative yield of the product as a yellow solid.
d) 5 ~ Ca rhoxy- 6 - ( 3, 4 - di f luorophenyl ) -1, 6 - dihydro -1-
methoxycarbonyl-2, 4-dimethylpyrimidine.
A solution of the above yellow solid ~0.63 g, 1.52
mmol) in methonal (20 mL) was subjected to
hydrogenation with a H2 balloon in the presence of
palladium (63 mg, 5% on C). The reaction was carried
out at room temperature for 30 min. The catalyst was
then filtered off and the solvent was removed in vacuo
to give the product in 99~ yield (0.487 g) as an off-
white solid.
e) 6-(3, 4 -Di f luorophenyl ) - 1, 6 - dihydro -1-
methoxycarbonyl - 5 - ( 3 - ( 4 -methoxycarbonyl - 4 -
phenylpiperidin- 1 -yl) -propylaminocarbonyl ) - 2, 4 -
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-14 1 -
dimethylpyrimidine.
A mixture of the above off-white solid (0.070 g, 0.~2
mmol.), 4-dimethylaminopyridine (0.040 g, 0.33 mmol.),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.060 g, 0.30 mmol.) and CH2Cl2 (5 mL)
was stirred at room temperature for 0.5 hr. After the
~ addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-l-
yl)propylamine (0.075 g, 0.27 mmol.), the mixture was
refluxed overnight. To the mixture was added another 25
mL of CH2Cl2 and washed with saturated NH4Cl solution.
After the removal of the solvent, the residue was flash
chromatographed over silica gel (eluent: 85:15 v/v
ethyl acetate-methonal) to give the title compound in
42~ yield (O.052 g) as a white solid: mp 55-57~C. Anal.
Calcd. for C3lH36F2N4O50.5CH2C12: C, 60.52; H, 5.97; N,
8.96. Found: C, 60.61; H, 6.09; N, 8.94.
Example 50
6 - ( 3, 4 -Dif luorophenyl ) -1, 6 - dihydro - 5 - ( 3 - ( 4 -
m e t h o x y c a r b o n y 1 - 4 - p h e n y 1 p i p e r i d i n - 1 -
yl) propylaminocarbonyl ) -1 -methoxymethyl - 2, 4 -
dimethylpyrimidine
a) 5 ~Benzyloxy~honyl- 6 - (3, 4 -dif luorophenyl) -1, 6 -
dihydro- 1 -methoxymethyl - 2, 4 - dimethylpyrimidine .
To a stirred slurry of NaH (24 mg, 60~ in mineral oil,
0.6 mmol.) in THF (5 mL) was added a solution of 5-
benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro-
2,4-dimethylpyrimidine (0.2 g, 0.56 mmol.) in THF (10
mL) at 0~C. After 10 min, chloromethyl methyl ether
(0.043 mL, 0.57 mmol.) was added at 0~C. Stirring was
continued at room temperature for 3 hrs. The mixture
was quenched with brine and extracted with ethyl
acetate. The organic layer was dried over Na2SO4 and
evaporated to give the product in 44.5~ yield as a
yellow oil.
.
b) S -Carboxy- 6 - ( 3, 4 -dif luorophenyl) -1, 6 -dihydro- 1-
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methoxymethyl-2, 4-dimethylpyrimidine .
A solution of the above yellow oil (0.17 g, 0.43 mmol)
in methanol (20 mL) was subjected to hydrogenation with
a H2 balloon in the presence of palladium (34 mg, 5~ on
C). The reaction was carried out at room temperature
for 0.5 hr. The catalyst was ~hen filtered off and the
solvent was removed in vacuo to give the product in
100~ yield (0.13 g) as an off-white solid.
c) 6 - (3, 4-Difluorophenyl) -1, 6-dihydro-5- (3 - (4 -
me thoxycarbonyl - 4 -phenylpiperidin - 1 -
yl ) propylaminocarbonyl ) -1 -methoxymethyl - 2, 4 -
dimethylpyrimidine .
A mixture of 5-carboxy-6-(3,4-difluoro-phenyl)-1,6-
dihydro-1-methoxymethyl-2,4-dimethylpyrimidine(0.13g,
0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84
mmol.), 1-~3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.16 g, 0.82 mmol.) and CH2Cl2 (5 mL) was
stirred at room temperature for 0.5 hr. After the
addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-1-
yl)propylamine (0.17 g, 0.62 mmol.), the mixture was
refluxed o~ernight. To the mixture was added another 25
mL of CH2Cl2 and washed with saturated NH4Cl solution.
After removal of the solvent, the residue was flash
chramotographed o~er silica gel (eluent: 80:20 v/v
ethyl acetate- methanol) to give the title compound in
32~ yield (0.075 g) as a pale yellow solld: mp 53-57~C.
Anal. Calcd. for C3~H38F2N40g0~25CHCl3 C, 62.71; H, 6.44;
N, 9.36. Found: C, 62.62; H, 6.79; N, 9.19.
Example 51
1,6-Dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl
- 4 - p h e n y l p i p e r i d i n - 1 - y l ) p e n t y 1 ) -
4-me~hyl-6-(4-nitrophenyl)-pyrimidine
a) 1,6-Dihydro-5-methoxycarbonyl-4-methyl-6-(4-
nitrophenyl)-pyrimidine.
Sodium (0.55 g, 23.9 mmol) was allowed to react with
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anhydrous EtOH (100 mL). Then the solution was cooled
by an ice water bath when formamidine acetate (2.29 g,
2 2 . 0 m m o l ) a n d m e t h y l 2 - ~ 4 -
nitrobenzylidenyl)acetoacetate (5.00 g, 20.1 ~mol) were
added. The mixture was stirred at room temperature for
3 h. The product was filtered off as a ye~low powder
(4.68 g, 80~). It was mixed with p-toluenesulfonic
acid monohydrate ~6.7 g, 35.2 mmol) in dry DMSO (125
mL) and heated at 110~C for 3 h. Ice water (450 mL) was
added and the product as a tosylate was filtered off as
an off-white solid (5.55 g, 78%).
b) 1-(s-chloropentyl)-l~6-dihydro-5-methoxycarbonyl-4
methyl-6-(4-nitrophenyl)pyrimidine.
The above solid (2.44 g, 5.45 mmol) was added to dry
TH~ (50 mL) containing sodium hydride (60~ oil
dispersion, 480 mg, 12.0 mmol) and cooled by an ice
water bath. Then l-bromo-5-chloropentane (3 mL, 22.8
mmol) was added. The mixture was stirred at room
temperature for 7 h before ice water was added.
Extraction with EtOAc gave a dark oil (4.455 g) which
was flash chromatographed over silica gel (120 g)
eluting with EtOAc/hexane/Et3N (15:15:1) to afford a
brown oil (1.43 g, 69%).
c)1,6-Dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbon
yl-4-phenyl-piperidin-1-yl)pentyl)-4-methyl-6-
(4-nitrophenyl)-pyrimidine.
The above oil t220 mg, 0.58 mmol) was mixed with 4-
methoxy-carbonyl-4-phenylpiperidine (127 mg, 0.58 mmol)
and potassium iodide (106 mg, 0.64 mmol) in dry glyme
(4 mL) cooled by an ice water bath. Then sodium
hydride (24 mg, 60% oil dispersion, 0.60 mmol) was
~ added. The mixture was heated at reflux overnight and
more KI (106 mg) was added. Reflux was continued for
two more days. Ice water was added. Extraction with
EtOAc (3 x 3 mL) gave a brown oil (158 mg). It was
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dissolved in CHCl3/EtOAc and flash chromatographed over
sllica gel (16 g) eluting with EtOAc/MeOH/Et3N (20:1:1)
to afford a yellow oil (89 mg, 27%). Anal. Calcd. for
C3lH3jN4O63/4H2O: C, 64.62; H, 6.91; N, 9.72. Found: C,
64.56; H, 6.84; N, 9.76.
Example 52
6-~2,4-Difluorophenyl)-1,6-dihydro-1-(5-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-
dimethyl-5-methylaminoca-bonyl-pyrimidine
a) Benzyl 3-oxo-2-~2,4-difluorobenzylidenyl)butanoate.
A mixture of 2,4-difluorobenzaldehyde (7.1 g, So
mmol.), benzyl acetoacetate (12.48 g, 65 mmol.), acetic
acid (0.15 g, 2.5 mmol.), piperidine (0.212 g, 2.5
mmol.) and 2-propanol (300 mL) was stirred at room
temperature for two days. After the removal of solvent,
the residue was then dissolved in ethyl acetate and
washed with saturated KHSO4, saturated NaHCO3, water and
then dried over Na2SO4. The solvent was evaporated, and
the residue was flash chromatographed over silica gel
(eluent: 1:5 v/v ethyl acetate-hexane) to give the
product in 91~ yield (14.3 g) as a yellow solid.
b) 5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6-
dihydro-2,4-dimethylpyrimidine. To a stirred solution
of acetamidine hydrochloride (2.84 g, 30 mmol.) in DMF
(20 mL) were added a solution of potassium tert-
~utoxide (2.46 g, 22 mmol.) in DMF (20mL) and a
solution of the above yellow solid (6.32 g, 20 mmol.)
in DMF (20 mL) at 0~C. After the mixture was stirred for
15 min at 0~C, p-toluenesulfonic acid monohydrate (7.6
g, 40 mmol.) was added. The mixture was heated at 100-
t 10~C for 2 hrs. After cooling, it was quenched with 2N
aqueous NaOH solution and extracted with ether. The
organic layer was dried over Na2SO4 and evaporated. the
residue was flash chromatographed over silica gel
(eluent: 100:5 v/v ethyl acetate-2M ammonia in
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Methanol) to give the product in 42% yield (1.5 g) as
an off-white solid.
c) 5-Benzyloxycarbonyl-1-(5-bromopentyl)-6-(2,4-
difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine. To
a suspension of NaH (123 mg, 60% dispersion in mineral
- oil, 3.08 mmol.) in THF (5 mL) was added a solution of
the above off-white solid (1.0 g, 2.8 mmol.) and HMPA
(0.5 g, 2.8 mmol.) in THF (5 mL) at 0~C. After 15 min,
1,5-dibromopentane (1.53 mL, 11.2 mmol.) was added.
The mixture was then refluxed for 30 min. The solid was
filtered off. After the removal of the solven~, the
residue was flash chromatographed over silica gel
(eluent: ethyl acetate) to give the product in 78
yield (1.1 g) as a yellow oil.
dJ 5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6-
dihydro-1-(5-(4-methoxycar~onyl-4-phenylpiperidin-1-
yl)pentyl)-2,4-dimethyl-pyrimidine. A mixture of the
above yellow oil (1.62 g, 3.2 mmol.), 4-
methoxycarbonyl-4-phenyl piperidine (1.4 g, 6.4 mmol.),
potassium carbonate (1.76 g, 12.7 mmol.), sodium iodide
(0.45 g, 3.0 mmol.) and 1,4-dioxane ~15 mL) was
refluxed overnight. The undissolved solid was then
filtered off and the solvent was evaporated. The
residue was flash chromatographed over silica gel
(eluent: 80:20 v/v ethyl acetate-2M ammonia in
methanol) to give the product in 66~ yield (1.36 g) as
a yellow oil.
e~ 5-Carboxy-6-(2,4-difluorophenyl)-1,6-dihydro-1-(~-
~4-mothoxycarbonyl-4-phenylpiperidin-1-yl)pentyl)-2,4-
dimethyl-pyrimidine. A solution of the above yellow
oil (0.36 g, 0.5~ mmol) in methanol ~20 mL) was
subjected to hydrogenation with a H2 balloon in the
presence of palladium (36 mg, 5% on C). The reaction
was carried out at room temperature for 30 min. The
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catalyst was then filtered off and the solvent was
removed in vacuo to give the product in quantitative
yield (0.31 g) as an off-white solid.
f) 6-(2,4-Difluorophenyl)-1,6-dihydro-1-(5-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-
dimethyl-5-methylaminocarbonyl-pyrimidine. A mixture
of the above off-white solid (0.244 g, 0.44 mmol.), 4-
dimethylaminopyridine (0.26 g, 2.12 mmol.), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.13 g, 0.66 mmol.) and CH2C12 (10 mL) was stirred at
room temperature for 2 hrs. After the addition of
methyl amine hydrogen chloride (0.089 g, 1.32 mmol.),
the mixture was stirred at room temperature overnight.
To the mixture was added another 25 mL of CH2Cl2 and
washed with saturated NH4Cl solution. After removal of
the solvent, the residue was flash chramotographed over
silica gel (eluent: 100:20 v/v ethyl acetate-2M ammonia
in methanol) to give the title compound in 22% yield
(0.055 g) as a yellow oil. Treatment of the free base
with 2 equivalents of lM HCl in ether gave the HCl salt
as a pale yellow solid: mp 152-155~C. Anal. Calcd. for
C32H40F2N4O32HCl 1.6H2O 0.8CHCl3: C, 51.57; H, 6.07; N,
7.33. Found: C, 51.38; H, 5.91; N, 7.27.
Exa~npl e 5 3
6 (R, S ) - ( 3, 4 - Di f luorophenyl ) - 1, 6 - dihydro - 5 -
methoxycarbonyl -1- ( 5 - ( 4 -me thoxycarbonyl - 4 -
phenylpiperidin -1 -yl ) - 4 (S ) -methyl ) pentyl - 2, 4 -
dimethylpyrimidine
a) (S) - (+) -3-Methylpiperidine. A mixture of (~)-
mandelic acid (45.64 g, 0.3 mol) in ethyl acetate ~300
mL) was heated to solution and treated with 3-
methylpiperidine (2g.75 g, 0.3 mol). The mi~ture was
allowed to come to room temperature before filtration.
The crystalline material was washed with 1:1 ethyl
acetate-ether (400 mL). Two recrystallizations of this
.
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salt from ethyl acetate gave the optically pure salt in
56~ yield (21.7 g).
b) (S)-(~)-N-Benzoyl-3-methylpiperidine. The above salt
~21 g, 0.088 mol) was dissolved in sodium hydroxide
solution (1.0 N, 200 mL). The solution was cooled tO
3~C, and benzoyl chloride (12.5 g, 0.089 mol) was added
dropwise over 10 min. After the addition was complete,
the mixture was transferred to a separatory funnel and
extracted with ether. The combined extracts were dried
(Na2SO4) and concentrated to give the pure amide in 98
yield ( 17.2 g): [~]D +45.9 (c 1.00, CH30H).
c) (S)~ 2-Methyl-l,S-dibromopentane. To the above
amide powder was added phosphorus tribromide (7.81 mL,
d 2.85, 0.082 mol) at 5~C over 20 min with vigorous
stirring. After the addition, the mixture was warmed to
room temperature, and Br2 (4 mL, 0.082 mol) was added
dropwise over 10 min. The mixture was then allowed to
stand at room temperature overnight and distilled under
vacuum (0.5-1 mm Hg) until the head temperature reached
80~C. The distillate was dissolved in hexane (100 mL)
and washed successively with water t20 mL),
concentrated sulfuric acid (4x30 mL), water (20 mL),
NaOH solution (lN, 2x40 mL), and water (20 mL). The
hexane solution was then dried (Na2SO4) and concentrated
to give the product in 31~ yield (6.4 g) as a light
yellow liquid.
d) 1-(5-Bromo-4(S)-methylpentyl)-6(R,S)-(3,4-
difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-
dimethylpyrimidine. To a suspension of NaH (47mg, 60
dispersion in mineral oil, 1.17 mmol.) in THF (3 mL)
was added a solution of 6-(3,4-difluoro-phenyl)-1,6-
dihydro-5~methoxycarbonyl-2,4-dimethylpyrimidine (0.3
g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4
mL) at 0~C. After 10 min, a solution of (-)-2-methyl-
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1,5-dibromopentane (0.86 g, 3.53 mmol.) in THF (~ mL)
was added. The mixture was then refluxed for 10 min.
The solid formed was filtered off. After the removal of
the solvent, the residue was flash chromatographed over
S silica gel (eluent: 100:5 v/v ethyl acetate-2.OM
ammonia in methanol) to give the product in 36% yield
(0.169 g) as a yellow oil.
e) 6(R,S)-~3,4-Difluorophenyl)-1,6-dihydro-5-
methoxycarbonyl -1- ( 5 - ( 4 -me thoxycarbonyl - 4 -
phenylpiperidin - 1 -yl ) - 4 ( S ) -me thyl ) pentyl - 2, 4 -
dimethylpyrimidine. A mixture of the above yellow oil
(0.169 g, 0.38 mmol.), 4-methoxycarbonyl-4-phenyl
piperidine (0.167 g, 0.76 mmol.), potassium carbonate
(0.21 g, 1.52 mmol.), sodium iodide (0.057 g, 0.38
mmol.) and 1,4-dioxane (8 mL) was refluxed overnight.
The undissolved solid was then filtered off and the
solvent was evaporated. The residue was flash
chromatographed over silica gel (eluent: 100:5 v/v
ethyl acetate-2M ammonia in methanol) to give the title
compound in 11% yield (0.025 g) as a yellow oil.
Treatment of the free base with 2 equivalents of lM HCl
in ether gave the HCl salt as a light yellow solid: mp
155-158~C. Anal. Calcd. for C33H41F2N3042HCl 0.5H20: C,
59.72; H, 6.64; N, 6.33. Found: C, 59.47; H, 6.66; N,
6.10.
Example 54
6- (3,4-Difuorophenyl) -1, 6-dihydro-5-methoxycarbonyl-1-
(3- (4-methoxycarbonyl-4-phenylpiperidin-1-
yl ) methyl ) benzyl - 2, 4 - dimethylpyrimidine
a) 1- (3-Bromomethylbenzyl) -6- (3, 4-difluorophenyl) -1, 6-
dihydro-~-methoxycarbonyl-2,4-dimethylpyrimidine. To a
suspension of NaH ~31 mg, 60% dispersion in mineral
oil, 0.77 mmol.) in THF (5 mL) was added a solution of
6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-
2,4-dimethylpyrimidine (0.3 g, 1.07 mmol.) and HMPA
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(0.193 g, 1.07 mmol.~ in THF (5 mL~ at 0~C. After 15
min, ~,~'-dibromo-m-xylene (0.99 g, 3.75 mmol.) was
added. The mixture was then refluxed for 15 min. The
solid was filtered off. After the removal of the
solvent, the residue was flash chromatographed over
silica gel (eluent: ethyl acetate~ to give the product
in 91~ yield (0.45 g~ as a yellow oil.
b) 6- (3,4-Difluorophenyl) -1,6-dihydro-5-
methoxycarbonyl-1- ~3- (4-methoxycarbonyl-4-phenyl-4-
phenylpiperidin -1- yl ) me thyl ) benzyl - 2, 4 -
dimethylpyrimidine .
A mixture of the above yellow oil (0.45 g, 0.97 mmol.),
4-methoxycarbonyl-4-phenyl piperidine (0.42 g, 1.9
mmol.), potassium carbonate (0.67 g, 4.86 mmol.),
sodium iodide ~0.14 g, 0.97 mmol.) and 1,4-dioxane (10
mL) was refluxed overnight. The undissolved solid was
then filtered off and the solvent was evaporated. The
residue was flash chromatographed over silica gel
(eluent: 100:5 v/v ethyl acetate-2M ammonia in
methanol) to give the title compound in 17~ yield tO.10
g) as a yellow oil. Treatment of the free base with 2
equivalents of lM HCl in ether gave the HCl salt as an
off-white solid: mp 181-183~C. Anal. Calcd. for
C3sH37F2N3042HCl l.OH20: C, 60.69; H, 5.97; N, 6.07.
Found: C, 60.73; H, 5.77; N, 5.94.
Example 55
6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-
2,4-dimethyl-1-(5-(3-phenylpropylamino)pentyl)-
pyrimidine
A mixture of 1-(5-bromopentyl)-6~(3,4-difluorophenyl)-
1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine
(0.186 g, 0.433 mmol.), 3-phenyl-1-propylamine (0.12 g,
0.89 mmol.), potassium carbonate (0.3 g, 2.17 mmol.),
sodium iodide (70 mg, 0.46 mmol.) and 1,4-dioxane (8
mL) was refluxed overnight. The undissolved solid was
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then filtered off and the solvent was evaporated. The
residue was flash chromatographed over silica gel
(eluent: 100:20:10 v/v/v CHCl3-methanol-2M ammonia in
methanol) to give the product in 54% yield (0.114 g) as
a yellow oil. Treatment of the free base with 2
equivalents of lM HCl in ether gave the HCl salt as a
white solid: mp 95-97~C. Anal. Calcd. for
C28H3~F2N3022HCl 0.5CH2C12: C, 57.15; H, 6.39; N, 7.02.
Found: C, 57.09; H, 6.65; N, 6.85.
Example 56
~+)-6-(3,4-Difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-
(4-~2-pyridyl)piperidin-1-yl)pentyl)-5-methoxycarbonyl-
2,4-dimethylpyrimidine
a) 3-BromG~ lepoxide.
To a solution of 5-~romo-1-pentene (2.15 g, 14.4 mmol.)
in CH2C12 (40 mL) was added MCPBA (3.0 g, 17.3 mmol.) at
0~C slowly. After stirred at room temperature overnight,
the mixture was poured into a mixture of ice and 2N
NaOH solution. The separated aqueous layer was
extracted with CH2Cl2. The combined organic layer was
then washed with water, brine and dried over Na2SOg. The
concentrated mixture was flash chromatographed over
silica gel (eluent: CH2C12) to give the product in 92
yield (2.19 g) as a pale yellow liquid.
b) 1-(4,5-Epoxypentyl)-6-~3,4-difluorophenyl)-1,6-
dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.
To a suspension of NaH (78 mg, 60~ dispersion in
mineral oil) in THF (10 mL) was added a solution of 6-
(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-
dimethylpyrimidine (0.5 g, 1.78 mmol.) and HMPA (0.3
mL, 1.78 mmol.) in THF (5 mL) at 0~C. After 20 min, the
above pale yellow li~uid (0.6 g, 3.6 mmol.) was added.
The mixture was then refluxed 2hrs. After the removal
of the solvent, the residue was flash chromatographed
over silica gel (eluent:100:5 v/v ethyl acetate-2.OM
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ammonia in methanol~ to give the product in 62% yield
(0.4 g) as a yellow oil.
c) 6-(3,4-Difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-
(4-(2-pyridyl)piperidin-1-)ylpentyl)-5-methoxycarbonyl-
2,4-dimethylpyrimidine.
A mixture of the above yellow oil (0.48 g, 1.32 mmol.~.
4-~2-pyridyl)piperidine (0.32 g, 1.98 mmol.) and 1,4-
dioxane (10 mL) was refluxed overnight. The
concentrated mixture was then flash chromatographed
over silica gel (eluent: 80:20 v/v ethyl acetate-2.0M
ammonia in methanol) to give all four diastereomers in
43~ yield (0.3 g). Chiral HPLC separation gave the
title enantiomer which was converted to a HCl salt: [~]~
= 120.6 (c 0.7, MeOH); mp 163-165~C. Anal. Calcd. for
C29H36F2N4O33HCl 0.7CHCl~: C, 49.57; H, 5.56; N, 7.79.
Found: C, 49.41; H, 5.96; N, 7.38.
Example 57
6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-
2,4-dimethyl-1-(5-(4-(2-pyridyl)piperidin-1-yl)-4-
oxo)pentyl pyrimidine
To a solution of oxalyl chloride (8 mg, 0.06 mmol.) in
CH2Cl2 (0.25 mL) was added a solution of DMSO (10 mg,
0.14 mmol.) in CH2Cl2 (0.3 mL) at -78~C. After 3 min, a
solution of 6-(3,4-difluorophenyl)-1,6-dihydro-1-(4-
hydroxy-5-(4-(2-pyridyl)-piperidin-1-yl)pentyl)-5-
methoxycarbonyl-2,4-dimethylpyrimidine (30 mg, 0.057
mmol.) in CH2C12 (1 mL) was added to the mixture which
was stirred for another 15 min. The mixture was
treated with triethylamine (0.04 mL) and stirred for
another 5 min. Then it was allowed to warm up to room
temperature. After the addition of water, it was washed
with lN NaOH and water. The organic layer was dried
over Na2SO4 and concentrated. The residue was purified
by preparative TLC (eluent: 100:20 v/v ethyl acetate-
2.0M ~on~a in methanol) to give the title compound in
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43~ yield (13 mg) as a yellow oil. Treatment of the
free base with 3 equivalents of lM HCl in ether gave
the HCl salt as a pale yellow solid: mp 135-137~C.
Anal. Calcd. for C29H34F2N4O33HC1 2H2O 0.9CH2Cl2: C, 48.11;
H, 5.78; N, 7.51. Found: C, 47.~9; H, 6.03; N, 7.35.
Example 58
~ 4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-
methoxyc~onyl-6-methyl-3-(5-(4-(2-pyridyl)piperidin-
1-yl)-pentyl-2(lH)-pyrimidone
a) 3-(5-Bromopentyl)-4-(3,4,5- trifluorophenyl)-3,4-
dihydro-5-methoxycarbonyl-6-methyl-2(lH)-pyrimidone.
To a suspension of NaH (0.23 g, 60~ dispersion in
mineral oil, 5.8 mmol.) in THF (40 mL) was added a
solution of 6-(3,4,5-trifluorophenyl-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methyl-pyrimidine (0.6 g,
1.9 mmol.) and HMPA (0.33 mL, 1.9 mmol.) in THF (10 mL)
at 0~C. After 20 min, 1,5-dibromopentane (1.75 g, 9.4
mmol.) was added. The mixture was then refluxed for 2
hrs and quenched by water. The mixture was partitioned
between ethyl acetate and water. The organic layer was
separated, treated with 6N HC1 ~10 mL) solution and
stirred at room temperature for 1 hr. It was then
separated and dried over Na2SO4. After the removal of
solvent, the residue was flash chromatographed over
silica gel (eluent: 80:20 v/v hexane-ethyl acetate) to
give the product in 73~ yield (0.62 g) as a yellow oil.
b)(+)-4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-
methG~yc~ yl-6-methyl-3-(5-(4-(2-pyridyl)piperidin-
1-yl)-pentyl-2(lH)-pyrimidone. A mixture of 3-(5-
bromopentyl)-4-(3,4,5-trifluorophenyl)-3,4-dihydro-5-
methoxycarbonyl-6-methyl-2(lH)-pyrimidone (0.3 g, 0.7
mmol.), 4-(2-pyridyl) piperidine (0.22 g, 1.4 mmol.),
potassium carbonate ~0.5 g, 3.6 mmol.), sodium iodide
(O.lg, 0.7 mmol.) and acetone (20 mL) was refluxed
overnight. The undissolved solid was then filtered off
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and the solvent was evaporated. The residue was flash
chromatographed over silica gel (eluent: 80:20 v/v
ethyl acetate-2.OM ammonia in Methanol) to give the
racemic product in 85% yield (0.3 g) as a yellow oil.
Chiral HPLC separation afforded the title enantiomer
which was converted to a HCl salt: [~] D = 122 (c 4.1,
- MeOH); mp 125-127~C. Anal. Calcd. for
C2aH33F3N4O3 2HCl 2H2O 0 2Et2~: C, 52.86; H, 6.32; N, 8.56.
Found: C, 52.66; H, 6.37; N, 8.15.
E x a m p l e S 9
4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbon
yl-6-methyl-3-(3-(4-~2-pyridyl)piperidin-1-yl)propylo
xycarbonyl)-2(1N)-pyrimidone.
a) 1-(3-Hydroxypropyl)-4-(2-pyridyl~piperidine.
A mixture of 4-(2-pyridyl)piperidine ~200 mg, 1.23
mmol), 3-bromopropanol (135 mL, 1.49 mmol), potassium
carbonate (620 mg, 4.49 mmol) and a catalytic amount of
sodium iodide in acetone (10 mL) was heated at reflux
overnight. Filtration followed by evaporation of the
solvent gave a light brown oil (324 mg) which was
dissolved in CHCl3 and flash chromatographed over silica
gel (20 g) eluting with EtOAc/MeOH/Et3N (20:1:1) to
afford a light brown solid (166 mg, 61~).
b
4-~3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbon
yl-6-methyl-3-(3-(4-~2-pyridyl)piperidin-1-yl)propylo
xycarbonyl)-2(lH)-pyrimidone.
A mixture of 1-(3-hydroxypropyl)-4-(2-pyridyl)-
piperidine (72 mg, 0.33 mmol) and 4-(3,4,5-
trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-
methyl-3-(4-nitrophenoxycarbonyl)-2(lH)-pyrimidine (lS2
mg, 0.33 mmol) in dry THF (8 mL) was heated at reflux
overnight. The residue obtained after evaporation of
the solvent was dissolved in EtOAc and flash
chromatographed over silica gel (18 g) eluting with
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EtOAc/MeOH/Et3N (100:3:3) to afford an off-white solid
(133 mg, 75~). It was dissolved in CH2Cl2 and treated
with lM HCl in ether (0.6 mL) to give an off-white
solid: mp 154~C (dec.). Anal. Calcd. fcr
C27H2gF3N4Os2HCl 2H2O: C, 49.47; H, 5.38; N, 8.55. Found:
C, 49.48; H, 5.16; N, 8.35.
Ex_mple 60
~ 1,2,3,6-Tetrahydro-l-{N-t4-cyano-4-(phenyl)cycloh
ex-1-yl]ethyl}carboxa~ido-5-methoxy carbonyl-4-methoxy
methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine
hydrochloride.
a) 2-~4-Cyano-4-(phenyl)cyclohex-1-yl]ethylamine.
A mixture of 4-phenyl-4-cyanocyclohexanone (5.00 g,
25.09 mmol) and ethylenediamine (5.58) and p-toluene
sulfonic acid in benzene (200 mL) were refluxed for 4
h in a Dean-Stork set-up to remove the water formed.
Solvent was e~aporated and the residue was redissolved
in methanol and cooled to 0 ~C. To this, sodium
borohydride tl.5 g) was added in portions and the
mixture was stirred at room temperature for 3 h.
Solvent was evaporated, the residue was dissolved in
dichloromethane (300 mL), washed with brine (2 X 200
mL) and dried (sodium sulfate). Sclvent was evaporated
and the residue was dried under vacuum to leave the
product as an oil ( 5.2 g). The lH-NMR showed this
product to be pure and found to contain the cis/trans
isomers in the ratio of about 9:1. It was used as was
in the next step.
b)(+)-1,2,3,6-Tetrahydro-1-{N-[4-cyano-4-(phenyl)cycl
ohex-1-yl]ethyl}carboxamido-5-methoxyca~h~yl-4-methoxy
methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine
hydrochloride.
A solution of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-
nitrophenoxy)carbonylpyrimidine t0.220 g, 0.448
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mmol),2- [4-cyano-4- (phenyl) cyclohex-l-yl] ethylamine
(0.130 g, 0.538 mmol) in tetrahydrofuran (100 mL) was
stirred at room temperature for 24 hours. The reaction
mixture was stirred for another 1 hour after addition
of 2 mL of 6N HCl. Sol~ent was evaporated at reduced
pressure and the residue was basified ~y treatment with
10% aqueous KOH solution, extracted with
dichloromethane (3 x 10 mL). The com}~ined extracts
were dried over potassium carbonate, and solvent
evaporated. The crude product was purified by
preparative thinlayer chromatography
(dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) . The
two possible isomer were obtained in the order of less
polar compound as the minor product and the more polar
compound as the major component (yields: 16 mg minor
and 160 mg major isomer). The HCl salts were obtained
by treatment with lN HCl in ether. The minor isomer HCl
salt:m.p. 124-126 ~C; [a!]D = +112 (c = 0.21 g in 100 mL
CHCl3); Anal. Calcd. for C30H34NsO5F2ClØ5 chloroform.
0.5 ether: C, 54.61; H, 5.57; N, 9.80. Found: C,
54.43; H, 5.29; N, 9.54. The major isomer HCl salt: m.
p. 136-138 ~C; [~Y]D = +142 (c = 0.21 g in 100 mL CHCl3);
Anal. Calcd. for C3UH34NsosF2cl~o~4 chloroform: C, 54.84i
H, 5.21; N, 10.52. Found: C, 55.16; H, 5.39; N, 10.42.
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General Procedure for the Preparation of 4,4-
Diarylpiperidine~:
A mixture of 0.5 g of 4-aryl-4-hydroxy piperidine, 3
mL of the aromatic substrate, and 1 g of aluminu n
chloride was stirred at room temperature for 3 days.
The reaction mixture was poured over 10 mL of ice,
diluted with t-butyl-methyl ether, the resulting
hydrochloride salt was filtered, washed with water
and ether, dried, and used in the next step after
spectral characterization.
4-Phenyl-4- (4-thiomethoxy-phenyl)-piperidine
hydrochloride:
From 4-phenyl-4-hydroxy-piperidine and thioanisole
(82~), Anal. Calc. for C1eH2lN1Sl+HCl+0.2H2O: C, 66. 83;
H, 6.98; N, 4.33. Found: C, 66.71; H, 6.81; N, 4.24.
4-(4-Fluorophenyl-4-(4-thiomethoxy-phenyl)-piperidine
hydrochloride:
From 4-(4-fluoro-phenyl-4-hydroxy-piperidine and
thioanisole (59~6), Anal. Calc. for
C18H2oF1N1S1+HCl+0.35CH2Cl2: C, 60 .14; H, 5.56; N, 3.90.
Found: C, 59.96; H, 5.95; N, 3.81.
4-(4-Fluorophenyl-4-(2-methoxy-5-fluoro-phenyl)-
piperidine hydrochloride:
From 4-(4-fluorophenyl)-4-hydroxy-piperidine and 4-
fluoroanisole (78 ~ ), Anal. Calc. for
C18H1gN1F201+HCl+0.2H2O: C, 62.96; H, 5.99; N, 4. 08.
Found: C, 62.72; H, 6.06; N, 4.06.
Bis-4-(4-Chlorophenyl)-piperidine hydrochloride:
From 4-(4-chlorophenyl~-4-hydroxy-piperidine and
chlorobenzene (92%), Anal. Calc. for C17H17N1Cl2+HCl: C,
59.58; H, 5.29; N, 3.90. Found: C, 59.58; H, 5.28; N,
3.90.
4-Phenyl-4-(4-Hydroxy-phenyl)-piperidine
hydrochloride:
From 4-phenyl-4-hydroxy-piperidine and phenol (5B~6).
General Procedure for the preparation of 4,4-diaryl-
N-(3-amino)-propylpiperidinec:
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A mixture of 4,4-diarylpiperidine hydrochloride
(0.100 mmol), ~3-bromopropyl)-carbamic acid tert-
butyl ester (0.100 mmol), diisopropylethylamine (l
mL), and dioxane (2 mL) were heated at reflux
temperature for 2 days, cooled, chromatographed
(silica prep-TLC plates) to give the BOC protected
4,4-diaryl-N-aminopropylpiperidine.
The BOC protected amine was dissolved in 1:1 TFA-
dichloromethane, stirred for 6 hours, concentrated in
vacuo, and the crude product was chromatographed
(silica gel prep-TLC plates) to give 4,4-diaryl-N-
(3-amino)propylpiperidines which were used after
spectral characterization.
General Procedure for the Preparation of
Dihydropyrimi~;~oneP:
Method A: Reaction of piperidines with
bromopropylcarbamoyl-dihydropyrimi~; no~es:
A mixture of the 3-~3-~romopropylcarbamoyl}-
4-~3,4-difluoro-phenyl)-6-methyl-
2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid
methyl ester (45 mg, 0.1 mmol) and 0.1 mmol of 4,4-
diarylpiperidine hydrochloride in a mixture of
dioxane-diisopropylethylamine (2-0.5 mL) was heated
at reflux temperature for 2 days, cooled, applied to
a preparative-TLC plate and eluted with MeOH-EtOAc
(2-3%) to give the dihydro-pyrimidine free base as
the product. The free base was dissolved in a
minimum of EtOAc and excess 1 N HCl in ether was
added. The product was filtered, washed with ether,
and dried.
Example 61:
3-{3-l(4-phenyl)-4-(4-thiomethoxy-phenyl)-piperidin-1
-yl]-propyl-
carbamoyl}-4-(3,4-difluoro-phenyl)-2-oxo-1,2,3,4-tetr
ahydro-
pyrimidine-S-carh~xylic acid methyl ester
.
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hydrochloride.
Prepared by method A. 63~ yield. Anal. Calc. for
C35H3~N4~2O4Sl+HCl+0.2CHCl3: C, 59.62; H, 5.57; N, 7.90.
Found: C, 60.07; H, 6.27; N, 7.40.
Example 62:
3-{3-[(4-phenyl)-4-(4-thiomethoxy-phenyl)-piperidin-1
-yl] -
propylcarbamoyl}-4-(3,4-di~luorophenyl)-2-oxo-1,2,3,4
-tetrahydro-pyrimidine-5-carboxylic acid methyl ester
hydrochloride.
Prepared by method A. 63~ yield. Anal. Calc. for
C3sH37N4F3O4S1+HCl+ether: C, 60.26; H, 6.22; N, 7.21.
Found: C, 60.46; H, 6.58; N, 7.41.
Example 63:
3-{3-14-(4-Fluorophenyl)-4-(2-methoxy-5-methyl-phenyl
)piperidin-
1-yl-propylcarbamoyl}-4-(3,4-difluoro-phenyl)-2-oxo-1
,2,3,4-
tetrahyd v~y~imidine-5-carboxylic acid methyl ester
hydrochloride.
Prepared by method A. 63% yield. Anal. Calc. for
C35H36N4F4O5+HCl+H20: C, 58.13; H, 5.44; N, 7.75. Found:
C, 57.97; H, 5.55; N, 7.31.
Example 64:
3-{3-~Bis-4-(4-
Chlorophenyl)piperidin-1-yl-propylcarbamoyl}-
4-(3,4-difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrim
idine-
5-car~oxylic acid methyl ester hydrochloride.
Prepared by method A. 71~ yield. Anal. Calc. for
C34H34Cl2N4F204+HCl+ether: C, 58.35; H, 5.80; N, 7.16.
Found: C, 5B.23; H, 5.71; N, 7.39.
Example 65:
3-{3-t(4-phenyl)-4-(4-hyd G~y~henyl)piperidin-l-yl]pr
opyl-carbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic acid methyl ester
hydrochloride.
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Prepared by method A. 63~ yield. Anal. Calc. for
C34H36N4F20s~+HCl+1.4ethanol: C, 61.08; H, 6.61; N,
7.75. Found: C, 60.86; H, 6.77; N, 7.32.
Method B. Reaction of 4,4-diaryl-~-(3-
aminopropyl)piperidines with p-
nitrophenylcarbamoyldihydropyrimi~;~o~s:
Example 66:
3,6-Dihydro-5-methoxycarbonyl-4-methoxymethyl-
2-oxo-1-{N-[4,4-
bis-(4-fluorophenyl)-piperidine-1-yl]-
propyl}carboxamido-
6-(2,3,6-trifluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacotyl-3-(2,3,6-
trifluorophenyl)acrylate. A mixture of 2,3,6-
trifluorobenzaldehyde (5.2 g, 33 mmol ), methyl 4-
methoxyacetoacetate ( 5.7 ml, 39 mmol~, and
piperidinium acetate (catalytic amount) in benzene
(10 ml) was stirred at room temperature for 3 days.
The solvent was evaporated, and the residue was
chromatographed on silica gel (hexane/ether = 7/1) to
yield the title compound (3.4 g, 36~) as a mixture of
cis and trans isomers as a colorless oil .
b) 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-6-(2,3,6-trifluorophenyl)pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-~2,3,6-
trifluorophenyl)-acrylate (3,4 g, 11.8 mmol), 0-
methylisourea hydrogen hemisulfate (2.3 g, 16.5
mmol), and 4-dimethylaminopyridine (32.0 g, 16.5
mmol) in ethanol (lO ml) was stirred at 65 ~C for 24
hours, cooled and filtered . The filtrate was
concentrated and chromatographed on silica gel
(hexane/ether = 2/1) to yield the title compound
(0.78 g, 20 ~ yield) as a colorless oil.
c) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-1-
(4-nitrophenyloxy)carbonyl-6-(2,3,6-trifluorophenyl)-
pyrimidine.
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To a solution of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-6-(2,3,6-trifluoro-
phenyl)-pyrimidine (0.76 g, 2.2 mmol) and 4-
dimethylaminopyridine (0.33 g, 2.7 mmol) in CH~C1. (5
ml), at room temperature, was added 4-nitrophenyl
chloroformate (0.54 g, 2.7 mmol). The reaction
solution was stirred at room temperature for 24
hours. It was filtered. The filtrate was
concentrated and chromatographed on silica gel
(hexane/ether = 2/1) to give the title compound (0.98
g, 87 ~ yield) as a pale yellow solid.
d) 3,6-D~hydro-5-methoxycarbonyl-4-methoxymethyl-
2-oxo-1-{N-t4,4-bis-(4-fluoro-
phenyl)-piperidine-1-yl]-propyl}carboxamido-
6-(2,3,6-trifluorophenyl)-pyrimidine dihydrochloride.
A mixture of
1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxy-
methyl-1-(4-nitrophenyloxy)carbonyl-6-
(2,3,6-trifluoro-phenyl)pyrimidine ~25 mg, 0.05
mmol) and 3-[4~4-bis-(4-fluoro-phenyl)-piperidin-l-
yl]-propylamine (20 mg, C.06 mmol) in CH2Cl2 ( 3 ml )
was stirred at room temperature for 12 hours. HCl
solution (6 N, 2 ml) was added. The reaction mixture
was stirred at room temperature for 6 hour. KOH
solution (1 N) was added to neutralize the reaction
mixture, and was extracted with CH2C12. The extracts
were dried (Na2SO4), concentrated and the product was
chromatographed on prep. TLC (CH2Cl2 : CH30H : 2 N NH3
in CH30H = 40:2:1) to obtain the title compound (18
mg, 53~) as a colorless oil. The hydrochloride of
the title compound was synthesized using HCl in
ether. Calculated for C3sH3sNso4F5 + 2.0 HCl: C,55.06~;
H,4.63~; N, 7.16~. Found: C,55.34~; H,4.91~;
N,7.38~.
Example 67:
3,6-Dihydro-5-methoxyr~ho~yl-4-methoxymethyl-
2-oxo-1-{N-[4-(4-chloro-phenyl)-4-(5-fluoro-2-
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methoxy-phenyl)-piperidine-l-yl]-propyl}carboxamido-
6-(3,5-difluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacetyl-3-~3,5-difluoro-phenyl)-
acrylate.
~ mixture of 3,5-difluorobenzaldehyde (10 g, 70 mmol
), methyl 4-methoxyacetoacetate ( 11 ml, 80 mmol),
and piperidinium acetate (catalytical amount) in
benzene (100 ml) was stirred at room temperature for
3 days. The solvent was evaporated, and the residue
was chromatographed on silica gel (hexane/ether =
5/1) to give the cis and trans mixture of the title
compound (3.7 g, 20~ yield) as a yellow oil .
b) l,6-dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-6-~3,5-difluoro-phenyl)-pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(3,5-
difluoro-phenyl)-acrylate (3.74 g, 13.8 mmol), O-
methylisourea hydrogen hemisulfate (2.68 g, 19.4
mmol), and 4-dimethylaminopyridine (2.37 g, 19.4
mmol) in ethanol (30 ml) was stirred at 65 ~C for 2
days, cooled and filtered . The filtrate was
concentrated and chromatographed on silica gel
(hexane/ether = 3/1) to get the title compound (1.7
g, 38 ~ yield) as a yellow solid.
c) l,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-
methoxymethyl-1-
(4-nitrophenyloxy)carbonyl-6-(3,5-difluorophenyl)-pyr
imidine.
To a solution of 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methoxymethyl-6-(3,5-
difluorophenyl)pyrimidine (1.67 g, 5.10 mmol) and 4-
dimethylaminopyridine (0.75 g, 6.1 mmol) in CH2Cl2 (10
ml), at room temperature, was added 4-nitrophenyl
chloroformate ~1.24 g, 6.1 mmol). The reaction
solution was stirred at room temperature for 24
hours, and filtered. The filtrate was concentrated
- and chromatographed on silica gel (hexane/ether =
2/1) to yield the title compound (1.82 g, 72 ~ yield)
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as a white solid.
d) 3,6-Dihydro-5-methoxycarbonyl-4-methoxymethyl-
2-oxo-1-{N-l4-(4-chloro-phenyl)-4-(5-fluoro-2-
methoxy-phenyl)-piperidine-l-yl]-propyl}ca hO~ i do-
6-(3,5-difluorophenyl)-pyrimidine dihydrochloride.
A mixture of
1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxy-
methyl-1-(4-nitrophenyloxy)carbonyl-6-(3,5-difluoro-
phenyl)pyrimidine (25 mg, 0.050 mmol) and 3-[4-(4-
chloro-phenyl)-4-(5-fluoro-2-methoxy-phenyl)-
piperidin-1-yl]-propylamine (23 mg, 0.060 mmol) in
CH2Cl2 ( 3 ml ) was stirred at room temperature for 12
hours. HCl solution (6 N, 2 ml) was added. The
reaction mixture was stirred at room temperature for
6 hour. KOH solution ~l N) was added to neutralize
the reaction mixture, and extracted with CH2Cl2. The
extracts were dried (Na2SO4), concentrated and
chromatographed on prep. TLC ( CH2Cl2: CH30H: 2 N NH3
in CH30H = 40:2:1) to give the title compound (18 mg,
50~) as a colorless oil. The hydrochloride of the
title compound was synthesized using HCl in ether.
Anal. Calculated for C36H3~ClN4O6F3 + 1.0 HCl + O. 5
CHC13: C, 54.45~; H,4.68~; N,6.36~. Found: C, 54.04~;
H, 4.91~; N, 6.91%.
Example 68:
(+)-1-(5-(4-Cyano-4-phenylpiperidin-1-yl)-4(S)-
methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-
(methoxycarbonyl)-4-methyl-2-pyrimidine.
a) (+)-1-(5-Lromo-4(S)-methyl)pentyl-6-(3,4-
difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4-
methyl-2-pyrimidone.
To a suspension of NaH (18 mg, 60~ dispersion in
mineral oil, 0.45 mmol.) in THF (5 mL) was added a
solution of (+)-6-(3,4-difluorophenyl-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methyl-pyrimidine (0.12
g, 0.4 mmol.) and HMPA (0.07 mL, 0.4 mmol.) in THF
(15 mL) at 0~C. After 20 min, 2(5)-methyl-1, 5-
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dibromopentane (0.2 mg, 0.82 mmol.) was added. The
reaction mixture was then refluxed for 2 h and
quenched by water. It was partitioned bewteen ethyl
acetate and water. The organic layer was separated,
treated with 6N HCl (5 mL) solution and stirred at
room temperature for 1 h. 'rhe organic layer was then
separated and dried over Na2SO4. After the removal of
solvent, the residue was flash chromatographed over
silica gel (eluent: 1:1 hexane/ethyl acetate) to give
the product in 81% yield (0.15 g) as a yellow oil.
b) (~)-1-(5-(4-Cyano-4-phenylpiperidin-1-yl)-4(S)-
methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-
(methoxycarhonyl)-4-methyl-2-pyrimidone.
A mixture of (+)-1-(5-Bromo-4(S)-methyl)pentyl-6-
(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4-
methyl-2-pyrimidone (0.138g, 0.31 mmol.), 4-cyano-4-
phenylpiperidine hydrochloride (0.13B 9, 0.62 mmol.),
potassium carbonate (0.22 g, 1.6 mmol.), sodium
iodide (47 mg, 0.31 mmol.) and dioxane (8 mL) was
refluxed overnight. The undissolved solid was then
filtered off and the solvent was evaparated. The
residue was purified by flash chromatographed over
silica gel (eluent: ethyl acetate) to give the
product in 18~ yield (0.030 g) as a yellow oil.
Treatment of the free base with one equivalent of lM
HCl in ether gave the ~ICl salt as a light yellow
solid: mp 133-135~Ci [~!]D = 87.4 (1.75 mg/mL, MeOH).
Anal. Calc. for C31H36F2N4O3.HClØ3CHCl3: C, 60.35; H,
6.04; N, 8.99. Found: C, 60.26; H, 6.29; N, 8.67.
Example 69:
1-(5-(4-(2-Aminocarbonyl)phenylpiperazin-1-yl)-
4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-
dihydro-5-methoxy-carbonyl-4-methyl-2-pyrimidone.
A mixture 1-(5-bromo-4(S)-methyl)pentyl-6-(3,4-
difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4-
methyl-2-pyrimidone (0.lg, 0.22 mmol.), 4-(2-
aminocarbonylphenyl)piperazine (0.070 g, 0.34 mmol.),
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potassium carbonate (0.16 g, 1.2 mmol.), sodium
iodide (33 mg, 0.22 mmol.) and dioxane (8 mL) was
refluxed overnight. The undissolved solid was then
filtered off and the solvent was evaparated. The
residue was purified by flash chromatographed over
silica gel (eluent: 20:1 ethy; acetate/2M ammonia in
methanol) to give the product in 41~ yield (0.052 g)
as a yellow oil. Treatment of the free base with one
equivalent of lM HCl in ether gave the HCl salt as a
pale yellow solid: mp 168-171~C; [CY]D = 83.5 (2 mg/mL,
MeOH). Anal. Calc. for C30H37F2NsO42HCl 0.5CH2Cl2: C,
53.48; H, 5.89; N, 10.22. Found: C, 53.74; H, 5.94;
N, 9.99.
Example 70:
1-(5-(4-Cyano-4-phenyl)piperidin-1-yl)pentyl-6-(3,4-
difluoro-phenyl)-1,6-dihydro-5-methoxycarbonyl-2-
methoxymethyl-4-methyl-pyrimidine.
a) 6-(3,4-Di~luorophenyl)-1,6-dihydro-5-
methoxycarbonyl-2-methoxy-methyl-4-methylpyrimidine.
To a solution of 2-methoxyacetamidine hydrochloride
tl.4 g, 11.2 mmol.) in DMF (6 mL) were added a
solution of potassium tert-butoxide (0.69 g, 6.1
mmol.) in DMF (6 mL) and a solution of methyl ~2-
(3,4-difluorophenyl) methylene}-3-oxobutanoate (1.4
g, 5.8 mmol.) in DMF (6 mL) at 0~C. After the mixture
was stirred for 0.5 hr at 0~C, p-toluenesulfonic acid
monohydrate (2.2 g, 11.6 mmol.) was added. The
mixture was heated at 100-120~C for 2.5 hrs. The
mixture was cooled to room temperature, quenched with
aqueous NaOH solution (2N, 30 mL), and extracted with
ether. The organic layer was dried over Na2SO4 and
evaporated. The residue was flash chromatographed
over silica gel (eluent: ethyl acetate) to give the
product in 44~ yield (0.8 g) as a yellow oil.
b) 1-(5-~romopentyl)-6-(3,4-difluorophenyl)-1,6-
dihydro-5-methoxycarbonyl-2-methoxymethyl-4-
methylpyrimidine.
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To a suspension of NaH (0.11 g, 609~ dispersion in
mineral oil, 2.8 mmol.) in THF (20 mL) was added a
solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5-
methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine
(0.8 g, 2.6 mmol.) in THF (5 mL) at 0~C. After 20 min,
1,5-dibromopentane (O.7 TnD, 5.2 mmol.) was added. The
mixture was then refluxed overnight. After the
removal of solvent, the residue was flash
chromatographed over silica gel (eluent: ethyl
acetate) to give the product in quantitative yield
(1.2 g) as a yellow oil.
c) 1-(5-(4-Cyano-4-phenyl)piperidin-1-yl)pentyl-6-
(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-
methoxymethyl-4-methylpyrimidine.
A mixture of 1-(5-~romopentyl)-6-(3,4-
difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-
methoxymethyl-4-methylpyrimidine (0.15 g, 0.33
mmol.), 4-cyano-4-phenylpiperidine hydrochloride
(0.15 g, 0.67 mmol.), potassium carbonate (0.23 g,
1.7 mmol.), sodium iodide (50 mg, 0.33 mmol.) and
acetone (6 mL) was refluxed overnight. The
undissolved solid was then filtered off and the
solvent was evaporated. The residue was flash
chromatographed over silica gel (eluent: 10:1 ethyl
acetate/2M ammonia in methanol) to give the title
compound in 44~ yield (0.080 g) as a yellow oil.
Treatment of the free base with 2 equi~alents of lM
HCl in ether gave the HCl salt as an off-white solid:
mp 98-101~C. Anal. Calc. for C32H38F2N4O3 2HCl l.lCHCl3:
C, 51.70; H, 5.39; N, 7.29. Found: C, 51.56; H, 5.52;
N, 7.27.
Example 71:
(I)-6-(3,4-Difluorophenyl)-16-dihydro-5-
methoxycarbonyl-2,4-dimethyl-1-(4~S)-methyl-5-(4-(2-
methylphenyl)-4-(4-methyl-phenyl)piperidin-1-
yl)pentyl)pyrimidine.
a) (I)-1-(5-Bromo-4(S)-methylpentyl)-6-~3,4-
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difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-
dimethylpyrimidine.
To a suspension of NaH (47 mg, 6096 dispersion in
mineral oil, 1.17 mmol.) in THF (3 mLJ was added a
solution of 6-(3, 4-difluorophenyl)-1,6-dihydro-5-
methoxycarbonyl-2,4-dimethyl-pyrimidine (0.3 g, 1.07
mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4 mL)
at 0~C. After 10 min, a solution of (-)-2-methyl-1,5-
dibromopentane (0.86 g, 3.53 mmol.) in THF (5 mL) was
added. The reaction mixture was then refluxed for 10
min. The solid formed was filtered off. After the
removal of solvent, the residue was flash
chromatographed over silica gel (eluent: 20:1 ethyl
acetate/2M ammonia in methanol) to give the product
in 3696 yield (0.169 g) as a yellow oil. Chiral HPLC
separation of the above diastereomers (Column:
Chiralcel OD 20 x 250 mm. Eluent: 2-
propanol/hexane/diethylamine 10:90:0.1) gave the
desired enantiomer: ~]D = 200.9 (25.5 mg/mL, CH2C12).
b) (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5-
methoxycarbonyl-2,4-dimethyl-1-(4(S)-methyl-5-(4-(2-
methylphenyl)-4-(4-methyl-phenyl)piperidin-1-
yl)pentyl)pyrimidine.
A mixture of (+)-1-(5-bromo-4(S)-methylpentyl)-6-
(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-
2,4-dimethyl-pyrimidine (0.1 g, 0.23 mmol.), 4-(2-
methylphenyl)-4-(4-methylphenyl)piperidlne
hydrochloride (0.08 g, 0.26 mmol.), potassium
carbonate (0.18 g, 1.3 mmol.), sodium iodide (0.033
g, 0.26 mmol.) and acetone (8 mL) was refluxed
overnight. The undissolved solid was then filtered
off and the solvent was evaporated. The residue was
flash chromatographed over silica gel (eluent: 10:1
ethyl acetate/2M ammonia in methanol) to give the
title compound in 64~ yield (0.090 g) as a yellow
oil. Treatment of the free base with 2 equivalents
of lM HCl in ether gave the HCl salt as a light
~. .
CA 02253862 lsss-ll-os
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yellow solid: mp 130-133~C; [tY]D = 62.4 (1.85 mg/mL,
MeOH). Anal. Calc. for C39H47F2N3O22HCl 2H2O 0.65CHCl3:
C, 58.48; H, 6.64; N, 5.16. Found: C, 58.27; H, 6.46;
N, 5.40.
Example 72:
(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5-
~ethoxycarbonyl-2-methoxymethyl-4-methyl-1-(5-(4-~2-
methylphenyl)-4-(4-methyl-phenyl)piperidin-1-
yl)pentyl)pyrimidine.
a) (+)-1-(5-Bromopentyl)-6-(3,4-difluorophenyl)-1,6-
dihydro-5-methoxycar~onyl-2-methoxymethyl-4-
methylpyrimidine.
To a suspension of NaH (0.11 g, 60~ dispersion in
mineral oil, 2.8 mmol.) in THF (20 mL) was added a
solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5-
methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine
(0.8 g, 2.6 mmol.) in THF (5 mL) at 0~C. After 20
min., 1,5-di~romopentane (0.7 mL, 5.2 mmol.) was
added. The mixture was then refluxed overnight. After
the removal of the solvent, the residue was flash
chromatographed over silica gel (eluent: ethyl
acetate) to give the product in quantitative yield
(1.2 g) as a yellow oil. Chiral HPLC separation
(Column: Chiralcel OD 20 x 250 mm. Eluent: 2-
propanol/hexane/diethylamine 10:90:0.1) gave the
title enantiomer: [a]D = 190.5 (55 mg/mL, CH2Cl2).
~) (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5-
methoxycarbonyl-2-methoxymethyl-4-methyl-1-(5-(4-(2-
methylphenyl)-4-(4-methyl-phenyl)piperidin-1-
yl)pentyl)pyrimidine.
A mixture of (~)-1-(5-bromopentyl)-6-(3,4-
difluorophenyl)-1, 6 -dihydro-5-methoxycarbonyl-2-
methoxymethyl-4-methylpyrimidine (0.08 g, 0.17
mmol.), 4-(2-methylphenyl)-4-(4-
methylphenyl)piperidine hydrochloride (0.063 g, 0.21
mmol.), potassium carbonate (0.14 g, 1.0 mmol.),
sodium iodide (26 mg, 0.17 mmol.) and acetone (6 mL)
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was refluxed overnight. The undissolved solid was
then filtered off and the sol~ent was evaporated.
The residue was flash chromatographed over silica gel
(eluent: 10:1 ethyl acetate/2M ammonia in methanol)
to give the title compound in 89~ yield (0.1 g) as a
yellow oil. Treatment of the free base with 2
equivalents of lM HCl in ether gave the HCl salt as a
pale yellow solid: mp 137-140~C; [~]~ = 56.5 (1.65
mg/mL, MeOH). Anal. Calc. for
C39H47F2N3O32HCl 2H2O 0.75CHC13: C, 56.68; H, 6.43; N,
4.99. Found: C, 56.55i H, 6.19; N, 5.02.
Example 73:
~ 1,2,3,6-Tetrahydro-l-{N-[3-~4,4-
diphenylpiperidin-1-yl)-
propyl]}ca~hoY~mido-5-methoxycarbonyl-2-oxo-6-~3,4-
difluoro-phenyl)-4-methoxymethylpyrimidine
hydrochloride.
A solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6-
tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxymethyl-1-
(4-nitrophenoxy)-carbonylpyrimidine (0.160 g) and 3-
(4,4-diphenyl-piperidin-1-yl)propylamine(0.150 g) in
tetrahydrofuran (10 mL) was stirred at room
temperature for 14 hours. The product was purified by
preparative thin layer chromatography on silica gel
using ethyl aceate as eluent to give 0.22 g of the
product as a syrup, which was converted to the
hydrochloride salt by treatment with lN HCl in ether;
m.p. 178-181 ~C; [~]D = +99.6 (c = 0.24, MeOH). Anal.
Calcd. for C3sH39ClF2N4OsØ2CH2Cl2: C, 60.93; H, 5.74;
N, 8.06. Found: C, 60.73; H, 5.89; N, 7.92.
Example 74:
(+)-1,2,3,6-Tetrahydro-l-{N-[3-(4,4-
diphenylpiperidinl-yl)-
propyll}carboxamido-5-acetyl-2-oxo-6-(3,4,5-
trifluorophenyl)-4-methylpyrimidine dihydrochloride.
A mixture of 6-(3,4,5-difluorophenyl)-
1,2,3,6-tetrahydro-2-oxo-
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5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim
idine (0.150 g) and 3-(4,4-
diphenylpiperidin-1-yl)propylamine~0.180 g) in T~F
(10 mL) was stirred at room temperature for 14 h. The
product was purified by preparative thin layer
chromatography on silica gel using ethyl aceate as
eluent to gi~e 0.23 g of the product as a syrup,
which was converted to the hydrochloride salt by
treatment with lN HCl in ether; m.p. 180-182 ~C.
Anal. Calcd. for C34H36ClF3N4O3.1CH2C12: C, 57.90; H,
5.28; N, 7.72. Found: C, 57.54; H, 5.10; N, 7.79.
Example 75:
(+)-1,2,3,6-Tetrahydro-1-{N-~3-~4-(2-methylphenyl)-4-
(4-
methylphenyl)piperidin-l-yl)-propyl]}carboxamido-5-ac
etyl-2-oxo-6-
(3,4,5-trifluorophenyl)-4-methylpyrimidine
hydrochloride.
A mixture of 6-(3,4,5-difluorophenyl)-
1,2,3,6-tetrahydro-2-oxo-
5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim
idine (0.02 g) and 3-[4-(2-methylphenyl)-4-(4-
methylphenyl)-piperidin-1-yl]-propylamine(0.02 g) in
THF (1 mL) was stirred at room temperature for 14 h.
The product was purified by preparative thinlayer
chromatography on silica gel using ethyl aceate as
eluent to give 0.03 g of the product as a syrup,
which was converted to the hydrochloride salt by
treatment with lN HCl in ether; m.p. 180-184 ~C.
Anal. Calcd. for C36H4CClF3N4O3Ø4CH2C12: C, 62.18; H,
5.85; N, 7.97. Found: C, 62.42; H, 6.00; N, 7.88.
Example 76:
(+)-6-(3,4-Difluorophenyl-1-[{N-~4-cyano-4-phenyl-
piperidin-l-yl]-
2,2-diflu~.o~ l}carboxamido]-5-methoxycarbonyl-
4-methoxymethyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine.
a) 3-~4-Cyano-4-phenyl-piperidin-1-yl](2-
. . . ~ , .
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hydroxypropyl)-phtha}imide.
A mixture of 4-cyano-4-phenylpiperidine (10 g, 44.9
mmol) and 2,3-epoxypropylphthalimide ~10.94 g, 53.9
mmol) in DMF (100 mL) was stirred and heated at 70 ~C
for 72 h. The solvent was evaporated under reduced
pressure and the residue was purified by column
chromatography on silica gel using chloroform-
methanol-2M ~mmo~ia in methanol (1000/28/14) as the
eluent, to obtain the desired product as a viscous
oil (16.45 g, 86~).
b) 3-[4-Cyano-4-phenyl-piperidin-1-yl](2-
G~ J~Y1) phthalimide.
To a stirred solution of DMSO (3.6 mL, 51.07 mmol) in
dichloromethane (100 mL) at -78 ~C, oxalyl chloride
(2.18 mL, 24.5 mmol) in dichloromethane ~15 mL) was
added and the mixture was stirred for 3 min. To
this, a solution of 3-[4-cyano-4-phenyl-
piperidin-1-yl](2-hydroxypropyl)phthalimide (8.70 g,
20.42 mmol) in dichloromethane (25 mL) was added and
the stirring was continued for 15 min. It was
warmed to room temperature and added 5 mL of water.
The p~ of the mixture was adjusted to 10-11 by adding
lN NaOH and the dichloromethane layer was separated.
The aqueous layer was extracted with more
dichloromethane (3 X 100 mL). The combined
dichloromethane extracts were dried (magnesium
sulfate), solvents evaporated, and the residue was
purified by flash chromatography on silica gel using
ethyl acetate/hexane as eluent (6.05 g, 70%).
c) 3-~4~Cyano-4-phenyl-piperidin-1-yl](2,2-
difluo~ G~yl)-phthalimide.
To a well stirred solution of 3-[4-cyano-4-phenyl-
piperidin-1-yl]-(2-oxopropyl)phthalimide (0.22 g,
0.52 mmol) in anhydrous dichloromethane (25 mL) at -
78~C, under argon atmosphere was added
~ diethyaminosulfur trifluoride (DAST) (0.251 mg, 1.56
mmol) and the mixture was allowed to warm to room
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temperature. After 36 h, the reaction mixture was
cooled to 0-5 ~C and to this saturated sodium
bicarbonate solution (20 mL) was added cautiously.
The dichloromethane layer was separated, dried
(sodium sulfate), and the solvent was evaporated.
The product was purified by flash column
chromatography on silica gel using 30~ ethyl acetate
in hexanes as eluent (80 mg, 38~ H-NMR was in
agreement with the product.
d) 3-~4-Cyano-4-phenylpiperidin-1-yl](2,2-
dif}uoro)propylamine.
A mixture of 3-[4-cyano-4-phenyl-piperidin-1-yl](2,2-
difluoro-propyl)phthalimide (120 mg, 0.29 mmol) and
hydrazine (0.5 mL g) in methanol (15 mL) was stirred
and refluxed for 4.5 h. It was cooled, filtered, and
the solid was washed with methanol (30 mL).
Evaporation of solvent from the filtrate gave the
product as a viscous oil (60 mg, 73%) which was used
in the next step without any further purification.
e) (~)-6-(3,4-Difluorophenyl-l-l{N-[4-cyano-4-phenyl-
piperidin-1-yl~-2,2-difluoropropyl}-carboxamido]-
5-methoxycarbonyl-4-methoxymethyl-2-oxo-
1,2,3,6-tetrahydro-pyrimidine.
A solution of (+)-5-methoxycarbonyl-4-methoxymethyl-
1~2~3~6-tetrahydro-2-oxo-6-(3~4-difluorophenyl)-l-
[(4-nitrophenyloxy)-carbonyl]pyrimidine (38 mg, 0.077
mmol) and 3-[4-cyano-4-phenyl-piperidin-l-yl](2~2
difluoropropyl)propylamine (30 mg, 0.107 mmol) in
dichloromethane (3 mL) was stirred at room
temperature for 12 hours. The mixture was purified
by preparative tlc on silica gel (60~ ethyl acetate
in hexanes) to give 38 mg (81~) as a white powder.
The HCl salt was prepared by treatment of a solution
of the free base in ether with lN HCl in ether. The
white powder was dried and recrystallized from
anhydrous 2-propanol. M.P. 184-186 DC; [alD = +96.36
(c = O.55, dichloromethane). Anal. Calcd. for
. . ,
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C30~32NsOsF4Cl:C, 55.12i H, 4.87; N, 9.95. Found: C,
55.09; H; 4.93; N, 9.71.
Example 77:
(+)-1,2,3,6-Tetrahydro-1-{N-14-(4-methoxycar~onyl-4-
phenyl-
piperidin-1-yl)-piperidinyl]}carbonyl-5-methoxycarbon
yl-2-
oxo-6-(3,4,5-trifluorophenyl)-4-methoxymethylpyrimidi
ne hydrochloride.
a) 1-~enzyl-4-(4-Methoxycarbonyl-4~
phenylpiperidinl-yl)-piperidine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine
(6.50 g, 0.0296 mol), N-benzyl-4-piperidone (5.62 g),
and p-toluenesulfonic acid (100 mg) in benzene (100
mL) was heated at 110 ~C for 14 h with a Dean-Stark
trap to remove the water that formed. Solvent was
evaporated and the residue was redissolved in
methanol ~20 mL). To this, sodium cyanoborohydride
(1.86 g) was added in portions and the mixture was
stirred at room temperature for 6 h. Solvent was
evaporated, the residue was mixed with lN NaOH (10
mL) and the resultant mixture was extracted with
ether (4 X 20 mL). The combined extracts were washed
with brine (20 mL), dried (sodium sulfate), and the
solvent evaporated. The residue was purified by
column chromatography on silica gel using dichloro-
methane/methanol/2M ammonia in methanol (50/20/10) as
eluent. The product was obtained as a viscous oil
(~.5 g), which on trituration with hexane became a
white powder.
b) 4-(4-Methoxycarbonyl-4-
phenylpiperidin-1-yl)-piperidine.
A mixture of 1-benzyl-4-(4-Methoxycarbonyl-4-
phenylpiperidin-1-yl)piperidine (3.92 g) and 10% Pd-C
(0.4 g) in ethanol (200 m~) was hydrogenated at 80
psi for 12h. The catalyst was removed by filtration
and the solvent was evaporated from the filtrate to
. _, ,
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leave the product (2.9 g, 96%) as a white powder.
c) (+)-1,2,3,6-Tetrahydro-1-{N-14-(4-methoxycarbonyl-
4-phenyl-
piperidin-l-yl)-piper~dinyl~}carbonyl-S-methoxycarbon
yl-2-oxo-6-
~3,4,5-trifluorophenyl)-4-methoxymethylpyrimidine
hydrochloride.
A solution of (+)-6-(3l4~5-trifluorophenyl)-l~2~3~6-
tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxymethyl-1-
(4-nitrophenoxy)-carbonylpyrimidine ~50 mg, prepared
similarly to (+)-6-(3,4-difluorophenyl)-1,2,3,6-
tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxy-methyl-
1-(4-nitrophenoxy)carbonylpyrimidine) and 4-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)piperidine(50
mg) in THF (2 mL) was stirred at room temperature for
14 hours. The product was purified by preparative
thin layer chromatography on silica gel using ethyl
aceate as eluent to give 70 mg of the product as a
syrup, which was converted to the hydrochloride salt
by treatment with lN HCl in ether; m.p. 178-181 ~C;
[~D = +135 (c = 0.65, MeOH). Anal. Calcd. for
C3sH38ClF3N4O7Ø4CH2Cl2: C, 55.02; H, 5.36; N, 7.68.
Found: C, 55.22; H, 5.48; N, 7.56.
Example 78:
(+)-1,2,3,6-Tetrahydro-l-{N-[2-(4-phenyl-4-
methoxyc~rh~nyl)-piperidin-1-yl)ethyl]}acetamido-5-
methoxycarbonyl-2-oxo-6-
(3,4-difluorophenyl)-4-methylpyrimidine
hydrochloride.
a)
(~)-1,2,3,6-Tetrahydro-1-~bezyloxycarbonylmethyl)-5-
met~oxy-
carbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimid
ine .
A mixture of (+)-1,6-dihydro-5-
methoxycarbonyl-2-methoxy-
6-(3,4-difluorophenyl)-4-methylpyrimidine (0.296 g),
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benzyl bromoacetate (0.229 g~, potassium carbonate
(0.600 g), and potassium iodide (30 mg) in acetone
(20 mL) was he~ted under reflux for 14 h. It was
filtered, washed with acetone (15 mL). To the
combined filtrates 6N HCl (0.5 mL) was added and
stirred for 4 h. Solvent was evaporated and the
product was purified by preparati~e thin layer
chromatography on silica gel using hexane/ethyl
acetate (1:1) to give the product as a foam (0.20 g)
which was used in the next step without further
characterization.
b) (+)-1,2,3,6-Tetrahydro-5-methoxyc~rho~yl-2-oxo-
6-(3,4-difluorophenyl)-4-methylpyrimidine-1-acetic
acid .
To a suspension of 10~ Pd-C (20 mg) in MeOH (10 mL)
and H2O (2 mL) was added a solution of
(+)-1,2,3,6-tetrahydro-1-(benzyloxy-carbonylmethyl)-
5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-
4-methylpyrimidine (200 mg) in methanol (1 mL) and
the mixture was hydrogenated at 80 psi for 4 h. The
black suspension was filtered through a pad of Celite
and washed thoroughly with MeOH (100 mL). Solvent
was evaporated from the combined filtrate to yield
the product (+)-1,2,3,6-tetrahydro-1-5-
methoxycarbonyl-2-oxo-6-
(3,4-difluorophenyl)-4-methylpyrimidine-1-acetic acid
as a white solid (0.15 g). It was used in the next
step without further purification.
c) (~)-1,2,3,6-Tetrahydro-1-{N-[2-(4-phenyl-4-
methoxycarbonyl)-piperidin-1-yl)ethyl~}acetamido-5-
methoxycarh~nyl-2-oxo-
6-(3,4-difluorophenyl)-4-methylpyrimidine
hydrochloride.
A mixture of (+)-1,2,3,6-tetrahydro-1-5-
methoxycarbonyl-2-oxo-
6-(3,4-difluorophenyl)-4-methylpyrimidine-1-acetic
acid ~20 mg), 2-(4-phenyl-4-
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methoxycarbonyl)piperidin-l-yl)ethylamine ~20 mg), l-
(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride ~20 mg), and 4-(N,N-
dimethylamino)pyridine (20 mg) in anhydrous
dichloromethane (4 mL) was stirred at room
temperature for 12 h. The reaction mixture was
purified by preparative thin layer chromatography on
silica gel using ethyl acetate as the eluent. The
product was dissolved in ether (0.5 mL), cooled to 0-
5 ~C and treated with lN HCl in ether (10 mL) and the
solvents evaporated to leave the product as a white
powder ~25 mg); mp 2~7-250~C; [a3D = ~108.2 (c = 0.50,
MeOH). Anal. Calcd. for C30H3sN4O6F~Cl: C, 58.02; H,
5.68; N, 9.02. Found: C, ~8.21; H; 5.70; N, 8.92.
Example 79:
1,6-Dihydro-l-{N-[2-(4-phenyl-4-
methoxy~ar~nyl)piperidin-l-yl)-ethyl]}acetamido-5-
methoxycarbonyl-6-(3,4,5-trifluorophenyl)-
2,4-dimethylpyr~midine dihydrochloride.
a) 6-~3,4,5-trifluorophenyl)-1,6-dihydro-5-
methoxyca~ yl-2,4-dimethylpyrim~dine.
To a solution of acetamidine hydrochloride (1.41 g,
14.9 mmol.) In DMF (10 mL) was added a solution of
potassium tert-butoxide (12 mL, 1.0 M in THF ) at 0~C.
After stirred for 10 minutes, a solution of methyl
{2-(3,4,5-trifluorophenyl)methylene}-3-oxobutanoate
(2.10 g, 10.0 mmol) in DMF (10 mL) was added and the
mixture was stirred for 2 hours while warmed up to
room temperature. p-Toluenesulfonic acid monohydrate
(4.50 g, 23.6 mmol) was added to the solution and the
reaction mixture was heated at 110-120 ~C for 2 hours.
The mixture was cooled to room temperature and poured
into ice (100 g) and aqueous NaOH solution (3 N, 200
mL), and extracted with ether ~3x100 mL). The organic
layers were combined, dried (K2CO3) and e~aporated.
The residue was purified by flash chromatography o~er
silica gel (eluent: 10-15~ MeOH in methylene
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chloride) to afford the product in 47~ yield ( 1.4 g
)as an oil.
b) 1,6-Dihydro-1-{bezyloxycarbonylmethyl)-5-
methoxycarbonyl-
6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine. A
mixture of 1,6-dihydro-5-
methoxycarbonyl-6-(3,4,5-trifluorophenyl)-
2,4-dimethylpyrimidine (0.298 g), benzyl bromoacetate
(0.229 g), potassium carbonate (0.600 g), and
potassium iodide (30 mg) in acetone (20 mL) was
heated under reflux for 14 h. It was filtered,
washed with acetone (15 mL). Solvent was evaporated
and the product was purified by preparative thin
layer chromatography on silica gel using hexane/ethyl
acetate (l:1) to give the product as a foam (0.34 g).
NMR confirmed it to be the desired product which was
used in the next step without any further
characterization.
c) 1,6-Dihydro-5-
methoxyc a ~honyl-6-(3,4,5-trifluorophenyl)-
2,4-d~methylpyrimidine-1-acetic acid. To a suspension
of 10~ Pd-C (30 mg) in MeOH ~10 mL) and H2O (2 mL)
was added a solution of
1,6-dihydro~ bezyloxycarbonylmethyl)-5-
methoxycarbonyl-
6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine (300
mg) in methanol (1 mL) and the mixture was
hydrogenated at 80 psi for 4 h. The black suspension
was filtered through a pad of Celite and washed
thoroughly with MeOH (100 mL). Solvent was
evaporated from the combined filtrate to leave the
product 1,6-dihydro-5-
methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethy
lpyrimidine-1-acetic acid as a white solid (0.225 g)~
It was used in the next step without further
purification.
d) 1,6-Dihydro-1-{N-l2-(4-phenyl-4-
, . ,
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-177-
methoxycarbonyl)piperidin-l-yl)ethyl]}acetamido-5-
methoxy~rh~nyl-6-(3,4,5-trifluoro-phenyl)-
2,4-dimethylpyrimidine dihydrochloride.
A mixture of l,6-dihydro-5-
methoxycarbonyl-6-(3,4,5-trifluoro-phenyl)-
2,4-dimethylpyrimidine-l-acetic acid (20 mg), 2-(4-
phenyl-4-methoxycarbonyl)piperidin-l-yl)ethylamine
(20 mg), l-(3-dimethyl-aminopropyl)-3-
ethylcarbodiimide hydrochloride ~20 mg), and 4-(N,N-
dimethylamino)pyridine (20 mg) in anhydrous
dichloromethane (4 mL) was stirred at room
temperature for 12 h. The reaction mixture was
purified by preparative thin layer chromatography on
silica gel using ethyl acetate as the eluent. The
product was dissolved in ether (0.5 mL), cooled to 0-
5 ~C and treated with lN HCl in ether (l0 mL) and the
solvents evaporated to leave the product as a white
powder (25 mg); m.p. 187-l90 ~C; Anal. Calcd. for
C31H3,N4O5F3Cl2: C, 55.28; H, 5.54; N, 8.32. Found: C,
55.36; H; 5.80; N, 8.41.
Example 80:
(+)l,2,3,6-Tetrahydro-l-{N-[4-(2-
ni~rophenyl)piperazin-l-yl]-propyl}-carhox~;do-4-
methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
a) l-(2-nitrophenyl)-piperazine.
A heterogenous reaction mixture containing 2-bromo-l-
nitrobenzene (2.02 g, l0.0 mmol) and piperazine (4.3
g, 50.0 mmol) was heated at 100~C for l0 h. The
orange-red solid was extracted with ethyl acetate and
washed thoroughly with 3 N NaOH solution followed by
brine. The organic layer was separated and dried
over Na2SO4, filtered and the solvent was removed in
vacuo. The resulting red oil was purified by column
chromatography on silica gel (l:l hexane/EtOAc
followed by 4:l EtOAc/MeOH) to yield l-(2-nitro-
~ phenyl)-piperazine as an orange-red oil (l.90 g,
92%). It was converted to its hydrochloride salt.
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Anal. calcd. for CloH14N3O2Cl 0.10 C~Cl3: C, 47.46; H,
5.56; N, 16.44. Found: C, 47.63; H, 5.69; N, 16.42.
b) (+)-1,2,3,6-Tetrahydro-1-{N-~4-(2-
nitrophenyl)piperazin-1-yl~propyl}-carboxamido-4-
methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of (+)-1-(3-bromo-propylcarbamoyl)-6-
(3,4-difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydro-
pyrimidine-5-carboxylic acid methyl ester (0.22 g,
0.5 mmol) and 1-(2-nitro-phenyl)-piperazine (0.15 g,
0.75 mmol) in 20 mL of anhydrous acetone was added
powdered K2CO3 ~0.34 g, 3.5 mmol) and KI (0.07 g, 0.5
mmol) and the resulting suspension was heated to
reflux for 10 h. The suspension was cooled, filtered
and the solvent was evaporated and the residue was
purified by column chromatography on silica gel with
EtOAc/MeOH (5:1) as the eluting system. (+)-1,2,3,6-
tetrahydro-1-{N-4-(2-nitrophenyl)piperazin-1-
yl]propyl~-carboxamido-4-methyl-6-(3,4-
difluorophenyl)-2-oxo-pyrimidine was obtained as a
yellow oil (0.08 g, 29~ yield). The product was
analyzed as its hydrochloride salt. M.P. 133-136~C;
[~D = +56.7 (c = 0.11, MeOH). Anal. calcd. for
C27H3lN6F2O6Cl 0.20 CH2Cl2: C, 51.62; H, 4.97; N, 13.28.
Found: C, 51.35; H, 5.18; N, 11.99.
Example 81:
(+)-1,2,3,6-Tetrahydro-1-{N-[4-(2-amino-
phenyl)piperazin-1-yl~propyl}-car~oxamido-4-methyl-6-
(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a cooled suspension of 10~ palladium on carbon (40
mg) in methanol (25 mL) was added a solution of (+)-
1,2,3,6-tetrahydro-1-{N-4-(2-nitrophenyl)piperazin-
lyl]propyl}-carboxamido-4-methyl-6-(3~4-
difluorophenyl)-2-oxo-pyrimidine (50 mg, 0.09 mmol)
in methanol (5 mL) and the resulting suspension was
hydrogenated at 100 psi at room temperature for 3 h.
The suspension was filtered through a pad of celite
and washed with 50 mL of methanol. The solvent was
~ . .
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removed in vacuo from the combined filtrate to get
0.03 g (6096) of (+)-1,2,3,6-tetrahydro-1-{N-l4-(2-
amino-phenyl)-piperazin-1-yl]propyl}-carboxamido-4-
methyl-6- (3,4-difluoro-phenyl)-2-oxo-pyrimidine as a
yellow oil. No purification was performed on this
material and it was characterized as its
dihydrochloride salt. Mass spectrum (low res.) 543
(M+l, 100~); [a]D = + 75.1 (c = 0.41, MeOH); Anal
calcd. for C27H34N6F2O4Cl2 0.03 CHCl3: C, 52.48; H, 5.54;
N, 13.59. Found: C, 52.35; H, 5.83; N, 12.50.
Example 82:
1,2,3,6-Tetrahydro-l-{N-[4-(6-(nitro)pyrid-2-
yl)piperazin-1-yl] propyl}-carboxamido-4-methyl-6-
(3,4-difluorophenyl)-2-oxo-pyrimidine.
a) 1-16-tn~ tro)pyrid-2-yl]piperazine.
To a solution of 2-chloro-3-nitropyridine (1.58 g,
10.0 mmol) in 1,4-dioxane (50 mL) was added
piperazine (4.3 g, 50.0 mmol) and powdered K2CO3 (50.0
mmol, 6.9 g) and the resulting suspension was heated
at reflux for 10 h. After the suspension was cooled,
it was extracted with ethyl acetate (2 X 50 mL) and
washed successively with 3 N NaOH (20 mL) and water
(20 mL). The organic layer was dried over Na2SO4,
~iltered and the solvent was removed in vacuo. The
resulting residue was purified by column
chromatography on silica gel (1:1 hexane/EtOAc
followed by 4:1 EtOAc/MeOH) to yield 1- [6-
(nitro)pyrid-2-yl] piperazine as a yellow solid. It
was charcterized as a hydrochloride salt.
Anal calcd. for CgH12N4O2Cl 0.25 CHCl3: C, 40.47; H,
4.86; N, 20.41. Found: C, 40.72; ~I, 4.97; N, 20.50.
b) 1,2,3,6-Tetrahydro-1-{N-[4-(6-(nitro)pyrid-2-
yl)piperazin-1-yl~propyl}-ca~ i do-4-methyl-6-
(3,4-difluorophenyl~-2-oxo-pyrimidine.
To a solution of 1-(3-bromo-propylcarbamoyl)-6-(3,4-
difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydro-
pyrimidine-5-carboxylic acid methyl ester (0.04 g,
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0.1 mmol) and 1-[6-(nitro)pyrid-2-yl]-piperazine
(0.03 g, 0.15 mmol) in 10 mL of anhydrous acetone was
added powdered K2CO3 (0.06 g, 0.6 mmol) and KI (0.01
g, 0.10 mmol) and the resulting suspension was heated
to reflux for 10 h. The suspension was cooled,
filtered and the solvent was evaporated in vacuo. The
residue was purified by column chromatography on
silica gel with EtOAc/MeOH (5:1) as the eluting
system. 1,2,3,6-tetrahydro-1-~N-[4-(6-(nitro)pyrid-2-
yl)-piperazin-1-yl]propyl}-carboxamido-4-methyl-6-
~3,4-difluoro-phenyl)-2-oxo-pyrimidine was obtained
as a yellow oil (0.04 g, 70~ yield). The product was
analyzed as its hydrochloride salt. M.P. 142-145~C;
Anal calcd. for C26H30N7F2O6Cl 0.30 CH2Cl2: C, 48.91; H,
4.74; N, 15.18. Found: C, 48.94; H, 4.94; N, 13.29.
Example 83:
~+)-1,2,3,6-Tetrahydro-1-{N-~2-(S)-methyl)-4-(2-
nitrophenyl)-piperazin-l-yl]propyl}-carboxamido-4-
methyl-6-~3,4-difluoro-phenyl)-2-oxo-pyrim~dine.
a) (S)-(+)-3-methyl-1-(2-nitrophenyl)piperazine.
To a solution of 2-bromo-1-nitrobenzene (0.6 g, 3.0
mmol) in 1,4-dioxane (15 mL) was added ~S)-(+)-2-
methylpiperazine (0.5 g, 0.5 mmol) and powdered K2CO3
(15.0 mmol, 1.5 g) and the resulting suspension was
heated at reflux for 10 h. After the suspension was
cooled, it was filtered through a sintered glass
funnel and the solvent was evaporated in vacuo. The
resulting residue was purified by column
chromatography on silica gel (1 1 hexane/EtOAc
followed by 4:1 EtOAc/MeOH) to yield (S)-(+)-3-
methyl-1-(2-nitrophenyl)-piperazine as an orange oil
(0.53 g, 80%).
b) (I)-1,2,3,6-Tetrahydro-l-{N-[2-(S)-methyl)-4-(2-
nitrophenyl)-piperazin-1-yl]propyl}-carboxamido-4-
methyl-6-(3,4-difluoro)-phenyl-2-oxo-pyrimidine.
To a solution of (+)-1-(3-bromopropylcarbamoyl)-6-
(3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydro-
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pyrimidine-5-carboxylic acid methyl ester (0.2 g, 0.5
mmol) and (S)-(+)-3-methyl-1-(2-
nitrophenyl)piperazine (0.17 g, 0.75 mmol) in 20 mL
of anhydrous acetone was added powdered K2CO3 (0.34 g,
3.5 mmol) and KI ~0.07 g, 0.5 mmol) and the resulting
suspension was heated to reflux for 10 h. TLC
~ indicated a new spot for the product (Rf = 0.3, 3:0.5
EtOAc/MeOH) and mostly the starting material. The
suspension was cooled, filtered and the solvent was
evaporated and the residue was purified by column
chromatography on silica gel with EtOAc/MeOH (5:1) as
the eluting system. (+)-1,2,3,6-Tetrahydro-l-~N-[2-
(S)-methyl)-4-(2-nitrophenyl)piperazin-1-yl~propyl}-
carboxamido-4-methyl-6-~3,4-difluorophenyl)-2-oxo-
pyrimidine was obtained as yellow oil (0.03 g, 10
yield). The product was analyzed as its
hydrochloride salt. M.P. 150-153~C; E~]D = 58.3 (c =
0.3, MeOH); Anal calcd. for Cz~H33N6F2O6Cl 0.20 CH2Cl2:
C, 52.92; H, 5.26; N, 13.13. Found: C, 52.84; H,
5.68; N, 12.94.
Example B4:
A)(+)-1,2,3,6-Tetrahydro-5-methoxycarhonyl-4-methyl-
2-oxo-1-{N-[2-(R)-methyl)-4-(2-nitrophenyl)piperazin-
1-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine.
a) (R)-(+)-3-methyl-1-(2-nitrophenyl)piperazine.
To a solution of 2-bromo-nitrobenzene (0.4 g, 2.0
mmol) in 1,4-dioxane ~10 mL) was added (R)-(+)-2-
methylpiperazine (0.25 g, 0.25 mmol) and powdered
K2CO3 (7.5 mmol, 0.8 g) and the resulting suspension
was heated at reflux for 10 h. After the suspension
was cooled, it was filtered through a sintered glass
funnel and the solvent was evaporated in vacuo. The
resulting residue was purified by column
chromatography on silica gel (1:1 hexane/EtOAc
followed by 4:1 EtOAc/MeOH) to yield (R)-(+)-3-
- methyl-1-(2-nitrophenyl)-piperazine as an orange-red
oil (0.26 g, 78~).
,
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b) (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-
2-oxo-1-{N-t2-(R)-methyl)-4-(2-nitrophenyl)piperazin-
1-yl]propyl}-6-~3,~-difluorophenyl)pyrimidine.
To a solution of (+)-1-(3-bromo-propylcarbamoyl)-6-
(3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydro-
pyrimidine-S-carboxylic acid methyl ester (0.11 g,
0.25 mmol) and (R)-(+)-3-methyl-1-(2-nitrophenyl)-
piperazine (0.11 g, 0.50 mmol) in 20 mL of anhydrous
acetone was added powdered K2CO3 (0.34 g, 3.5 mmol)
and KI (0.07 g, 0.5 mmol) and the resulting
suspension was heated to reflux for 10 h. TLC
indicated a new spot for the product (Rf = 0.3, 3:0.5
EtOAc/MeOH) and mostly the starting material. The
suspension was cooled, filtered and the solvent was
evaporated and the residue was purified by column
chromatography on silica gel with EtOAc/MeOH (5:1) as
the eluting system.(+)-1,2,3,6-Tetrahydro-5-
methoxycarbonyl-4-methyl-2-oxo-1-{N-[2-(R)-methyl)-4-
(2-nitrophenyl)piperazin-1-yl]propyl~-6-(3,4-
difluorophenyl)-pyrimidine was obtained as yellow oil
(0.02 g, 14~ yield). The product was analyzed as its
hydrochloride salt. M.P. 135-138~C; ~] D = + 63.5 (c
= 0.2, MeOH); Anal calcd. for C28H33N6F2O6C1 1.0 CHCl3:
C, 46.g2; H, 4.62; N, 11.32. Found: C, 46.94; H,
4.97; N, 11.47.
Example 85:
~ 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-
methoxymethyl-2-oxo-1-{N-~4-(2-methoxy-5-
methyl)phenyl-4-phenyl-piperidin-1-yl]propyl}-6-(3,4-
difluorophenyl) pyrimidine.
a) 4-(2-Nethoxy-5-methyl)phenyl-4-phenylpiperidine
hyd Gchloride.
To a 100 mL round bottom flask equipped with a rubber
septum and a stirring bar was added 4-hydroxy-4-
phenyl-piperidine (1.25 g, 7.0 mmol) followed by 10
mL of 4-methylanisole. The resulting solution was
stirred at room temperature under argon atmosphere
..
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and then AlCl3 (2.82 g, 21.0 mmol) was added in one
portion. An exotherm was observed. The reaction
mixture was stirred for 8 h and then poured carefully
over 150 ml of ice-water. The white solid that
precipitated out was filtered and washed thoroughly
with water followed by diethyl ether to obtain 4-(2-
methoxy-5-methyl)-phenyl-4-phenyl-piperidine
hydrochloride ~1.59 g, 50%) as a white solid. Mass
spectrum: 282 (M+1, 100~). Anal calcd. for
ClgH24NOCl 0.15 CH2Cl2: C, 69.57; H, 7.41; N, 4~24.
Found: C, 69.62; H, 7.31; N, 4.36.
b) 3-l4-(2-methoxy-5-methyl)phenyl-4-phenyl-
piperidin-l-yl~-propylamine.
To a solution of 4-(2-methoxy-5-methyl)-phenyl-4-
phenyl-piperidine (0.6 g, 2.1 mmol) in 30 mL dioxane
was added 3-bromo-N-tert-butoxycarbonyl-propylamine
(0.6 g, 2.5 mmol) and K2CO3 (0.6 g, 6.0 mmol) and the
resulting suspension was heated to reflux for 10 h.
The suspension was allowed to cool, filtered and the
solvent was evaporated to obtain yellow residue which
was purified by column chromatography (Rf = 0.4, 3:1
EtOAc/MeOH) to obtain 3-[4-(2-methoxy-5-
methyl)phenyl-4-phenyl-piperidin-l-yl~-N-tert-
butoxycarbonyl-propylamine as a yellow oil (0.35 g).
It was dissolved in 15 mL of CH2Cl2 and 3.0 mL of
trifluoroacetic acid was added with stirring at room
temperature under argon atmosphere for l h. The
solvent was evaporated in vacuo and the residue was
basified to pH 10 by adding minimum amount of 1 N KOH
solution. The product was extracted with CH2Cl2 (3 X
25 mL), dried over MgSO4, filtered and the solvent
was remo~ed in ~acuo to obtain 3-[4-(2-methoxy-5-
methyl)phenyl-4-phenyl-piperidin-1-yl]propylamine as
a yellow oil (0.25 g, 35~ for two steps). It was
used in the next step without further purification.
- c) (~)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-
methoxymethyl-2-oxo-l-{N-~4-(2-methoxy-5-
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methyl)phenyl-4-phenyl-piperidin-1-yl3propyl}-6-(3,4-
difluorophenyl) pyrimidine.
To a solution of 3-[4-(2-methoxy-5-methyl)phenyl-4-
phenyl-piperidin-1-yl]propylamine (0.12 g, 0.36 mmol'
in 5.0 mL THF was added (+)l~6-dihydro-5-
methoxycarbonyl-4-methoxymethyl-2-oxo-1-(4-
nitrophenyloxy)carbonyl-6-(3,4-
difluorophenyl)pyrimidine (0.12 g, 0.33 mmol) at room
temperature and the resulting yellow solution was
stirred for 6 h. The solvent was removed in vacuo
and the resulting residue was subjected to column
chromatography over silica gel (1:1 hexane/EtOAc to
EtOAc to g:1 EtOAC/MeOH) to obtain (+)-1,2,3,6-
tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-
~N-[4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-
1-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine (0.12
g, 65~ as a yellow oil. It was converted into its
HCl salt (pale yellow powder). M.P. 102-105~C- [~] D
= + 49.4 (c = 0.65, MeOH) Anal calcd. for
C32H36N3O4F2Cl 1.5 CH2Cl2: C, 55.31; H, 5.40; N, 5.78.
Found: C, 55.55; H, 5.06; N, 6.08.
Example 86:
(+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-
methoxymethyl-2-oxo-1-{N-[4-(4-methyl)-phenyl-4-(2-
methyl)phenyl piperidin-1-yl~-propyl}-6-~3,4-
difluorophenyl) pyrimidine.
a) 4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidine
hydrochloride.
To a 100 mL round bottom flask equipped with a rubber
septum and a stirring bar was added 4-hydroxy-4-(4-
methyl)phenyl-piperidine (1.25 g, 6.54 mmol) followed
by 20 mL of anhydrous toluene. The resulting solution
was stirred at room temperature under argon
atmosphere and then AlCl3 ~1.4 g, 10.2 mmol) was added
in one portion. An exotherm was observed. The
reaction mixture was stiired for 10 h and then poured
carefully over 100 ml of ice-water. The white solid
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that precipitated out was filtered and washed
thoroughly with water followed by diethyl ether ~o
obtain 4-(4-methyl)phenyl-4-(2-
methyl)phenylpiperidine hydrochloride (1.95 g, 99~)
as a white solid. Mass spectrum: 266 (M+1, 100%).
Anal calcd. for C19H24NCl 0.15 CH2C12: C, 73.11; H,
~ 7.79; N, 4.45. Found: C, 73.33; H, 7.B2; N, 3.92.
b) 3-~4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-
1-yl~-propylamine.
To a solution of 4-(4-methyl)-phenyl-4-(2-
methyl)phenyl piperidine hydrochloride (2.6 g, 9.8
mmol) in 100 ~L dioxane was added 3-bromo-N-tert-
butoxycarbonyl-propylamine (2.57 g, 10.8 mmol) and
K2CO3 (4.06 g, 29.4 mmol) and the resulting suspension
was heated to reflux for 10 h. The suspension was
allowed to cool, filtered and the solvent was
evaporated to obtain a yellow residue which was
purified by column chromatography over silica gel (Rf
= 0.4, 3:1 EtOAc/MeOH) to give 3-14-(4-methyl)phenyl-
4-(2-methyl)phenylpiperidin-1-yl]-N-tert-
butoxycarbonyl-propylamine as a yellow oil (2.30 g).
It was dissolved in 60 mL of CH2C12 and 10.0 mL of
trifluoroacetic acid was added with stirring at room
temperature under argon atmosphere for l h. The
solvent was evaporated in vacuo and the residue was
basified to pH 10 by adding minimum amount of l N KOH
solution. The product was extracted with CH2Cl2 (3 X
25 mL~, dried over MgSO4, filtered and the solvent
was removed in vacuo to obtain 3-[4-(4-methyl)-
phenyl-4-(2-~ethyl)phenyl piperidin-1-yl]propylamine
as a yellow oil (1.39 g, 44% for two steps). It was
used in the next step without further purification.
C) (t )-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-
methoxymethyl-2-oxo-1-{N-l4-(4-methyl)-phenyl-4-(2-
methyl)phenylpiperidin-1-yl~-propyl}-6-(3,4-
difluorophenyl)pyrimidine.
To a solution of 3-[4-(4-methyl)phenyl-4-(2-
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methyl)phenyl- piperidin-l-yl]propylamine ~0.10 g,
0.31 mmol) in 10.0 mL THF was added (+)-1,6-Dihydro-
5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-(4-
nitrophenyloxy)carbonyl-6-(3,4-
difluorophenyl)pyrimidine (0.10 g, 0.28 mmol) at room
temperature and the resulting yellow solution was
stirred for 8 h. The solvent was removed in vacuo
and the resulting residue was subjected to column
chromatography over silica gel ~1:1 hexane/EtOAc to
EtOAc to 9:1 EtOAC/MeOH) to obtain (+)-1,2,3,6-
Tetrahydro-s-methoxycarbonyl-4-methoxymethyl-2
{N-[3-[4-(4-methyl)phenyl-4-(2-
methyl)phenylpiperidin-l-yl]propyl}-6-(3,4-
difluorophenyl)pyrimidine (0.11 g, 70~) as a yellow
oil. It was converted into its HCl salt (pale yellow
powder). M.P. 103-107~C. [~]D = + 104.8 (c = 0.31,
MeOH) Anal calcd. for C38H46N4OsF2Cl 0.66 CH2C12: C,
60.44; H, 6.32; N, 6.71. ~ound: C, 60.44; H, 6.21; N,
7.19.
Example 87:
(+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-
oxo-l-{N-[3-(4-(4-methyl)phenyl-4-(2-
methyl)phenylpiperidin-l-yl]propyl}-6-~3,4-
difluorophenyl)pyrimidine.
To a solution of 3-[4-(4-methyl)phenyl-4-(2-
methyl)phenyl-piperidin-1-yl]propylamine (0.25 g,
0.78 mmol) in 10.0 mL THF was added (+)-1,6-dihydro-
5-methoxycarbonyl-4-methyl-2-oxo-1-(4-
nitrophenyloxy)carbonyl-6-(3,4-
difluorophenyl)pyrimidine (0.22 g, 0.67 mmol) at room
temperature and the resulting yellow solution was
stirred for 8 h. The solvent was removed in vacuo
and the resulting residue was subjected to column
chroma~ography over silica gel ~1:1 hexane/EtOAc to
EtOAc to 9:1 EtOAC/MeOH) to obtain (+)-1,2,3,6-
Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-~N-~3-
E4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-1-
,
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yl]-propyl~-6-(3,4-difluorophenyl)pyrimidine (0.19 g,
64~) as a yellow oil. It was converted into its HCl
salt (pale yellow powder). M.P. 143-147~C. [~]~ = +
79.8 (c = O.25, MeOH). Anal. calcd. for
C37H44N4O4F2Cl 0.50 CH2Cl2: C, 62.19; H, 6.26; N, 7.73.
Found: C, 62.15; H, 5.92; N, 7.21.
~ Example B8:
1,2,3,6-Tetrahydro-1-{[4-ben~;do-piperidin-1-
yl]propyl}-c~h~Yamido-4-methyl-6-t3,4-
difluorophenyl)-2-oxo-pyrimidine.
a) 4-Amino-l-benzylpiperidine.
To a solution of hydroxylamine hydrochloride (3.67 g,
52.8 mmol) in water ~10 mL) and ethyl alcohol (80 mL)
was added 1-benzyl piperidone (10.0 g, 52.8 mmol) at
room temperature. The reaction mixture was heated to
reflux for 4 h and then stirred at room temperature
overnight. The resulting white solid was filtered,
washed with ether and dried (8.4 g, 80~). It was
added in small portions to a suspension of lithium
aluminum hydride (2.3 g, 60.0 mmol) in diethyl ether
(150 mL) at room temperature and the suspension was
heated to reflux for 8 h. The reaction mixture was
cooled to 0~C and quenched with successive addition of
water (3 mL), 3 N NaOH (3 mL) and water (9 mL). The
white suspension was filtered and the filtrate was
dried over MsSO4. The solvent was removed in vacuo
after filtration. 4-Amino-1-benzyl-piperidine was
obtained as a colorless oil (6.0 g). It was used in
the next step without purification.
b) 1-Benzyl-4-ben~ dopiperidine.
To a biphasic solution of 4-amino-1-benzylpiperidine
(6.0 g, 31.6 mmol), K2CO3 (8.71 g, 63.1 mmol) in CH2Cl2
(200 mL) and water (100 mL) was added ~enzoyl
chloride (4.86 g, 34.7 mmol) in 20 mL of CH2Cl2 at 0~C
with stirring. After stirring for 4 h at room
temperature, the layers were separated. The organic
layer was washed with water, dried over MgSO4 and
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filtered. The solvent was removed in vacuo to obtain
l-benzyl-4-benzamidopiperidine (8.16 g, B7~ yield) as
a white solid. It was used in the next step without
purification.
c) 4-Benzamido-piperidine.
To a suspension of 10% palladium on carbon (0.2 g) in
30 mL of ethyl alcohol was added a solution of 1-
benzyl-4-benzamido- piperidine (0.5 g, 1.79 mmol) ln
ethyl alcohol (10 mL). The resulting suspension was
hydrogenated at 100 psi at 50~C for 30 h after which
it was filtered through a pad of celite and the
solvent was removed in vacuo to obtain 0.34 g (100%)
of 4-bp~m;dopiperidine as a white solid. It was
used in the next step without purification.
d) 1,2,3,6-Tetrahydro-1-{[4-benzamido-piperidin-1-
yl]propyl}-carboxamido-4-methyl-6-(3,4-
difluorophenyl)-2-oxo-pyr$midine.
To a solution of 1-(3-bromopropylcarbamoyl)-6-(3,4-
difluoro-phenyl)-~-methyl-2-oxo-1,6-
dihydropyrimidine-5-carboxylic acid methyl ester
(0.04 g, 0.10 mmol) and 4-benzamidopiperidine (0.03
g, 0.15 mmol) in 15 mL of anhydrous THF was added
triethylamine ~2 mL) and the resulting solution was
heated to reflux for 10 h. The suspension was
cooled, filtered and the solvent was evaporated. The
residue was purified by column chromatography on
silica gel with EtOAc/MeOH (5:1) as the eluting
system. 1,2,3,6-tetrahydro-1-{[4-benzamidopiperidin-
1-yl]propyl}carboxamido-4-methyl-6-(3~4-
difluorophenyl)-2-oxo-pyrimidine was obtained as a
yellow oil (0.02 g, 37% yield). The product was
analyzed as its hydrochloride salt. M.P. 121-125~C.
Anal calcd. for C29H34NsF2OsCl 0.53 CHCll: C, 53.03; H,
5.20; N, 10.37. ~ound: C, 52.90; H, 5.61; N, 9.97.
Example 89:
4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-~3-(4-
phenyl-4-(thiophen-2-yl)piperidin-1-yl)-
- r -
CA 02253862 1998-11-09
W097/42956 PCT~S97/0~35
-189-
propylcarbamoyl}-1,2,3,4-tetrahyd G~y~ imidine-5-
carboxylic acid methyl ester.
a) 4-Phenyl-4-(thiophen-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenylpiperidine (1.0 g,
5.6 mmol) and thiophene to.88 ml, 11 mmol) in 20 ml
of CH2Cl2 was added AlCl3 (0.75 g, 5.6 mmol) at -78 ~C
- and the resulting reaction mixture was stirred for 1
h. The reaction mixture was basified with sat~d
aqueous NaHCO3 and extracted with EtOAc. The organic
layer was dried over Na2CO3 and concentrated in ~acuo
to provide the product as a colorless oil which was
subjected to the following reaction without further
purification.
b) 3-(4-Phenyl-4-(thiophen-2-yl)piperidin-1-
yl)propylamine.
A solution of 4-phenyl-4-(thiophen-2-yl)piperidine
and 3-Boc-aminopropylbromide (1.0 g, 4.4 mmol) with 1
g of K2CO3 in 20 ml of dioxane was stirred at reflux
for 12 h. The reaction mixture was diluted with
water and extracted with EtOAc. The organic solution
was dried over Na2SO4 and concentrated in vacuo to
yield an oil which was subjected to column
chromatography over silica gel (EtOAc) to provide
0.43 g (1.1 mmol, 20% for two steps) of 3-(4-phenyl-
4-(thiophene-2-yl)piperidin-1-yl)-propylcarbamic acid
tert-butyl ester as colorless oil. The ester in 5 ml
of CH2Cl2 was added with 1 ml of CF3CO2H and resulting
solution was stirred for 1 h at 25 ~C. The reaction
mixture was concentrated in vacuo to yield oily
mixture, which was dissolved in EtOAc and washed with
aqueous NaHCO3. Concentration of the reaction mixture
provided the desired product as an oil (0.29 g, 0.96
mmol, 88%) which was used in the next step without
further purification.
c) 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-
[3-(4-phenyl-4-(thiophen-2-yl)piperidin-1-
yl)~pylcarbamoyl}-l~2~3~4-tetrahydropyrimidine
-
CA 02253862 1998-11-09
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-190-
carboxylic acid methyl e~ter.
To a solution of 6-(3,4-difluorophenyl)-4-
methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-
dicarboxylic acid 5-methyl ester 1-(4-
nitrophenyl)ester (29 mg, 0.06 mmol) in 2 ml of CH7Cl.
was added 3-(4-phenyl-4-thiophen-2-yl-piperidin-1-
yl)propylamine (20 mg, 0.07 mmol) and the resulting
solution was stirred for 2 h at 25 ~C. The reaction
mixture was concentrated in vacuo to provide an oil
which was subjected to column chromatography over
silica gel (5~ MeOH/CHCl3) to yield 25 mg (64~) of the
desired product which was converted to a HCl salt and
recrystallized from EtOAC-Et20 to afford 22 mg of the
product as a white solid: mp 157-159~C; Anal. Calc.
For C33H36F2N40sS requires C, 58.6; H, 5.33; N, 8.29.
Found: C, 57.3; H, 5.45; 7.90.
Example 90:
4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-[3-(4-
phenyl-4-(furan-2-yl)piperidin-1-yl)propyl]carbamoyl-
1,2,3,4-tetrahydropyri~idine-5-carboxylic acid methyl
e~ter.
a) 4-Phenyl-4-(furan-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenyl-piperidine (0.3
g, 1.7 mmol) and furan (0.50 ml, 6.8 mmol) in 20 ml
of C~I2Cl2 was added AlC13 (0.50 g, 3.7 mmol) at 25 ~C
and the resulting reaction mixture was stirred for
h. The reaction mixture was basified with sat'd
aqueous NaHCO3 and extracted with EtOAc. The organic
layer was dried over Na2CO3 and concentrated in vacuo
to provide a colorless oil which was identified as
the desired product by NMR analysis and subjected to
the following reaction without further purification.
b) 3-(4-Phenyl-4-(furan-2-yl)piperidin-1-
yl)propylam~ne.
A solution of 4-phenyl-4-furan-2-yl-piperidine and 3-
Boc-aminopropylbromide (0.30 g, 1.3 mmol) with 0.5 g
of K2C03 in 20 ml of dioxane was stirred at reflux for
CA 02253862 1998-11-09
W097/429S6 PCT~S97/08335
- 1 9 1 -
12 h. The reaction mixture was diluted with water
and extracted with EtOAc. The organic solution was
dried over Na2SO4 and concentrated in vacuo to yield
an oil which was subjected to column chromatography
over silica gel (EtOAc) to provide 0.21 g (0.54 ~mol,
32~ for two steps) of 3-(4-phenyl-4-(furan-2-
~ yl)piperidin-1-yl)propylcar~amic acid tert-butyl
ester as a colorless oil. The ester in 5 ml of CH2Cl2
was added with 1 ml of CF3CO2H and resulting solution
was stirred for 1 h at 25 ~C. The reaction mixture
was concentrated in vacuo to yield oily mixture,
which was dissolved in EtOAc and washed with aqueous
NaHCO3. Concentration of the reaction mixture
pro~ided the desired product as an oil (0.13 g, 0.45
mmol, 84%).
c) 4-~3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-
t3-(4-phenyl-4-(furan-2-yl)piperidin-1-
yl)propylcarbamoyl}-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid methyl ester.
To a solution of 6-(3,4-difluorophenyl)-4-
methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-
dicarboxylic acid 5-methyl ester 1-(4-
nitrophenyl)ester (20 mg, 0.04 mmol) in 2 ml of CH2Cl2
was added 3-(4-phenyl-4-furan-2-yl-piperidin-1-yl)-
propylamine (12 mg, 0.04 mmol) and resulting solution
was stirred for 2 h at 25 ~C. The reaction mixture
was concentrated in vacuo to provide an oil which was
subjected to column chromatography over silica gel
(5% MeOH/CHCl3) to yield 22 mg (85%) of the desired
product, which was converted to HCl salt and
recrystallized from EtOAC-Et2O to afford 18 mg of the
product as a white solid: mp 153-155 ~C; Anal. Calc.
For C33~36F2N4O6 requires C, 60.1; H, 5.46; N, 8.49.
Found: C, 58.9; H, 5.53; 8.45.
Example 91:
~ 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-{3-[4-
phenyl-4-~l-methylpyrrol-2-yl)-piperidin-1-yl]-
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WO 97/42956 PCTrUS97/08335
-192-
propylcarbamoyl}-1,2,3,4-tetrahyd,u~y.imidine-5-
carboxylic acid methyl ester.
a) 4-Phenyl-4-(1-methylpyrrol-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenylpiperidine (0.5 g,
2.8 mmol) and l-methylpyrrole (0.50 ml, 5.6 mmol) 1n
20 ml of CH2Cl2 was added AlC13 (O. 75 g, 5.6 mmol) at
25 ~C and the resulting reaction mixture was stirred
for 1 h. The reaction mixture was basified with
sat'd aqueous NaHCO3 and extracted with EtOAc. The
organic layer was dried over Na2CO3 and concentrated
in vacuo to pro~ide the desired product as a
colorless oil.
b) 3-t4-Phenyl-4-(1-methylpyrrol-2-yl)piperidin-1-
yl]-propylamine.
A solution of 4-phenyl-4-(1-methylpyrrol-2-yl)-
piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.5
mmol) with 1.5 g of K2CO3 in 20 ml of dioxane was
stirred at reflux for 12 h. The reaction mixture was
diluted with water and extracted with EtOAc. Organic
solution was dried over Na2SO4 and concentrated in
vacuo to yield an oil which was subjected to column
chromatography over silica gel (EtOAc) to provide
0.44 g (1.1 mmol, 20~ for two steps) of 3-[4-phenyl-
4-(l-methylpyrrol-2-yl)-piperidin-l-y])-
propylcarbamic acid tert-butyl ester as a colorless
oil. The ester in 10 ml of CH2Cl2 was added with 1 ml
of CF3CO2H and resulting solution was stirred for 1 h
at 25 ~C. The reaction mixture was concentrated in
~-acuo to yield an oily mixture, which was dissolved
in EtOAc and washed with aqueous NaHCO3.
Concentration of the reaction mixture provided an oil
(0.26 g, 0.87 mmol, 79%) which was identified as the
desired product.
c) 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-
{3-[4-phenyl-4-(1-methylpyrrol-2-yl)-piperidin-1-
yl~propylcarbamoyl}-1,2,3,4-tetrahydropyrimidine-5-
car~oxylic acid methyl ester.
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W097/429~6 PCT~S97/08335
-lg3-
To a solution of 6-(3,4-difluorophenyl)-4-
methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-
dicarboxylic acid 5-methyl ester 1-(4-
nitrophenyl)ester (24 mg, 0.05 mmol) in 2 ml of CH.Cl~
was added 3-[4-phenyl-4-(1-methylpyrrol-2-yl)-
piperidin-l-yl]-propylamine (15 mg, 0.05 mmol) and
resulting solution was stirred for 2 h at 25 ~C.
Reaction mixture was concentrated in vacuo to provide
an oil which was subjected to column chromatography
over silica gel ~5~ MeO~/CHCl3) to yield 22 mg ~69%)
of the desired product, which was converted to HCl
salt and recrystallized from EtOAC-Et2O to afford 16
mg of the product as a white solid: mp 139-142~C.
Exam~le 92
As a specific embodiment of an oral composition of a
compound of this invention, lOOmg of one of the
compounds described herein is formulated with
sufficient finely divided lactose to provide a total
amount of 5~0 to 590 mg to fill a size 0 hard gel
capsule.
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-194-
Pharmacoloaical Profiles of the Com~ounds in Cloned
H~ n Adrener~ic Receptors.
Binding affinities were measured for selected compounds
of the invention at six cloned human alpha-1 and alpha-
2 receptor subtypes, as well as at the L-type calcium
channel. The protocols for these experiments are given
below.
Protocol for the Determination of the Poten~y of
Antaqonists
The activity of compounds at the different human
receptors was determined in vitro using cultured cell
lines that selectively express the receptor of
interest. These cell lines were prepared ~y
transfecting the cloned cDNA or cloned genomic DNA or
constructs containing both genomic DNA and cDNA
encoding the human ~-adrenergic receptors as follows:
~ Human Adrenergic Receptor: The entire coding region
of ~lD (1719 bp), including 150 base pairs of 5'
untranslated sequence (5' UT) and 300 bp of 3'
untranslated sequence (3' UT), was cloned into the
BamHI and ClaI sites of the polylinker-modified
eukaryotic expression vector pCEXV-3, called EXJ.~R.
The construct involved the ligation of partial
overlapping human lymphocyte genomic and hippocampal
cDNA clones: 5' sequence were contained on a 1.2-kb
SmaI-XhoI genomic fragment (the vector-derived BamHI
site was used for subcloning instead of the internal
insert-derived SmaI site) and 3' sequences were
contained on an 1.3 kb XhoI-ClaI cDNA fragment (the
ClaI site was from the vector polylinker). Stable cell
lines were obtained by cotransfection with the plasmid
~lA/EXJ (expression vector containing the ~lA receptor
gene (old nomenclature)) and the plasmid pGCcos3neo
(plasmid containing the aminoglycoside transferase
.
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W097/429S6 PCT~S97/08335
-195-
gene) into LM(tk-) cells using calcium phosphate
technique. The cells were grown, in a controlled
environment (37~C., 5% CO2), as monolayers in Dulbecco's
modified ~agle's Medium (GIBCO, Grand Island, NY)
containing 25mM glucose and supplemented with 10
bovine calf serum, 100 units/ml penicillin g, and 100
~g/ml streptomycin sulfate. Stable clones were then
selected for resistance to the antibiotic G-418 (1
mg/ml), and me~branes were harvested and assayed for
their ability to bind [3H]prazosin as described below
(see "Radioligand Binding assays"~.
The cell line expressing the human ~lD receptor used
herein was designated L a1A (old nomenclature) and was
deposited with the American Type Culture Collection,
12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the
International Recognition of the Deposit of
Microorganisms for the Purposes of Patent Procedure.
The cell line expressing the human ~lD receptor, was
accorded ATCC Accession No. CRL 11138, and was
deposited on September 25, 1992.
a~s Human Adrenergic Receptor: The entire coding region
of al~ (1563 bp~, including 200 base pairs and 5'
untranslated sequence (5' UT) and 600 bp of 3'
untranslated sequence (3' UT), was cloned into the
EcoRI site of pCEXV-3 eukaryotic expression vector.
The construct involved ligating the full-length
containing EcoRI brainstem cDNA fragment from ~ ZapII
into the expression vector. Stable cell lines were
selected as described above. The cell line used herein
was designated L~ and was deposited with the American
Type Culture Collection, 12301 Parklawn Drive,
Rockville, Maryland 20852, U.S.A. under the provisions
of the Budapest Treaty for the International
Recognition of the Deposit of Microorganisms for the
.. .. .
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Purposes of Patent Procedure. The cell line L-CY1E was
accorded ATCC Accession No. CR 11139, on September 29,
1992.
~ Human Adrenergic Receptor: The entire coding region
of ~lA (1401 bp), including 400 base pairs of 5~
untranslated sequence (5' UT) and 200 bp of 3'
untranslated sequence (3' UT), was cloned into the KpnI
site of the polylinker-modified pCEXV-3-derived
eukaryotic expression vector, EXJ.RH. The construct
involved ligating three partial overlapping fragments:
a 5' 0.6kb HincII genomic clone, a central 1.8 EcoRI
hippocampal cDNA clone, and a 3' 0.6Kb PstI genomic
clone. The hippocampal cDNA fragment overlaps with the
lS 5' and 3' genomic clones so that the HincII and PstI
sites at the 5' and 3' ends of the cDNA clone,
respectively, were utilized for ligation. This full-
length clone was cloned into the KpnI site of the
expression vector, using the 5' and 3' KpnI sites of
the fragment, derived from vector (i.e., pBluescript)
and 3'-untranslated sequences, respectively. Stable
cell lines were selected as described above. The
stable cell line expressing the human ~lA receptor used
herein was designated L-~lC (old nomenclature) and was
deposited with the American Type Culture Collection,
12301 Parklawn Drive, Rock~ille, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the
International Recognition of the Deposit of
Microorganisms for the Purposes of Patent Procedure.
The cell line expressing the human ~lA receptor was
accorded Accession No. CR 11140, on September 25, 1992.
Radioligand ~ ing A~says: Transfected cells from
culture flasks were scraped into 5ml of 5mM Tris-HCl,
5mM EDTA, pH 7.5, and lysed by sonication. The cell
lysates were centrifuged at 1000 rpm for 5 min at 4~C,
and the supernatant was centrifuged at 30,000 x g for
.
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W O 97/42956 PCT~US97/08335 -197-
20 min at 4~C. The pellet was suspended in 50mM Tris-
HCl, lmM MgCl2, and 0.1~z ascorbic acid at pH 7.5.
Binding of the ~1 antagonist [3H]prazosin ~0.5 nM,
specific activity 76.2 Ci/mmol) to membrane
preparations of LM(tk-) cells was done in a final
volume of 0.25 ml and incubated at 37~C for 20 min.
Nonspecific binding was determined in the presence of
- 10 ~M phentolamine. The reaction was stopped by
filtration through GF/B filters using a cell harvester.
Inhibition experiments, routinely consisting of 7
concentrations of the tested compounds, were analyzed
using a non-linear regression curve-fitting computer
program to obtain Ki values.
~2 Human Adrenergic Receptors: To determine the potency
of ~1 antagonists at the ~2 receptors, LM ( tk-) cell
lines stably transfected with the genes encoding the
~2A~ ~2~, and ~2C receptors were used. The cell line
expressing the ~2A receptor is designated L-~2A~ and was
deposited on November 6, 1992 under ATCC Accession No.
CRL 11180. The cell line expressing the ~2~ receptor is
designated L-NGC-~2~, and was deposited on October 25,
1989 under ATCC Accession No. CRL10275. The cell line
expressing the ~2C receptor is designated L-~2C, and was
deposited on November 6, 1992 under ATCC Accession No.
CRL-11181. All the cell lines were deposited with the
American Type Culture Collection, 12301 Parklawn Drive,
Rockville, Maryland 20852, U.S.A. under the provisions
of the Budapest Treaty for the International
Recognition of the Deposit of Microorganisms for the
Purposes of Patent Procedure. Cell lysates were
prepared as described above (see Radioligand Binding
Assays), and suspended in 25mM glycylglycine buffer (pH
7.6 at room temperature). Equilibrium competition
binding assay were performed using [3H]rauwolscine
- (O.SnM), and nonspecific binding was determined by
incubation with lO~M phentolamine. The bound
CA 022~3862 1998-11-09
W097/429~ PCT~S97/08335
-198-
radioligand was separated by filtration through GF/B
filters using a cell harvester.
Det~r~;nAtion of the Activity of ~l Antagonists at
S Calcium ~h~nn~ls
The potency of ~l antagonists at calcium channels may be
determined in competition binding assays of
[3H]nitrendipine to membrane fragments of rat cardiac
muscle, essentially as described by Glossman and Ferry
(Methods in Enzymology 109:513-550, 1985). Briefly,
the tissue is minced and homogenized in 50mM Tris-HCl
(pH 7.4) containing O.lmM phenylmethylsulfonyl
fluoride. The homogenates are centrifuged at 1000 g
for 15 minutes, and the resulting supernatant
centrifuged at 45,000 g for 15 minutes. The 45,000 g
pellet is suspended in buffer and centrifuged a second
time. Aliquots of membrane protein are then incubated
for 30 minutes at 37~C in the presence of
[3H]nitrendipine (lnM), and nonspecific binding
determined in the presence of lO~M nifedipine. The
bound radioligand is separated by filtration through
GF/B filters using a cell harvester.
The compounds described above were assayed using cloned
human alpha adrenergic receptors. The preferred
compounds were found to be selective ~lc antagonists.
The binding affinities of compounds 13-17 are
illustrated in the following table.
CA 02253862 1998-11-09
W097/42956 PCT~S97/08335
--19 9--
Binding affinities of compounds 13-17 at cloned human ~ld,
~lb and ~la receptors.
Example h~ld halb h~la
pKi SEM n pKi SEM n pKi SEM n
13 6.14 0.02 3 6.21 0.09 3 9.74 0.02 3
14 6.46 0.04 3 6.59 0.08 3 9.68 0.05 3
6.01 0.03 3 6.33 0.06 3 9.41 0.09 3
16 6.24 0.06 3 6.37 0.06 3 9.54 o.og 3
17 6.17 0.04 4 6.32 0.06 4 8.99 0.12 4
h = human
SUBSTITUTE SHEET(RULE 26)
CA 02253862 1998-11-09
WO 97/42956 PCTrUS97/08335
-200-
~N ~2
B = ~. 4-~eO-Ph
Ph
~ ~ BW~ ~ ~ ~ R- ~ k
H
R ~r'''~~~'X~2.E~r
r 1 ~ E = OE. COO~e, COOEt
E ~2Co3~ 4-Dio~ne ~ OC~
~Hz
Scheme 1. General synthetic schemes f or the syn~hesis
of the piperidine sidechains.
CA 02253862 l998-ll-09
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-201-
N
O
O =~
~ <
O p;'~
N 0~ ~,
o h
~ ~ O
~ / ~ ~
=( x ¢ 9 CJ rq
0~ ~ ~ U
< ~
_. ( ~
> ~ r~
", E
N ~ O
n ~ h
0~ ~0 Z; ~ _~ 0
P:~ Z ~ ~ 0
U
0'~
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WO 97/42956 PCT/US97/08335
-202-
O ~ N
O ~ <
0~ ~0
O L
r , ~ l r-
~ Q 4 U
~ < ~ ~ E
~ ~ C_
o ~ rO ~"
o~
o r~ Z
. . .
,~ ~ r~
CA 02253862 1998-11-09
W O 97/42956 PCTAUS97/08335
-203-
~ _~ ,..
r~
o=~ o '1 ;' t~ C~ 2 ~
0~ (z +~ ~Z +
O=~ _ 0~ ~
O _ ,.1 ~
E~- O
E
2 ~ N W
o ~ E
~ ( .o
~o ~o -- L~
o _ o ,~,
o ~ 3
u
U~
CA 022S3X62 1998-11-09
WO 97142956 rCT/US97108335
-204 -
~~'Ctt3~ ~0 ~ _~~--CN O~N~C~0
O O O O Piperidine. ~OI~c
Isu~luranol
N02
~ o ~ CX E~ ~ o~e O ¢
C
~~2
0
~C o ~,~N~--N~
~07 ~ },
0~ 0
~--~-
E o~'o
1. 4-Nitrophenyl chloro~ormate, NaHC~3, CH7Cl2, H20.
2. 3-[(4-Methoxycarbonyl-4-phenyl)piperidin-1-
yl]propylamine.
3. 6N HCl.
. NaOH, Acetone.
5. DMAPECD, DMAP, NH3, CH2Cl2.
Scheme 4. Synthetic scheme for example 13.
CA 02253862 1998-11-09
W097l42956 PCT~S97/08335
-205-
~3~ ~~ ~ C o o Plperidl~e. ~OAc
~ ~ ~enzene
F
o O NH2 I F
~3 NallCO ~3--o J~ I--NH
F
o ~O ~N02
N one ~ ~ F
~ ~ N ~ O
F 4 ~ H o~f
~ F
O ~ O
H2N ~ ~ H
H O~'O
I
1. 4-Nitrophenyl chloroformate, DMAP, THF
2. 3-[(4-Methoxycarbonyl-4-phenyl)piperidin-1-
yl]propylamine.
3. 6N HCl.
4. H2, Pd-C, MeOH.
5. DMAPECD, DMAP, NH40H, CH2Cl2.
Scheme 5. Synthetic scheme for example 14.
SUBSTITUTE SHEET (RULE 26)
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W O 97/42956 PCT~US97/08335
-206-
~ CN
HO ~ ~ OK 1) Na2CO3 ~nCl ~ ~ n-(CqHg)4N HSO4 ~ CN
N 2) 5OC12, ~eOH NNaOH, Toluene
81~ Bn 65 C N
~n
~ N
l)Conc. H2SO4. RT
2) ~eOH. ff ~ J
44X N
Bn
1) ~2~ Pd(OH)2/C.200 psi ~
2) 5r'~~'~'NH~OC ~ N
CO3~ DioIane.reflu
I8) TFA.CH2C12.98%
Bn S
NH2
Scheme 6. Synthetic scheme for the preparation of 3-[4-
(2-Pyridyl)-piperidin-1-yl]propylamine (Example 21 part
d).
Sl~ 111 UTE SHEET (RULE 26)
CA 02253862 1998-11-09
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-207-
O O F
OR NH2 1 ~ F
HN OCH3 3 ~ ,1
o ~ o ~ NOz 3 o ~ o
N'~ OCH CH30 ~ ~~~-~N
o ~ Fo
H
1. NaOAc, DMF.
2. 4-Nitrophenyl chloroformate, NaHCO3, CH2C12, H20.
3. 3-[(4-Pyridyl)-piperidin-1-yl]propylamine, CH2Cl2.
4. 6N HC1/THF.
Scheme 7. Synthetic scheme for example 15.
SUBST~TUTE SHEET (RULE 26)
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-208-
N ~
J~ HN 3 CH30 I~lN
~l-o
,--~ t~~
C}130
h ' ~
CH30J~';h h~
.
1. NaOAc, DMF.
2. 4-Nitrophenyl chloroformate, NaHCO3, CH2Cl2, H20.
3. 3-[(4-(2-Pyridyl)-piperidin-l-yl]propylamine, CH2Cl2.
4. 6N HCl/THF.
Scheme 8. Synthetic scheme for example 16.
CA 02253862 1998-11-09
WO 97/42956 PCT/US97/08335
- 2 0 9 -
~eO~ ~ J~d"f l ~J~ er~~
O k
neo ~ ~ ~ tCE~n - Cl
21eO~ --~(CE~,~n N~
o O~e
1. (a) t-BuO~, DMF, 0~C; (b) TsOH.H2O, DMF, 100-120~C.
2 . NaH, THF, reflux.
3. 4-Methoxycar~onyl-4-phenylpiperidine, K2CO3, NaI, 1, 4-
dioxane, reflux.
Sc~me 9. Synthetic scheme for example17.
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o
a~ ~
o
Z~ ~<0
\~/0~ 0=( ~0 V ~a
~Z
o~
~ ~ N
z
~C ~ ~ '
~ O ~ J ~ ~
0~ ~ X
O ,~ O ~ o
o~ ~o O U
o ~; ~Z C
0~ ~ m
o~
Z
~ ~ ~
o _~
~; o~
S~ 111 UTE SHEET (RULE 26)
CA 02253862 l998-ll-09
WO 97/42956 PCTrUS97/08335
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O
h O ~ ~ ~
~
O
N
~; N
O ~ ~
_~_ ~ O
0_,
O J
~~ ~
~= ~ oa(
CA 02253862 l998-ll-09
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-212-
~Z3:
~<
o~o
~ h ~ Z~
~Z~
Z~ ~ 0~ 0
~_~z~ ~Z:~
0~ S
O ~
~0 ~ r
S~ o
U
~ ~ ~ '3
~ s
m m ~ ''
O
SUBSTITUTE SHEET (RULE 26)
CA 02253862 1998-11-09
WO 97/429S6 -213- PCT/US97/08335
O,,
Z
~ C ~
_ _, =O ~
Z '
Z ~ ~
Cl r ~)
0~ ~ _
~_ 0~ ~ O _4
d~
~ S o o
o: o~ ~ Z
Z
o Z ~ ;~.
~_~; oz~
_)e U
CA 02253862 l998-ll-09
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-214-
C N ~
~ ~ a
Z 0~~\o
~ ~ ~~
Z o
~ ~ N ~, O
~N X
~ N 5_1
~0 ~ ~ ~D z
~ ~I N ~z~ .
oZ~~ ~ O
t l
Z ~ U
SUBSTITUTE SHEET (RULE 26)
CA 02253862 l998-ll-09
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-215-
~Z
~Z~
~ ~ z
~ ~ N ~
C
.~ ~
O~Z~o X
~)h ~C V ~J
~1
+ ~ Z J
SI~ ITE SHEET (RULE 26)
CA 02253862 lsss-ll-os
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-216-
O O 2 4-difluoro- ~ OBn HzN ~ NH
o~n Plperidine,HOAc ~ NaHCO3
F ~ EtOH,
O ~ ~ 1. p-Nitrophenylchloroformate
Ll 1 2. R ~+)-Phenethylamine 11
3 Separate diastereomers BnO ~ NH
(+)
1. p-Nitrophenyl-
chloroformate ~ ~ F
2. a. R'NH2, THF ~\ ~ L IL,F
b. aq. HCl ~ ~ ~ 1. H2 / Pd-CO ~ O
BnO ~ N ~ N 2. NH3, EDC H2N ~ N N'
N O 3. HCl / Et20 ~ N ~ O
( ) HCl
R' = ~ N
CN
Scheme 14 (Cont.). Preparation Of example 22 (part-2)
SU~,~ 111 lJTE SHEET (RULE 26)
CA 02253862 1998-11-09
WO 97142956 -217- PCT/US97/08335
~\ ~ + Z
o= O
0~ 0 ~ ~
,~ _I
, O 0
~ ~ J~
:C ~
O
~ z ~ :r
~~~ '~
o~ o\ ~~
C
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X
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Z ,.. , o
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E
o=~ o s
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SUBSTITUTESHEET(RULE26)
CA 02253862 l998-ll-09
W O 97/42956 PCTAUS97/08335
~ -218-
~0
_~0 $~
~o~ ~Z?
o~ o
~ ,¢ ~
,, ~
E
~o ~ o
~ -~
SUBSTITUTE SHEET ~RULE 26)
CA 02253862 l998-ll-09
W O 97/42956 PCTrUS97/08335
~ -219-
~:~~
0~ 0
o O~
o
Z
O O O C~;N
O \ Z
:~ t_) ~ N
Xo
N ~J
N a;N
~ Z ~
O ~0 ~=~0
N ~ O =~ O
~0 ~
o=~ O ~ O O
O O
SUBSTITUTE SHEET (RULE 26)
.
CA 02253862 1998-11-09
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-220-
0~ ~
Z Z ~
~ o~ o Z ~
~
~o o
o
o~ ~
o ~ Oo ~ ~,
~ ,, . ~ ~
o ~ ~ ~
SUBSTITUTE SHEET (RULE 26)
CA 02253862 l998-ll-09
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-221-
~Y 0~ 0
O
O
O _,
x a
~ ~,
~D
\
=~z~
f -- ~ E
~
V
,, o "
o
o
m
SlJ~;~ ~ JTE SHEET (RULE 26)
CA 02253862 1998-11-09
WO 97142956 PCTIUS97/08335
,~ -222-
~ Y
~Z X
k~ 0~ 0
~Z:~ ~
o X~
O ~ V
~0=~ ~o > :~
~/ \~ Z:~ ~
_ ZX
0 ~ ~ A
O Vr~ ~
T- ,C a)
Z~ ~ ~
L , ~ O
J X
Z~ Z
~z <~ E
¢ ~ ~ O
z
G
SUBSTITUTE ''I ._t I (RULE 26)
CA 02253862 1998-11-09
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-223-
O ~r O ~r O Ar
R , J~" ~ h~) ~ --I
r - H,~ ~CO~Mc
o ~~'~R ~J ~R
¦ 3
O ~r O O ~r
' ~ OM- RH
1~
O ~ O
~N~N ~ ~ OMe
1. (a) KtBuO, DMF; ~b) TsOH H2O, DMF, 100-110~C.
2. (a) NaH, THF, 1,S-dibromopentane; ~b) 4-Methoxycarbonyl-4-
phenylpiperidine, K~.CO3, dioxane.
3. ~a) H2, PdtC, MeOH. (b~ CH3NH2, DMAPECD, CH2Cl2.
4. NaH, ClCO2Me, THF.
5. (a) H2, PdtC, MeOH. ~b) 3-~4-Methoxycarbonyl-4-
phenylpiperidin-1-yl)propylamine, DMAPECD, CH2Cl2.
Sch-m~ 21 ~part-2). Synthetic scheme for examples 49, 50 and ~l.
~m~ PH~
~ (~) M~ldic ~ ç~ 2
Schem- 21 (part-1). Synthesis of ~S)-(-)-2-methyl-1,5-
di~romopentane tThurkauf et al. J. Org. Chem. 1987, 52, 5466-
5467).
CA 02253862 1998-11-09
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-224-
o .~,
M~O~ O ~r
~ 40~
o ~, o
2 MbO ~ ~ ~ 3M~O ~ ~ .
~ ~ OH ~ ~ ~ ~
1. mCP3A, CH2C12-
2. 4-(2-Pyridyl)piperidine, dioxane.
3. Oxalyl chloride, DMSO, CH2Cl2.
Sch~me 22. Synthetic scheme for examples 56 and 57
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-225-
H~3 Ek ~OH
O At O ~NO2
~e OJ~N loJ~
O Ar O
N ~O
H ~-O~N ~O ~f N
H ~3
SchQmo 23. Synthetic scheme for example 59
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~ ~ 3 ~ ~
Rl =H,F,CI,CH3 / 11 (~~
R2= 4-fluoro-1-methoxy,CH3 / R4~ N ~ N ~ ~ Br
4-methyl-1-methoxy, thiomethoxy, Cl, F / 11 L H
3~Rs ~ R3 = methyl, methoxymethyl
Il 11 R4 = CH3, OCH3
R4~ ~NJ~N~~N~_ R5 = multifluoro
H Q ~ ~N~2
2 ~
Rl ~ Rl ~ R2
1 . ~rCH2CH2CH2NE~OC
2. TFA ~--NH2
Scheme for the synthesis of examples 61-67.
SUBSTITUTE SHEET (RULE 26)
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Br ~ R O ~
N ~ O MeO ~ N ~ Br
H H
A Ar O
MeO ~ N ~ N ~
or HN NAr N O R ~ XAr
X = N, C-CN
Synthetic scheme for examples 68 and 69.
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F F
MeO~ Br ~ Br ~ Br
N XX=Me, CH20Me N X R
HN ~ Ar O ~ F
MeO ~ N ~ N
Y = CN, Arl ~ N ~ X y
Synthetic scheme for examples 7~72.
CA 02253862 1998-11-09
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O ~ I
~D
,~
o~ E
~ ~Z~ i
Z ~ C
~Z :~ o~ o
+ o
LL o ~
I
O
SUBSTITUTE SHEET (RULE 26)
CA 02253862 1998-11-09
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z I
~ O
,o
~ I
2~ ~~
m ~ ~ =~C
Z ~
E
I z ~~
O=( O
+
O ~Z
SU~S 111 UTE SHEET (RULE 26)
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-231-
~.~ ~
I~ ~ ~ ~ ~ T
.,C ~ O _ "~ O
C
r, ~ r~ ~
SUBSTITUTE SHEET (RULE 26)
.
CA 02253862 1998-11-09
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-232-
Z I
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~
C o~ ~ O
C I 1' o Z 21 E C
N , N
I; ~1 ,; .m ~z
I Z Z I tr K t~: m c Z ~
~ZX ~ U~ ~
SUBSTITUTE SHEET (RULE 26)
CA 02253862 1998-11-09
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-233-
~ /~ 0~
O o ~ I
0 1~ ~ ~Z I 0
~' ~ o ~
E
Z~{~Z ~ ~ ~
Z .U~
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C
I E
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a~
O ~
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~ ~~
O ~ ~ ,0
S~Jt~:~ 111 IJTE SHEET (RULE 26)
.
CA 02253862 1998-11-09
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-234-
~3
O \ _,
Z a~
'~ ~
_ ~
X
. o
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x~ z
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