Note: Descriptions are shown in the official language in which they were submitted.
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INHIBITORS OF T8E ENZYMATIC ACTIVITY OF PSA
Field of the Invention
This invention relates to novel azetidinone compounds,
to certain intermediates and processes for preparing these
azetidinone compounds, and to formulations containing the
same. The present invention also relates to the use of
these azetidinones as inhibitors of the enzymatic activity
of Prostate-Specific Antigen (PSA) as well as for treating
prostatic cancer (Pca), Pca metastasis, benign prostatic
hyperplasia (BPH), breast cancer (Bc) and Bc metastasis.
Another aspect of the invention relates to methods for
treating Pca, Pca metastasis, BPH, Bc and Bc metastasis by
administering any PSA inhibiting compound.
Background of the Invention
PCa is the second most common cancer in American men.
According to Wingo et a [P.A. Wingo, et al., CA Cancer J.
Clin., 41 (1), 8-30, (I995)], 244,000 new cases are
diagnosed and 40,400 cancer related deaths occurred in the
United States in 1995. The statistics represent 36~ of all
male cancers and 13~ of male cancer-related deaths.
Presently, there are no effective preventive or
treatment methods for Pca. When the cancer is in its early,
hormone-dependent stage, it is commonly treated by
orchiectomy or chemical castration, and the androgen
flutamide is sometimes administered. In the later stages of
Pca, the disease becomes hormone-independent and
metastasizes widely, usually metastasizing through the
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skeleton. In the advanced stage of the disease, radiation
is used to alleviate pain and to slow metastasis in the
radiated areas, but there are no effective methods which can
put Pca into remission in late stage disease. Thus, Pca is
not only relatively common, but is refractory to treatment
once the disease advances into the hormone-independent
stage.
BPH is another prostatic disease. BPH is a non-
cancerous condition characterized by excessive prostatic
cellular growth resulting in an enlarged prostate gland.
The enlarged prostate gland causes obstruction of the
urethra and associated symptoms often include hesitancy and
straining to urinate, slow or intermittent urinary stream,
frequent urination and postmicturition dribbling.
Additional symptoms not directly related to the urinary
tract may also include hernias, hemorrhoids, change in bowel
habits, and other manifestations of increased abdominal
pressure and straining during voiding. It is estimated that
BPH affects about 80~ of males over age 50 and that 20~ of
males over age 80 require surgical intervention to relieve
resulting symptoms. P. Narayan and R. Indudhara, The
Western Journal of Medicine, 161, 495 (1994).
Bc is another devastating disease for which improved
therapies are greatly needed. Bc is a major cause of
mortality in women, as well as a cause of disability,
psychological trauma, and economic loss. A large number of
women contracting this disease eventually die from its
effects either directly or indirectly from complications,
e.g., metastasis, loss of general health, or collateral
effects from therapeutic interventions, such as surgery,
radiation, or chemotherapy. Even with the best combinations
of treatment modalities (surgery, radiation, and/or
chemotherapy), the long-term prognosis for breast cancer
patients is variable, and is poor if metastatic disease is
present.
PSA is believed to be a causative factor in Pca, Pca
metastasis, BPH, Bc and Bc metastasis. PSA is an androgen-
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dependent, 28-kDa glycoprotein produced almost exclusively
by the prostatic epithelium, and its presence is most
abundant in seminal fluid [A.F. Prestigiacomo, et al., J.
Urol., 152, 1515-9 (1994) and G.G. Klee, et al., Uroloav,
44, 76-82 (1994)].
PSA is currently used as a serum marker for PCa
diagnosis and monitoring. A wealth of data has accumulated
over the last decade on the association of elevated serum
PSA levels and PCa. In normal males, 85-95% of the
circulating PSA is bound to either ocl-antichymotrypsin
(ACT) or a2-macroglobulin. Id. Bound PSA is enzymatically
inactive or unable to interact with its physiological
substrate. Changes in the ratios of bound PSA to free PSA
occur in the serum of patients with BPH and PCa. PSA has
also been discovered in breast tumor extracts and this has
led to the suggestion that PSA can be used as a prognostic
indicator for Bc. H. Yu, et al., Cancer Research, 55, 2104-
10 (1995) .
In addition, a physiological role for PSA in male
reproductive function has been hypothesized, based upon the
enzymatic activity of this serine protease on the
liquefaction of seminal plasma. More recently, PSA has been
demonstrated to be expressed in non-prostatic tissues and to
mediate proliferative and metastatic responses in cell
culture systems. Critical evaluation of these recently
reported preclinical data supports potential
pathophysiological roles for PSA as a growth factor mediator
in the stimulation and metastasis of Pca and in BPH.
Evidence also supports a correlation between PSA and IGFBPs
(insulin growth factor binding proteins) in the serum of PCa
patients. H. Kanety, et al., J. Clin. Endocrinol Metab.,
77, 229-33 (1993). PSA has been shown to degrade certain
IGFBPs and this action has been proposed as contributory to
prostatic cellular growth, leading to BPH and Pca. P. Cohen,
et al., J. Endocrinol., 142, 407-415 (1994). PSA has also
been shown to directly stimulate in vitro growth of prostate
epithelial cells. Additionally, the ability of certain
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IGFBPs to inhibit the growth of Bc cells is consistent with
PSA playing a similar role in the treatment of Bc as in the
treatment of of Pca.
It would be advantageous to find additional means of
arresting the growth of cancer cells and tumors that can
either be used alone or in conjunction with other
treatments. In addition, it would be advantageous to find a
means of preventing, delaying or decreasing the likelihood
of the onset of Pca, Pca metastasis, BPH, Bc, and Bc
metastasis.
Summarv of the Invention
The present invention is directed to a compound of the
Formula I:
R' R2
N
O \ R3
I
wherein:
Rl is aryl; aryl(C1-C6 alkylene); where the aryl or
ring of the aryl(C1-Cg alkylene) is optionally substituted
with one or two substituents independently selected from
halo, Cl-C6 alkoxy, methoxycarbonyl, phenyl, Cl-C6 alkyl,
carboxy, nitro, acetyl, formyl, carboxymethylene, and
hydroxymethylene; phthalimido; or a moiety selected from:
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O Ra Rs R \ N Rs
O
N o
O ~ Rs N O Rs N
1
(a) (b) (c)
R5
R8 Rs
~N O Ra
0i\ O N
N
O
and
(d) (e)
where R4 is
hydrogen;
C1-C6 alkyl;
aryl; or
heterocycle;
where the aryl or heterocycle is optionally
substituted with one or two substituents independently
selected from the group consisting of halo, C1-C~ alkoxy,
methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro,
acetyl, formyl, carboxymethylene, and hydroxymethylene;
R5 is:
hydrogen;
Cl-C4 alkyl;
C3-C~ cycloalkyl;
Cl-C4 alkoxycarbonyl;
phenyl; or
naphthyl;
- 20 where the phenyl or naphthyl is optionally
substituted with one or two substituents independently
selected from the group consisting of C1-C4 alkyl, C1-C4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino,
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mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4
alkylsulfonylamino, and vitro;
R6 is:
hydrogen
C1-C4 alkyl optionally monosubstituted with a
substituent selected from the group consisting of hydroxy,
protected carboxy, carbamoyl, benzylthio and C1-C4
alkylthio;
phenyl optionally substituted with one or two
substituents independently selected from the group
consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy,
cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4
alkyl)amino, C1-C4 alkylsulfonylamino, and vitro; or
Cl-C4 alkoxycarbonyl;
R~ is:
C1-C4 alkoxycarbonyl;
benzyloxycarbonyl;
benzoyl;
where the phenyl ring in benzyloxycarbonyl or benzoyl
is optionally substituted with one or two substituents
independently selected from the group consisting of C1-C4
alkyl, Cl-C4 alkoxy, halogen, cyano, vitro, amino,
carbamoyl, hydroxy, mono(C1-C4 alkyl)amino, and di(C1-C4
alkyl)amino;
Rg and R9 are independently:
hydrogen;
C1-C5 alkanoyloxy;
benzoyloxy optionally substituted with one or two
substituents independently selected from the group
consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano,
vitro, amino and C1-C4 alkoxycarbonyl;
benzyloxy;
diphenylmethoxy; or
triphenylmethoxy;
with the proviso that only one of Rg or R9 can be
hydrogen;
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R2 is:
C2-C6 alkenyl;
aryl; or
heterocycle;
where the aryl or heterocycle is optionally
_ substituted with one or two substituents independently
selected from the group consisting of halo, n-oxide, C1-C6
alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy,
nitro, acetyl, formyl, carboxymethylene, and
hydroxymethylene;
-CH2CH2-R10
where R10 is
carboxy;
aryl; or
heterocycle;
where the aryl or heterocycle is optionally
substituted with one or two substituents independently
selected from the group consisting of halo, n-oxide, C1-C6
alkoxy, methoxycarbonyl, phenyl, C1-Cg alkyl, carboxy,
vitro, acetyl, formyl, carboxymethylene, and
hydroxymethylene;
-CH=C(R12)-R11
where R11 is hydrogen or phenyl and
R12 is:
nitrile;
aryl; or
heterocycle;
where the aryl or heterocycle is optionally
substituted with one or two substituents independently
selected from the group consisting of halo, n-oxide, C1-C6
alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy,
vitro, acetyl, formyl, carboxymethylene, and
hydroxymethylene;
with the proviso that when R11 is phenyl, R12 is aryl; or
-C=C-R13;
where R13 is:
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aryl; or
heterocycle;
where the aryl or heterocycle is optionally
substituted with one or two substituents independently
selected from the group consisting of halo, n-oxide, C1-C6
alkoxy, methoxycarbonyl, phenyl, Cl-C6 alkyl, carboxy,
nitro, acetyl, formyl, carboxymethylene, and
hydroxymethylene; and
R3 is a heterocycle, C02R14, or
H
~NwRis
r I IS
where
R14 is C2-C6 alkenyl, C1-C6 alkyl, Cl-Cg
haloalkyl, C3-C~ cycloalkyl, substituted
C3-C~ cycloalkyl, aryl-(Cl-C6 alkyl), aryl,
or heterocycle; where the aryl or
heterocycle, or the ring of the aryl(Cl-C6
alkylene), is optionally substituted with one
or two substituents independently selected
from the group consisting of halo, C1-C6
alkoxy, methoxycarbonyl, phenyl, Cl-C6 alkyl,
carboxy, nitro, acetyl, formyl,
carboxymethylene, and hydroxymethylene;
R15 is aryl or heterocycle-(Cl-C6 alkylene); where
the aryl or the ring of the heterocycle-(C1-C6
alkylene), is optionally substituted with 1-4
substituents independently selected from the group
consisting of halo) C1-C6 alkoxy, methoxycarbonyl,
phenyl, C1-C6 alkyl, carboxy, nitro, acetyl,
formyl, carboxymethylene, trifluoromethyl, and
hydroxymethylene; and
pharmaceutical salts and solvates thereof.
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The present invention also provides a method for
inhibiting the proteolytic activity of Prostate-Specific
Antigen (PSA) by administering a compound of Formula I.
The present invention also provides methods for
treating Pc, Pca metastasis BPH, Bc and Bc metastasis by
. administering to a mammal in need of such treatment a
prostatic specific antigen inhibiting compound. Preferred
prostatic specific antigen inhibiting compounds include
those of Formula I. This aspect of the invention resides in
the discovery that PSA inhibiting compounds have a
therapeutic effect on such diseases. Persons skilled in the
art can readily determine if a compound is a PSA inhibiting
compound by known methods.
Another aspect of the invention includes processes and
intermediates useful in preparing the compounds of Formula I
and formulations containing the same compounds of Formula I.
Detailed Description of the Inven ion
The terms and abbreviations used in the instant
specification have their normal meanings unless otherwise
designated. For example, "°C" refers to degrees Celsius;
"N" refers to normal or normality; "mmol" refers to
millimole or millimoles; "g" refers to gram or grams; "ml"
means milliliter or milliliters; "M" refers to molar or
molarity; "MS" refers to mass spectrometry; "IR" refers to
infrared spectroscopy; "NMR" refers to nuclear magnetic
resonance spectroscopy.
The term "aryl", as used herein, represents an
unsaturated aromatic carbocyclic group of from 6 to 14
carbon atoms having a single ring (such as phenyl) or a
multiple fused ring system (such as naphthyl and anthracyl).
When substituted, the substituents may be located at any
available position on the aryl rings) that are sterically
feasible and afford a stable structure. The aryl may
optionally be substituted with one or two moieties.
Examples of substituted aryl groups include 4-fluorophenyl,
4-chlorophenyl, 4-iodophenyl, 4-nitrophenyl, 4-
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carbomethoxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-
ethoxyphenyl, 1-naphthyl, 2-naphthyl, 2-chloronaphthyl, 2,3-
dichloronaphthyl, 2-iodonaphthyl, 3-iodonaphthyl, 2-
fluoronaphthyl, 3-fluoronaphthyl, 2-methylnaphthyl and 3-
methylnaphthyl.
The term "substituted C3-C~ cycloalkyl", as used
herein, represents a cycloalkyl group of 3 to 7 carbon atoms
substituted with one or two moieties chosen from the group
consisting of halo and C1-C6 alkyl. Examples of substituted
cycloalkyls include 2-isopropylcyclohexyl, 5-
methylcyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-
chlorocyclohexyl, 3-chlorocyclohexyl, 4-iodocyclohexyl, 3-
iodocyclohexyl, 3-chlorocyclopentyl, and 3-
chlorocycloheptyl.
The term "heterocycle", as used herein, represents a
monovalent saturated or unsaturated group having a single
ring (5 or 6 membered) or a multiple fused ring system (9 or
10 membered), and up to 4 nitrogen atoms and/or up to 2
oxygen atoms and/or up to 2 sulfur atoms, arranged to afford
a stable structure that is sterically feasible. Exemplary
heterocycles include: 2-thienyl or 3-thienyl, 2-furyl or
3-furyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl,
pyrrolidinyl, piperidinyl, azepinyl, indolyl, isoindolyl,
quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl,
benzimidazolyl, benzoxadiazolyl and benzofurazanyl. The
heterocycle may optionally be substituted with one or two
moieties such as, Cl-C4 alkyl, C1-C4 alkoxy, halogen,
hydroxy and oxo. Examples of substituted heterocyclic
groups include n-oxide-pyridin-3-yl, n-oxide-pyridin-4-yl,
and 4-methyl-pyridin-3-yl and the like.
The term "C1-C6 alkyl", as used herein, represents a
branched or linear, monovalent alkyl group having from one
to six carbon atoms. Typical C1-C6 alkyl groups include
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-
methylpentyl, and the like. Also encompassed within the
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term Cl-C6 alkyl are more narrow ranges such as Cl-C4 alkyl
and C2-C5 alkyl.
The term "C2-C6 alkenyl", as used herein, represents a
straight or branched, monovalent, unsaturated aliphatic
chain having from two to six carbon atoms with one double
bond. Typical C2-C6 alkenyl groups include ethenyl (also
known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-
hexenyl, 2-methyl-2-propenyl, 1-propenyl, 1-butenyl, 2-
pentenyl, and the like.
The term "C1-C6 alkoxy", as used herein, represents a
straight or branched -O-(C1-C6 alkyl) chain. The oxygen
atom bonds at the point of attachment to the parent
molecule. Typical C1-C6 alkoxy groups include methoxy,
ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and
the like.
The term "C1-C6 haloalkyl", as used herein, represents
straight or branched alkyl chain having from one to six
carbon atoms with one or more halogen atoms bonded thereto.
Typical C1-C6 haloalkyl groups include 3-chlorobutyl, 4-
chlorobutyl, 3-iodobutyl, 4-iodobutyl, 3-fluorobutyl, 4-
fluorobutyl, and the like.
The term "C1-C6 alkylene", as used herein, represents a
straight chain having from one to six carbon atoms with two
bonds thereto. Typical C1-C6 alkylene groups include
ethylene, trimethylene, tetramethylene and the like.
The term "aryl(C1-C6 alkylene)", as used herein,
represents an aryl(C1-C6 alkylene)- substituent where the
alkylene group is linear, such as phenylethylene or the
like. The alkylene portion bonds at the point of attachment
to the parent molecule. The ring of the aryl(C1-C6
alkylene) may optionally be substituted with one or two
moieties. The substituents may be located at any available
position on the aryl ring.
The term "halo" or "halogen", as used herein, means
fluorine, chlorine, bromine, or iodine.
The term "C1-C4 alkoxycarbonyl", as used herein,
represents a C1-C4 alkoxy group attached to a carbonyl group
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[-C(O)-(C1-C4 alkoxy)]. The alkoxycarbonyl is bonded to the
parent molecule via the carbonyl group.
The term "benzylthio", as used herein, represents a
benzyl group attached to a sulfur atom (-S-CH2-phenyl). The
sulfur atom bonds at the point of attachment to the parent
molecule.
The term "C1-C4 alkylthio", as used herein, represents
a 1 to 4 carbon alkyl chain attached to a sulfur atom [-S-
(C1-C4 alkyl)]. The sulfur atom bonds at the point of
attachment to the parent molecule.
The term "carbamoyl", as used herein, represents the
radical NH2C0-.
The term "hydroxymethylene", as used herein, represents
the radical -CH20H.
The term "n-oxide", as used herein, refers to the
radical O bonded to an available nitrogen atom.
The term "C1-C5 alkanoyloxy", as used herein, refers to
the group (C1-C5 alkyl)-C(O)-O-. Examples of C1-C5
alkanoyloxy's include acetoxy, pivaloyloxy, and the like.
The term "treating" as used herein includes prophylaxis
of the named physical condition or delay in the onset of the
named physical condition or amelioration or elimination of
the disease or condition once it has been established.
The compounds of the present invention, broadly
expressed as azetidinones, are a new class of compounds
useful for inhibiting the proteolytic activity of PSA
(hereinafter "PSA inhibitors"). Representative compounds of
the present invention have an increased selectivity for
inhibiting the proteolytic activity of the serine protease,
PSA, compared to the inhibition of other serine proteases
[i.e., HLE (Human Leukocyte Elastase), tPA (tissue
Plasminogen Activator) and thrombin].
The compounds of the present invention are known to
form solvates with appropriate solvents. Preferred solvents
for the preparation of solvate forms include water,
alcohols, tetrahydrofuran (THF), DMF, and DMSO. Preferred
alcohols are methanol and ethanol. Other appropriate
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solvents may be selected based on the size of the solvent
molecule. Small solvent molecules are preferred to
facilitate the corresponding solvate formation. The solvate
is typically formed in the course of recrystallization or in
the course of salt formation. One useful reference
: concerning solvates is Sykes, Peter, A Guidebook to
Mechanism in Oraanic Chemistry, 6, 56 (1986), John Wiley &
Sons, New York. The term "solvate" as used herein includes
hydrate forms such as monohydrate and dihydrates.
The compounds claimed herein can also form acid
addition salts with a wide variety of inorganic and organic
acids. Typical acids which can be used include sulfuric,
hydrochloric, hydrobromic, phosphoric, hypophosphoric,
hydroiodic, sulfamic, citric) acetic, malefic, malic,
succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic,
g-toluenesulfonic, benzenesulfonic, methanesulfonic,
trifluoroacetic, hippuric and the like. The preferred
pharmaceutically acceptable salts are those formed with
hydrochloric acid or acetic acid.
While the compounds of Formula I are useful as PSA
inhibitors, certain groups of compounds of Formula I are
preferred for such use. Accordingly, the preferred
embodiments of the present invention includes compounds of
Formula I above wherein:
R1 is benzyl, phthalimido, or a moiety of the formula:
Rs Rs
O~N~
~~ I(O
where
R5 is hydrogen, C1-Cg alkyl, or phenyl;
R6 is hydrogen, isopropyl, or phenyl;
- R2 is phenyl, C2-C4 alkenyl, -CH2CH2R10, -CH=C(R11)-R12~ or
C=C-R13;
where
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R10 is carboxy or phenyl;
R11 is hydrogen or phenyl;
R12 is cyano, phenyl, naphthyl, furan-2-yl, or
furan-3-yl, pyridinyl, pyrimidinyl, or
quinolinyl;
where the phenyl group is optionally
substituted once with C1-C4 alkyl, C1-C4
alkoxy, or nitro and where the pyridinyl
group is optionally substituted once with n-
oxide;
R13 is phenyl;
R3 is a heterocycle, C02R14, or
H
NWRis
~S
where
the heterocycle is pyridinyl, pyrimidinyl, 1,3,5-
triazinyl, quinazolinyl, or benzoxazolyl where
said heterocycle is optionally substituted 1 or 2
times independently with nitro, trifluoromethyl,
C1-C4 alkoxy, or phenyl;
R14 is C2-C4 alkenyl, C1-C4 alkyl, C1-C4
haloalkyl, C4-C~ cycloalkyl, 2-isopropyl-5-
methylcyclohexanyl, benzyl, or phenyl;
where the phenyl group is optionally
substituted once with halo, C1-C4 alkoxy,
carbomethoxy, or nitro;
R15 is phenyl, naphthyl, furan-2-ylmethyl, or
furan-3-ylmethyl;
where phenyl is optionally substituted one to
four times independently with halo or
trifluoromethyl; and
pharmaceutical acid addition salts and solvates thereof.
A most preferred embodiment of the present invention
includes the compounds of Formula:
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/~ ,,,, w
o ,1., -
0
O R
where R3 is a heterocycle, C02R14, or
H
~NwRis
f IS
where
the heterocycle is pyridinyl, pyrimidinyl, 1,3,5-
triazinyl, quinazolinyl, or benzoxazolyl where
said heterocycle is optionally substituted 1 or 2
times independently with nitro, trifluoromethyl,
C1-C4 alkoxy, or phenyl;
R14 is C2-C4 alkenyl, C1-Cg alkyl, C1-C4
haloalkyl, C4-C~ cycloalkyl, 2-isopropyl-5-
methylcyclohexanyl, benzyl, or phenyl;
where the phenyl group is optionally
substituted once with halo, Cl-C4 alkoxy,
carbomethoxy, or nitro;
R15 is phenyl, naphthyl, furan-2-ylmethyl, or
furan-3-ylmethyl;
where phenyl is optionally substituted one to
four times independently with halo or
trifluoromethyl; and
pharmaceutical acid addition salts and solvates thereof.
As used herein, the numbering system noted below shall
apply. The compounds of the present invention are comprised
of an azetidinone nucleus, said nucleus bearing asymmetric
carbons at the 3- and 4-positions as illustrated in the
following figure:
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R' R2
3 4I
2 11
N~Rs
The compounds of the invention may, therefore, exist as
single diastereomers, mixtures of diastereomers or as a
racemic mixture, all of which are within the scope of the
present invention. The individual enantiomers can be
isolated using well-known classical resolution techniques.
One particularly useful reference which describes such
methods is Jacques et al., Enantiomers, Racemates, and
Resolutions (John Wiley and Sons 1982). Appropriate
resolution methods include direct crystallization,
entrainment, and crystallization by optically active
solvents. Chrisey, L.A. Heterocvcles, 257, 30 (1990).
The compounds of the above formula can exist in the
form of two geometric isomers, a trans isomer and a cis
isomer, or in the form of a mixture of such isomers. The
"trans" isomers are considered to be those isomers in which
the R1 moiety will be in the opposite or trans-position with
regard to the R2 moiety. The "cis" isomers are considered
to be those isomers in which the R1 moiety will be in the
same or cis-position with regard to the R2 moiety.
The present invention therefore encompasses both the R
and the S configurations with regard to the 3- and 4-
positions. The terms "R" and "S" are used herein as
commonly used in organic chemistry to denote the specific
configuration of a chiral center. See, R.T. Morrison and
R.N. Boyd) Organic Chemistry, pp. 138-139 (4th Ed. Allyn &
Bacon, Inc., Boston) and Orchin, et ai. The Vocabulary of
Organic Chemistry, p. 126, (John Wiley and Sons, Inc.).
In one preferred embodiment of the present invention,
the R1 moiety will be in the cis-position with regard to the
R2 moiety, and in the configuration:
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R2
3 4~
N\
O 3S,4R
Racemic mixtures of the cis isomers (both the 3S,4R and
3R,4S configuration)
2
1 , R R1 H
R2
i,, ,..,,,v
3 4~
N\ N
O 3S,4R ~ 3R,4S
are also contemplated within the present invention. In an
alternative embodiment of the present invention, the R1
moiety will be in the trans-position with regard to the R2
moiety, and in the 3R,4R configuration:
R~ H H R2
,,,..
~3 41
3R,4R
or 3R,4S configuration:
R~ H H z
",~,,vR
3 4
' N
3S,4S
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Racemic mixtures of the trans isomers (both the 3R,4R and
3S,4S orientation) are also included within the present
invention. In still a third embodiment, mixtures of the cis
and trans isomers are contemplated.
In the more preferred embodiments the azetidinone
nucleus exists as the trans isomer, preferably in the trans,
3R,4R configuration.
Racemic mixtures of the cis isomers, the trans isomers
and mixtures of the cis and trans isomers are contemplated.
While compounds possessing all combinations of
stereochemical purity are contemplated, it is preferred that
the chiral centers be of a single absolute configuration.
The skilled artisan will also appreciate that when R1 is 4-
substituted oxazolidin-2-on-3-yl, the 4 position on that
ring is asymmetric.
The following group is illustrative of compounds
contemplated within the~scope of this invention:
-1-[4-(fluoro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; trans-1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-
1-[4-(nitro)benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; 1-[(4-
chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; trans-1-[(4-
chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; trans-1-[(4-
iodobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-
1-benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone; 1-[(propen-2-yl)oxycarbonyl]-3-(phthalimid-
2-0)-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-[(2-isopropyl-5-
methyl)cyclohexyl]oxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; trans-1-[4-
(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; trans-1-[4-
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(methoxy)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone; traps-1-[(propyl-1-
ene)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone; 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
hydrochloride; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-
[2-(phenyl)ethyl]azetidinone; traps-1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-[2-(carboxy)ethyl]azetidinone; 1-
phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(diphenyl)ethen-1-
yl]azetidinone; cis-1-[4-(methoxycarbonyl)phenoxycarbonyl]-
3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; cis-
1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone; traps-1-[4-(chloro)phenoxycarbonyl]-3-
(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; cis-1-
phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen- 1-
yl]azetidinone; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-
[2-(phenyl)ethyne-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-phenylazetidinone; 1-phenoxycarbonyl-3-
[5-phenyl-oxazolidin-2-on-3-yl]-4-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-
2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; 1-
phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-
phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-
phenoxycarbonyl-3-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-
phenoxycarbonyl-3S-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-
phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yi]-4R-[2-
(quinoline)ethen-1-yl]azetidinone hydrochloride; 1-
phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3S-[4S-
phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-
yl]azetidinone; 1-phenoxycarbonyl-3-benzyl-4-[2-
(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-
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benzyl-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
hydrochloride; cis-1-phenoxycarbonyl-3-benzyl-4-[2-
(cyano)ethen-1-yI]azetidinone; 1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-buten-1-ylazetidinone; 1-phenoxycarbonyl-
3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3
yl)ethen-1-yl]azetidinone carboxylic acid; cis-1
phenoxycarbonyl-3-[oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-
1-yl]azetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-2-yl)ethen-1-
yl]azetidinone; trans-1-phenoxycarbonyl-3R-[5-
(isopropyl)oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-
yl]azetidinone; cis-1-phenoxycarbonyl-3-[(5-
isopropyl)oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-
yl]azetidinone; 1-phenyloxycarbonyl-3R-[4R-phenyl-
oxazolidin-2-on-3-yl]-4S-[2-(phenyl)ethen-1-yl]azetidinone;
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(n-oxide-pyridin-3-yl)ethen-1-yl]azetidinone; trans-1-
phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-
yl]azetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-
2-on-3-yl]-4R-[2-(pyridin-4-yl)ethen-1-yl]azetidinone
hydrochloride; 1-[(4-chlorobutyl)oxycarbonyl]-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone;
1-phenoxycarbonyl-3R-[4R-phenyl-oxazolidine-2-on-3-yl]-4S-
[2-(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-
(phthalimid-2-o)-4-buten-1-ylazetidinone; trans-1-
phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-
(naphthyl)ethen-1-yl]azetidinone; trans-1-phenoxycarbonyl-3-
[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(naphthyl)ethen-1-
yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(3-methoxyphenyl)ethen-1-
yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(3-nitrophenyl)ethen-1-
yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-ethen-1-ylazetidinone; tracts-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(2-thiophenyl)ethen-1-yl]azetidinone; trans-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
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(3-furanyl)ethen-1-yl]azetidinone; trans-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(5-pyrimidinyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(3,5-dimethylphenyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(2-nitrophenyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-(2-
(4-nitrophenyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(2-nitronaphthyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(4-nitronaphthyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(2-quinolinyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(4-quinolinyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(7-quinolinyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(3-isoquinolinyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(8-isoquinolinyl)ethen-1-yl]azetidinone; traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(2-benzothiazolyl)ethen-1-yl]azetidinone; and traps-1-
phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-
(2-benzoxazolyl)ethen-1-yl]azetidinone; -1-
isopropoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
sec-butoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
p-nitrobenzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-
yl)ethen-1-yl]azetidinone; tr ns-1-[2-(2-isopropyl-5-
methyl)cyclohexyl]oxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-ylJazetidinone; trans-
1-methoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
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(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
benzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
cyclohexyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
cyclobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
cyclopentoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
allyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
isobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
vinyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone.trans-1-[4-
trifluoromethylpyrimid-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-
[6-nitropyridin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone;
traps-1-[2-phenylquinazol-4-yl]-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; trans-
1-[benzoxazol-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[4,6-
dimethoxy-1,3,5-triazin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone. traps-1-
benzylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[2-
bromophenylthioamido]-3R-(4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[3-
fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-[2-
fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[4-
fluorophenylthioamido]oxycarbonyl-3R-[4S-phenyl-oxazolidin-
2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone;
traps-1-[2,3,5,6-tetrafluorophenylthioamido]-3R-(4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
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yl]azetidinone; trans-1-[3-furfurylthioamido-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone; trans-1-naphthylthioamido-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
.
yl]azetidinone; trans-1-[4-trifluoromethylphenylthioamido]-
3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-(2-(pyridin-3-
yl)ethen-1-yl]azetidinone.
The compounds of the present invention can be prepared
using chemical methods known in the art as well as by the
additional processes disclosed below. Scheme I depicted
below illustrates the general methods used to synthesize the
compound which serves as the backbone for the Formula I
compounds of Examples 1 through 46. In all Schemes and
Examples, unless otherwise indicated, preparation of the
racemic mixtures of the invention are illustrated by
disclosure of a single isomer.
SCHEME I
STEP 1 R2
O
H2N OCH3 Solvent N
H R \ (tu)
(i) /
LOCH
3
STEP 2
R, O (v) R,
(vi)
CI ~CI
O OOH IOI O CI ST P 3
Solvent Solvent
(iv) Base
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FOR TRANS
R R STEP 4A R1 R2
Li-t-OBu
O ~ ~ Solvent O
STEP 5A OCH3 FOR CIS OCH3
CAN CAN STEP 4B
R' R2 ~ R' R2
(ix) N i (xii)
N~
O 'H O H
Base O O
Solvent Base
/R3 R3 Solvent
S CI O
TEP 6A CI O STEP 5B
(x) (x)
R1 n2 R1 R2
(X111)
(xi)
N
O ~O~Rs
O
According to Scheme I, the preferred starting material
is an aldehyde (i) in which R2 is defined above for Formula
I and p-anisidine (ii). Reactive moieties within the R2
definition may be blocked by procedures well-known to those
skilled in the art. Many of the aldehydes utilized are
available from commercial sources. The aldehydes which are
not commercially available, were prepared by methods known
in the art such as those noted below in Method A. The
aldehyde (i) and p-anisidine (ii) are reacted to produce an
imine (iii) [STEP 1]. In a separate reaction, an acid
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chloride (vi) is produced by reacting oxalyl chloride (v)
with an acid (iv) in which R1 is as defined above for
Formula I [STEP 2]. Reactive moieties within the R1
definition may be blocked by procedures well-known to those
skilled in the art. The 1-(4-methoxy)phenylazetidinones
(vii) are obtainable by the 2+2 cycloaddition of the
appropriately substituted, reactive imine (iii) and acid
chloride (vi) [STEP 3]. The preparation of the appropriate
imines (iii) and most of the required acid chlorides (vi),
as well as the cycloaddition procedure, are generally
described in U.S. Patent No. 4,665,171 and U.S. Patent No.
4,751,299, each incorporated herein by reference. Those not
described are commercially available or are prepared by
analogous procedures or procedures well known in the art.
The next step depends upon whether a traps compound or
a cis compound is desired. For traps compounds, the 1-
(methoxy)phenylazetidinone (vii) compounds are epimerized
with Li-t-OBu at the 3 position to give the traps
configuration [STEP 4A]. When the compound epimerized is a
racemic mixture, then a mixture of racemic traps products
will be obtained. For example, when a racemic mixture of a
cis compound in which R1 is phthalimido is epimerized, a
mixture which contains traps compounds having the 3(R),4(R)
and 3(S),4(S) configuration will result. When a chiral
auxiliary is used, the corresponding traps enantiomer will
result. The epimerized compound (viii) is then subjected to
CAN (cerric ammonium nitrate) oxidation to remove the
p-methoxyphenyl substituent [STEP 5A]. The resulting
compound (ix) is then acylated with the appropriate
chloroformate (x) to produce the substituted
oxycarbonylazetidinone (xi) having the traps configuration
[STEP 6A].
Alternatively, for the is compounds, the 1-
(methoxy)phenylazetidinone (vii) compound is subjected to
CAN oxidation to remove the g-methoxyphenyl substituent
[STEP 4B]. The resulting compound (xii) is then acylated
with the appropriate chloroformate (x) to produce the
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substituted oxycarbonylazetidinone (xiii) having the
corresponding cis configuration.
As discussed supra, the compounds prepared as described
in Synthetic Scheme I may be pure diastereomers, mixtures of
diastereomers, or racemates. The exact stereochemical
composition of the compound will be dictated by the specific
reaction conditions, combination of substituents, and
stereochemistry of the reactants employed in Synthetic
Scheme I. The skilled artisan will appreciate that
diastereomeric mixtures may be separated by chromatography
or fractional crystallization to provide single dia-
stereomers if desired.
The bases that can be used in Synthetic Scheme I
include, among others, lithium bis(trimethylsilyl) amide,
aliphatic tertiary amines, such as trimethylamine and
triethylamine (TEA), dimethylaminopyridine (DMAP), cyclic
tertiary amines such as N-methyipiperidine and N-
methylmorpholine, aromatic amines, such as pyridine and
lutidine, and other organic bases such as 1,8-
diazabicyclo[5,4,0]under-7-ene (DBU).
The solvents useful for the reactions described in
Synthetic Scheme I include those solvents in which the
reactants may be dissolved without interfering with the
reaction. The solvents which are useful include, among
others, solvents such as dioxane, ethyl acetate,
acetonitrile (CH3CN), dimethylsulfoxide, N,N-
dimethylformamide, tetrahydrofuran (THF), ethyl formate,
N,N-dimethylacetamide, hexane, diethyl ether, benzene,
toluene, tert-butyl methyl ether, diisopropyl ether,
ethylene glycol dimethyl ether, dichloromethane, chloroform,
carbon tetrachloride, trichloroethylene, and 1,2-
dichloroethane, either alone or in the form of a mixed
solvent.
In order to obtain acid addition salts for the present
compounds, the acids noted above were also added to the
product along with solvent following acylation.
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Appropriate selection of the primary amine, substituent
or protective group on the primary amine, reaction solvent
and reaction temperature, among other things, leads to the
preferential formation of one of the two isomers.
The following is a more detailed description of the
steps described in Synthetic Step I. While the chemistry
described below is applicable to azetidinones bearing the
moieties defined in R1 and R2, for purposes of simplicity,
R1 is depicted as phenyl oxazolidinone or phthalimido, R2 is
depicted as (2-phenyl)ethen-1-yl and (2-pyridine)ethen-1-yl
and R3 is depicted as phenyl oxycarbonyl. Those of ordinary
skill in the art will recognize that the various R groups
can be replaced by other moieties for which the R groups are
defined without changing the overall general chemistry. The
following descriptions and examples further illustrate the
synthesis of the compounds of the present invention, are
merely illustrative, and are not meant to limit the
invention in any manner.' Other methods for preparing the
compounds of the present invention, although not explicitly
depicted are contemplated within the scope of the present
invention.
METHOD A: Preparation of Aldehvdes (i)
As indicated above, many of the aldehydes utilized can
be purchased from commercially available sources. The
aldehydes that are not commercially available are prepared
for example by methods known in the art such as by oxidation
of a primary alcohol in the presence of pyridinium
chlorochromate or by reducing acyl chlorides by treating
them with lithium tri-t-butoxyaluminium hydride at -78 C.
Preferably, the aldehydes are prepared according to the
procedure disclosed in Anaew. Chem., 87, 486 (1975) by
reacting one equivalent of an appropriately substituted
carboxyaldehyde with one equivalent of FMTTP [formyl
methylene triphenylphosphorane, (Ph)3PCHCHO}] in the
presence of a solvent, preferably benzene or toluene. The
reaction is stirred at a temperature from about 75°C to
about 85°C, preferably about 80°C until all of the reactants
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are consumed as indicated by NMR. When excess starting
material is present, additional formyl methylene
triphenylphosphorane can be added to further react with the
excess carboxyaldehyde. The final product can be recovered
using standard techniques such as filtration and/or the
removal of organics by vacuum.
More specifically, by way of example, the aldehydes are
produced by the method depicted below:
N / N / / H
O
O
Purpose: Large scale aldehyde production.
Procedure:
Materials FW Amt. Mole Eauiv.
pyridine 107.11 1008 .9336 1.0
FMTPP 304.33 284.138 .9336 1.0
To a 12 L round bottom flask (RBF) was charged 1008 of
3-(pyridine)carboxaldehyde (pyridine), &L of benzene
(solvent) and 284.138 of (Ph)3PCHCHO (FMTPP). The resulting
slurry was then heated to 80°C and stirred overnight at
80°C. The mixture was checked by NMR for completion of the
reaction. NMR showed remaining starting material. Another
20% of the FMTPP was added and the mixture was stirred
overnight. NMR analysis showed only a tiny amount of
starting material remaining. The reaction mixture was
cooled to room temperature and organics were removed by
vacuum. 3L of chilled diethyl ether was added to the
residue and stirred. Solids were filtered off and organics
were removed by vacuum. The residue was recovered (123 g)
as a dark solid. Yield=99.8 MS=132
STEP 1: Preparation of Imines (iii)
The imines of the present invention are prepared by
methods known in the art, for example by charging one
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equivalent of the aldehyde to be utilized into a reaction
vessel with a solvent, preferably dichloromethane. One
equivalent of a primary amine (p-anisidine) is then added to
the mixture. To the mixture is added a drying agent,
typically magnesium sulfate, sodium sulfate or silica gel in
the amount of approximately one gram of drying agent per 3.8
grams of amine. The reaction is stirred overnight at room
temperature until all of the reactants are consumed as
measured by readily available techniques. The mixture is
then filtered and the organics removed by vacuum to provide
the desired imine.
More specifically, by way of example, the imines can be
prepared as follow:
\ NHz
CH30 \
H
Solvent ~ / N
N
OCH3
Purpose: Large scale imine production.
Procedure:
Materials FW Amt. Mole Eauiv.
Aldehyde 132.1 2208 .9311 1.0
Anisidine 123.2 114.78 .9311 1.0
To a 2 L RBF was charged about 120 g of the aldehyde
and 1 L of dichloromethane. To this mixture was charged
114.78 of g-anisidine. The mixture was rinsed with about
0.8 L of dichloromethane. Thirty (30)8 of magnesium sulfate
was then added as a drying agent. The mixture was stirred
overnight at room temperature. NMR showed a complete
reaction. The magnesium sulfate was filtered off and the
organics were removed by vacuum to afford 210.65 g of imine.
Yield=94.98 MS=238
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STEP 2: Preparation of Acid Chloride (vi)
The acid chlorides used in the present invention are
also produced by methods known in the art such as the method
disclosed in U.S. Patent No. 4,665,171, incorporated herein
by reference. For example, 1.8 molar equivalents of oxalyl
chloride is reacted with one equivalent of the appropriately
substituted acid in the presence of a solvent (preferably
toluene or benzene) to produce the acid chloride. The
reaction is heated to about 60°C for about 3-4 hours under
inert gas (i.e., nitrogen gas, helium gas or argon gas).
The reaction mixture is cooled to room temperature and the
organics removed by vacuum.
By way of example, the acid chlorides are produced as
follows:
0
cl
ci
0
Solvent
o~ O~
o 0 o C-ci
Purpose: Acid chloride formation.
Procedure:
Materials FW Amt. Mole Eauiv.
Acid 221.7 100g .4511 1.0
OC 126.3 103.68 .8162 1.8
The acid was slurried in 2840 ml of toluene at room
temperature. Oxalyl chloride (103.6 g) was added all at
once. The solution was heated to 60°C for 4 hours under a
nitrogen purge. The mixture was then cooled to room
temperature and the toluene was removed by vacuum to give an
oil. The oil solidified upon standing at a sub-zero
temperature. 113 g of the acid chloride was produced.
STEP 3: 2+2 Cvcloaddition
The process of 2+2 cycloaddition is well known in the
art. Specific reference to this procedure is noted in G.I.
Georg, Ed.; The Oraanic Chemistrv of J3-lactams, Verlag
Chemie, New York, 1992, Chapter 6 as well as in U.S. Patent
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No. 4,751,299 and U.S. Patent No. 4,665,171, each
incorporated herein by reference. Generally, 1 equivalent
of the appropriate acid chloride and dichloromethane are
charged into a reaction vessel and the mixture is cooled to
about -78°C. 1.5 equivalents of an appropriate tri(C1-
. C4)amine, typically TEA, was then added to the mixture while
keeping the temperature < 70°C. The reaction mixture is
stirred thoroughly. The imine, dissolved in dichloromethane
(lOml dichloromethane/2 g imine), is slowly added keeping
the temperature around approximately -70°C. While the
addition time is not critical, best results are achieved
when the addition generally takes place dropwise over a
period of from about 1 to about 6 hours. The reaction
mixture is then stirred for an additional period of time,
from about 2 to about 4 hours. The reaction is carried out
at a temperature from about -78°C to about 25°C, preferably
from about -78°C to about 0°C and even more preferably from
about -78°C to about -75°C in a solvent in the present of
tri(C1-C4)amine. The reaction mixture is then allowed to
warm to room temperature and the reaction is quenched by the
addition of saturated aqueous ammonium chloride. The
resulting mixture is separated and the organics are removed
by vacuum. Ethyl acetate is added to the solid residue and
stirred 1 hour. The resulting wet cake is rinsed in large
amounts of ethyl acetate. A final rinse with ether is
performed. The resulting product is then dried in vacuum
overnight at 40°C.
More specifically) by way of example, the 2+2
cycloaddition is performed as follows:
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:.\ .\ I
..
~N
\ / N ~ Amme i O ~ \
~ Solvent
N + O
\ O O N
I / O I \
OCH3
OCH3
Purpose: Large scale 2+2 Cycloaddition to form the
~i-lactam.
Procedure:
Materials FW Amt. Mole Eauiv.
Imine 238 21o.65g .8851 1.0
Acid C1 239 210.9 .8825 1.0
TEA 101.2 133.96g 1.324 1.5
To a 12 L RBF was charged 210.9g of the acid chloride
and 2 L of dichloromethane. The mixture was cooled to -
78°C. To this pink/purple mixture was added 133.96 g of TEA
keeping the temperature around 70°C. The reaction mixture
was stirred for 15 minutes. The imine, dissolved in 2 L
dichloromethane, was slowly added keeping the temperature
around -70°C. The addition time was approximately 5 hours.
The reaction mixture was stirred for 2 hours at -75°C. The
reaction mixture was then slowly warmed to room temperature.
TLC was done at 0°C. TLC performed at room temperature
showed no difference from that performed at 0°C. The
reaction was quenched with 3 L of saturated NH4C1 (about
5008 NH4C1), separated and the organics were removed by
vacuum. 1 L of ethyl acetate was added to the solid residue
and stirred 1 hour. The resulting wet cake was rinsed in
large amounts of ethyl acetate. A final rinse with diethyl
ether was performed. The resulting product was dried in
vacuum overnight at 40°C. Gross Weight=176 %Yield=46%
MS=441.3
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Theory Found
C 70.73 70.60
H 5.25 5.14
N 9.52 9.43
STEPS 4A-6A: Preparation of TRAMS Isomers
STEP 4A: Epimerization
Epimerization of the 2+2 cycloaddition product with Li-t-
OBu was performed in order to obtain the isomers having the
trans configuration. Surprisingly, it was discovered that
higher yields and better purity resulted from epimerization
with Li-t-OBu than other reagents, such as, K-t-OBu.
The substituted cis azetidinone can readily be
epimerized into a substituted trans azetidinone by the
addition of 1.1 equivalent of Li-t-OBu to a mixture of 1
equivalent of the material [the substituted
(methoxy)phenylazetidinone) dissolved in a solvent,
preferably dry tetrahydrofuran, at a temperature of about
0°C. The reaction is quenched with saturated NH4C1 and
partitioned. The organic layer is DarcoTM treated
(activated carbon), dried with magnesium sulfate, filtered
and dried by vacuum.
More specifically, by way of example, epimerization may
be carried out as follows:
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Li-t-OBu
THF p
C
I /
~OCH OCH3
3
Purpose: Epimerization of the 2+2 product using Li-t-
OBu.
Procedure:
Materials FW Amt. Mole Eauiv.
Cis 2+2 441 50.Og .1134 1.0
Li-t-OBu 80.05 9.988 .1247 1.1
To a 12 L RBF was charged 50.Og of 1-methoxyphenyl-3S-
[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-
1-yl]azetidinone (cis 2+2) and 2500m1 of dry tetrahydrofuran
at room temperature. The mixture was cooled to 0°C in an
ice bath. 9.988 of Li-t-OBu was added all at once. The
mixture was stirred for about 20 minutes. The ice water was
removed from the bath and the mixture was slowly allowed to
warm to room temperature. The intermediate which had come
out of solution went back into solution at 2°C. NMR at room
temperature showed a slight amount of the cis material. The
mixture was stirred overnight at room temperature. NMR
showed a slight amount of cis still remaining. The reaction
was quenched with 2 L of saturated NH4C1 solution. The
organic layer was DarcoTM treated, dried with magnesium
sulfate and filtered. The organics were removed by vacuum.
Gross=42.78 oYield=85.4 MS=441
Theorv Found
C 70.74 70.96
H 5.25 5.39
N 9.52 9.55
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STEP 5A: CAN (Cerric Ammonium Nitrate) Oxidation
CAN oxidation is known in the art as depicted in J.
Ora. Chem., 47, 2765-68 (1982). Treatment of a compound
with CAN in the presence of acetonitrile under relatively
mild conditions yields a product in which the methoxyphenyl
- group has been removed. More specifically, by way of
example, oxidation of the trans isomer is achieved as
follows:
:W
II '
v
N%. ~ \ N CAN O N ' \ N
aq. CH3CN O
\ O H
O
OCH3
Purpose: CAN Oxidation.
Procedure:
Materials FW Amt. Mole Eauiv.
Intermed. 441 35.788 .0821 1.0
CAN 548.2 177.98 .3245 4.0
To a 12 L flask was charged 35.788 of 1-(4-
(methoxy)phenyl-3R-[4-phenyl-oxaxolidin-2-on-3-yl]-4R-[2-
pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) and 3.5L of
the solvent acetonitrile. The mixture was cooled to -10°C.
To this mixture was slowly added a solution containing
177.98 of CAN and 3.5 L of deionized H20 keeping the
temperature at -10°C. The mixture was stirred at -10°C and
the progress of the reaction was monitored by TLC(ETOAC).
. Since the reaction did not go to completion, another 0.5
equivalents of CAN was added and the mixture was stirred for
1 hour. TLC indicated that the reaction was complete.
7.0 L sodium bicarbonate and 3.0 L of ethyl acetate were
added and the mixture was warmed to room temperature. The
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mixture was then filtered through CeliteTM. The layers were
separated and the aqueous layer was back extracted with 2 X
2 L ethyl acetate. The combined organic layers were washed
with 4 L of 10~ sodium sulfite. The organic layer was then
DarcoT~'' treated and dried with magnesium sulfate. Organics
were removed by vacuum. Gross=16.9g Yield=62.36 MS=335.2
Theory Found
C 68.05 68.06
H 5.11 5.11
N 12.53 12.43
STEP 6A: Acvlation
Acylation is carried out by dissolving the substituted
azetidinone in a solvent, preferably dichloromethane. Base
is then added to the reaction mixture. The substituted
chloroformate is then added and the reaction is stirred
until completion. The reaction is then quenched with
ammonium chloride, DarcoTM treated and dried with a drying
agent. The resulting solid is then washed in solvent and
then dried. Mare specifically, by way of example, acylation
was performed generally as follows:
/ ~ Solvent
N \ N DMAP O N~
\ TEA
O NvH O \ O I/
O ~O ~ O
CI /
Purpose: Acylation of free amine.
Procedure:
Materials FW Amt. Mole Eauiv.
Intermed. 334.0 l5.Og .0449 1.0
DMAP 122.2 CAT
TEA 101.2 9.09m1 .0898 2.0
PCF 156.6 14.06m1 .0898 2.0
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To a 12 L RBF was charged lS.Og of the 3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone (Intermed.) and 4690m1 of dichloromethane.
DMAP (dimethylaminopyridine) was added at room temperature
and the mixture was stirred for 10 minutes. TEA was added
. all at once and the mixture was stirred for 10 minutes.
Phenyl chloroformate (PCF) was then added slowly. TLC at
end of the addition showed starting material remaining. The
mixture was stirred for about 2 hours at room temperature.
TLC showed no change. Another 2 equivalents each of TEA and
PCF were added and the mixture was stirred for 1 hour at
room temperature. TLC showed no change. Still another 2
equivalents each of TEA and PCF were added and the mixture
was stirred for 1.5 hours. TLC showed little change. An
addition 4.0 equivalents each of TEA and PCF were added
along with 0.1 equivalents of DMAP. The mixture was allowed
to stir overnight at room temperature. TLC showed little
change. The reaction was quenched with 4 L of saturated
NH4C1, DarcoTM treated and dried with magnesium sulfate.
The organics were removed to give a white solid. The solid
was slurried in diethyl ether and filtered. The solid would
not dissolve in 4L ethyl acetate so 4L of dichloromethane
was added to get dissolvation. 72m1 of 1M hydrochloric acid
in ether was added and the mixture was stirred for 1 hour.
Organics were removed by vacuum to produce a white solid.
The solid was slurried in ether and filtered. Extended
drying at 60°C was needed to get rid of residual solvents.
Gross=6.2 %Yield=30.4 MS=455.5
Theory Found
C 63.48 63.27
H 4.51 4.46
N 8.54 8.44
C1 7 . 21 6 . 97
STEPS 4B-5B' Preparation of Cis Isomers
The compounds of the present invention that are cis
isomers are generally prepared by subjecting the product
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obtained from the 2+2 cycloaddition step above to CAN
oxidation followed by acylation as depicted below:
STEP 4B: CAN (ferric Ammonium Nitrate) Oxidation
CAN Oxidation is known in the art as depicted in ,7.
Ora. Chem., 47, 2765-2768 (1982). The procedure is carried
out in the same manner as noted above in STEP 5A. More
specifically, by way of example, the oxidation was carried
out as follows:
O
CAN O
aq. CH3CN
O 'H
~OCH3
Materials FW Amount Mole Eauiv
Intermed. 424.5 20.08 47.12mmole 1
CAN 548.2 77.688 141.36mmole 3-4
The cis-1-methoxyphenyl-3S-(phthalimid-2-o)-4R-[2-
(phenyl)ethen-1-yl]azetidinone (Intermed.) was slurried in
600m1 acetonitrile and cooled to 0°C. A solution of CAN in
600m1 H20 was then added dropwise to the slurry at 0°C. The
mixture was covered and allowed to sit for a 30 minute
period. The mixture was then stirred an additional 30
minutes at 0°C before being extracted with 500 ml ethyl
acetate. The aqueous component was then back extracted with
2 X 300m1 ethyl acetate. The wash was then combined with 1
X 500m1 5o sodium bicarbonate and 3 X 500m1 10~ sodium
sulfite. The combined organics were slurried with 508
DarcoTM for 30 minutes and then 1008 magnesium sulfate was
added. The mixture was stirred for an additional 15 minutes
before being filtered through Celite. The solution was
concentrated under vacuum to give an oil. The oil was
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dissolve in 60m1 ethyl acetate and triturated with 250m1
ether. The mixture was filtered and a fine white solid
2.708 pure product was collected. The filtrates were
purified over silica gel to obtain an additional 4.048 pure
product. Gross=6.748 Yield=44.99 MS=317.5
STEP 5B: Acvlation
Acylation was performed in the same manner as noted
above in STEP 6A. More specifically, by way of example,
acylation was performed as follows:
PCF
N LIHMDS
p ~ THF
H
Purpose: Acylation of free amine.
Procedure:
Materials FW Amt. Mole Eauiv.
Intermed. 318 .2g .629 1.0
PCF 156.6 0.16m1 1.26mM 2
LHMDS 0.63m1 .629mM 1.0
The 3-phthalimid-2-o-4-[2-(phenyl)ethene-1-
yl]azetidinone (Intermed.) was combined with 6 ml dry
tetrahydrofuran. The mixture was cooled to -75QC. 1. OM
LHMDS (lithium bis(trimethylsilyl)amide) was added to the
reaction dropwise under nitrogen via syringe. The mixture
was stirred at -75gC for 30 minutes. PCF was added all at
once and the mixture was stirred at room temperature for one
hour. The reaction was then quenched with NH4C1 and
extracted with ethyl acetate. The organics were purified
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over silica gel. 0.1058 of a white solid were obtained.
MS=438
Theorv Found
C 71.23 71.53
H 4.14 4.27
N 6.39 6.49
Preparation of 1:I mixtures of cis-trans isomers
Alternatively, 1:1 mixtures of the cis:trans isomers of
the present invention may be prepared by combining the steps
as follows:
Et~imerization and Acylation
/ O / o ~ / o
N \ ~ N ~ \
\ .)
O N CI OPh O
Solvent N O
o H TEA o \
O
CIS TRANS
Materials FW Amt. Mole E iv
Intermed. 318 2g 6.29mmole 1
PCF 156.6 1.58m1 12.58mmole 2
TEA 101.2 8.77m1 62.90mmole 10
DMAP 222.2 CAT
The cis Intermed. was combined with 50m1
dichloromethane at room temperature. TEA was added to the
mixture all at once. A solution of phenyl chloroformate in
20m1 dichloromethane was added to the reaction dropwise,
slowly at room temperature. The solution was stirred
overnight at room temperature. The reaction was quenched
with 1N hydrochloric acid. The organics were separated and
purified over silica gel using 100% Hexane (1:1 Hexane/ethyl
acetate). A 1.698 mixture of cis/trans isomers was
obtained. The mixture was dissolved in 100m1 ethyl acetate,
300m1 of hexane was added, and seeded with pure traps. The
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mixture was allowed to stand overnight. The mixture was
filtered and a fine white crystal was collected. 99.4
traps 0.6~ cis Obtained 0.898 traps MS=438
Theorv Found
C 71.23 71.46
4.14 4.35
N 6.39 6.18
The following Examples further illustrate the compounds
of the present invention and the methods for their
synthesis. The Examples are not intended to limit the scope
of the invention in any respect, and should not be construed
as such. The starting materials for Examples 1 through 46
were prepared according to the general procedures set forth
in Synthetic Scheme I.
Example 1
traps-1-[4-(fluoro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
N
O
O
Materials FW Amt Mole E iv
Intermed. 318 0.1508 0.4716mM 1
4-FPCF 174.56 0.124m1 0.9432mM 2
T~ 101.2 0.651m1 4.716mM 10
DMP~P 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
ylazetidinone (Intermed.) was dissolved in 10 ml
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dichloromethane at room temperature. DMAP
(4-dimethylaminopyridine) and TEA were added all at once.
4-fluorophenyl chloroformate (4-FPCF) in 10m1
dichloromethane was added dropwise to the reaction at room
temperature under nitrogen. The mixture was stirred at room
temperature for 24 hours and then quenched with 1N
hydrochloric acid. The organics were separated and purified
over silica gel. 106 mg of a white solid were obtained at a
yield of 49.3%. MS=456
Example 2
trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
Materials FW Amt Mole Ectuiv
Intermed. 318 2g 6.29mM 1
PCF 156.6 1.58m1 12.58mM 2
TEA 101.2 8.77m1 62.90mM 10
DMAP 222.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was combined with 50m1
dichloromethane at room temperature. TEA and DMAP were
added to the mixture all at once. A solution of phenyl
chloroformate (PCF) in 20 ml dichloromethane was added to
the reaction dropwise, slowly at room temperature. The
solution was stirred overnight at room temperature. The
mixture was then quenched with 1N hydrochloric acid. The
organics were separated and purified over silica gel using
~ / \
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100% hexane (1:1 hexane/ethyl acetate). A 1.69g mixture of
cis/trans isomers was obtained. The mixture was then
dissolved in 100 ml ethyl acetate, 300 ml of hexane was
. added and then the mixture was seeded with pure trans. The
mixture was allowed to stand overnight. A fine white
crystal was collected by filtration. 1H-NMR showed no cis
isomers. HPLC showed 99.337% trans and 0.553% cis. 0.89 g
of trans were obtained. MS=438
Theory Found
C 71.23 71.47
H 4.14 4.35
N 6.39 6.18
Example 3
trans-1-[4-(nitro)benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
Materials FW Amt Mole E iv
Intermed. 318 O.lg 0.3144mM 1
4-nitro 215.6 0.136g 0.6288mM 2
T~ 101.2 0.438m1 3.144mM 10
DMAP 122.2 CAT
3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone
(Intermed.) was dissolved in 4m1 dichloromethane under dry
tube at room temperature. TEA and DMAP were added all at
once. 4-nitrobenzyl chloroformate (4-nitro) in 6 ml
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dichloromethane was then added dropwise to the mixture at
room temperature. The resulting mixture was stirred
overnight then quenched with 1N hydrochloric acid. The
organics were then separated and purified over silica gel.
123 mg of a white solid were obtained at a yield of 79~.
MS=497
Example 4
1-[(4-chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
O /
N
O
.. ~O
/jO
O
CI
Materials FW Amt Mole Ecruiv
Intermed. 318 0.5g 1.57mM 1
TEA 101.1 2.18m1 15.70mM 10
4C 171.02 0.43m1 3.14mM 2
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in l0ml
dichloromethane. TEA and DMAP were added all at once
followed by the dropwise addition of 4-
chlorobutylchloroformate (4C) in 10m1 dichloromethane at
25°C. The mixture was stirred at room temperature with dry
tube for 72 hours. The mixture was then quenched with 1N
hydrochloric acid. The organics were separated and purified
over silica gel. 204 mg of a 1:1 cis/trans mixture was
obtained. Yield=57 MS=451.9
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Example 5
trans-1-[(4-chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-
[2-(phenyl)ethen-1-yl]azetidinone
O
O
~N O
O~~
O
CI
The trans isomer was obtained in the same manner as
Example 4. The trans isomer was isolated from the silica
gel instead of the cis isomer. Yield=57 MS=451.2
Example 6
trans-1-[(4-iodobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
0
Materials FW Amt Mole E iv
' 452 0.18 0.2212mM 1
NaI 150 0.1668 1.106mM 5
. The product of~Example 5 and sodium iodide were
combined in 10 ml of acetone. The mixture was stirred
overnight at room temperature. The mixture was then
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filtered. The filtrate was concentrated under vacuum to
give 73mg of a yellow solid. oYield=60.6 MS=544
Example 7
1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone
Materials FW Amt Mole E iv
Intermed. 318 0.2 0.629mM 1
PCF 150.6 0.26m1 1.26mM 2
TEA 101.2 0.88m1 6.19mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was combined with 5m1
dichloromethane at room temperature. TEA and DMAP were
added all at once. Phenyl chloroformate (PCF) was added
dropwise. The reaction mixture was stirred at room
temperature for 16 hours. The reaction mixture was then
quenched with NH4C1 solution followed by extraction with
ethyl acetate. The organics were purified over silica gel
to obtain 120mg of a white solid as a 1:1 cis/trans mixture.
Yield=43.5 MS=438
o / \
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Example 8
trans-1-benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
Materials FW Amt Mole Eauiv
Intermed. 3I8 0.1508 0.4716mM 1
BCF 110.6 0.135m1 0.9432mM 2
TEA 101.2 0.657m1 4.716mM 20
DMAP 122.2 CAT
The 3S-(phthalimid-2-o)-4R-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 5m1
dichloromethane at room temperature. TEA and DMAP were
added all at once followed by benzyl chloroformate (BCF)
dropwise at room temperature. The mixture was stirred at
room temperature for 24 hours. The mixture was then
quenched with 1N hydrochloric acid. The organics were
separated and purified over silica gel. 160 mg of a white
solid was obtained. Yield=75 MS=452.2
Theorv Found
C 71.67 71.86
H 4.45 4.95
- N 6.19 6.17
O
O
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Example 9
1-[(2-propen-1-yl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
Materials FW Amt Mole E iv
Intermed. 318 0.2g 0.6289mM 1
AC 120.54 0.13m1 1.2578mM 2
TEA 101.2 0.88m1 6.289mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in approximately
8 ml dichloromethane at room temperature. TEA and DMAP were
added all at once. A solution of allyl chloroformate (AC)
in dichloromethane was added dropwise at room temperature.
The mixture was stirred at room temperature overnight and
then quenched with 1N hydrochloric acid. Organics were
separated and purified over silica gel. 185 mg of a white
solid was obtained. °sYield=73 MS=402.4
O
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Example 10
1-[(2-isopropyl-5-methyl)cyclohexyl]oxycarbonyl-3-
(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone
Materials FW Amt Mole- Eauiv
Intermed. 315 0.2g 0.629mM 1
5MC 219 0.288 1.26mM 2
TEA 101.2 0.88m1 6.29mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 5ml
dichloromethane at room temperature. TEA and DMAP were
added all at once followed by 2-mentayl chloroformate
dropwise. The mixture was stirred at room temperature for
24 hours and then quenched with 1N hydrochloric acid. The
organics were separated and purified over silica gel. 105
mg of a white solid were obtained. Yield=33.4 MS=500
O
O
::
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Example 11
traps-1-[4-(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-
2-0)-4-[2-(phenyl)ethen-1-yl]azetidinone
O
O
O
Materials FW Amt Mole E iv
Intermed. 318 1g 3.14mM 1
TEA 101.2 4.38m1 31.45mM 10
MCPCF 214.6 1.358 6.28mM 2
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 25m1 of
dichloromethane at room temperature under dry tube. TEA was
added all at once with DMAP. A solution of 4-methoxy
carbonylphenyl chloroformate (MCPCF) in 10m1 dichloromethane
was added slowly dropwise to the rapidly stirred reaction
mixture. The reaction mixture was stirred overnight at room
temperature. The reaction mixture was then quenched with 1N
hydrochloric acid. The organics were separated and purified
over silica gel using 100°s hexane (1:1 hexane/ethyl
acetate). 750mg of a white solid were obtained.
Yield=48.2 MS=496
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Examble 12
trans-1-[4-(methoxy)phenoxycarbonyl]-3-(phthalimid-2-o)-4-
[2-(phenyl)ethen-1-yl]azetidinone
O
0
O-
Materials FW Amt Mole E iv
Intermed. 318 0.5g 1.57mM 1
TEA 101.2 2.19m1 15.72mM 10
p-OCH3PCF 186.6 0.467m1 3.14mM 2
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 25m1
dichloromethane at room temperature. TEA and DMAP, followed
by 4-methoxy phenylchloroformate (p-OCH3PCF) were added
dropwise. The mixture was stirred for 16 hours at room
temperature and then quenched with 1N hydrochloric acid.
Organics were separated and purified over silica gel. 370
mg of a white solid were obtained. Yield=50.4 Ms=468
Theorv Found
C 69.23 69.11
H 4.30 4.28
N 5.98 5.94
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Example 13
traps-1-[(2-propen-1-yl)oxycarbonyl]-3-(phthalimid-2-o)-4-
[2-(phenyl)ethen-1-yl]azetidinone
~o / I
0
o N oU
0
Materials FW Amt Mole Ecruiv
Intermed. 318 0.1508 0.4716mM 1
chloroformate 256.6 0.2428 0.9432mM 2
TEA 101.2 0.657m1 4.716mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in tetrahydrofuran
at room temperature. TEA and DMAP were added all at once.
A solution of chloroformate in tetrahydrofuran was added to
the reaction dropwise at room temperature. The mixture was
stirred overnight then partitioned between ethyl acetate/1N
hydrochloric acid. Organics were purified over silica gel.
150 mg of a white solid were obtained. Yield=61 MS=522
Example 14
1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(pyridin-3-
yl)ethen-1-yl]azetidinone
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~O /
O
O
O
Materials FW Amt Mole E iv
Intermed. 319 100mg 0.3134mM 1
TEA 101.2 0.437m1 3.134mM 10
PCF 156.6 0.074m1 0.6268mM 2
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in dichloromethane
at room temperature. TEA and DMAP were added all at once.
A solution of phenyl chloroformate (PCF) in dichloromethane
was added to the reaction dropwise via a syringe. The
reaction was protected with dry tube. The mixture was then
quenched with 1N hydrochloric acid. Organics were separated
and purified over silica gel. 89mg of a white solid were
obtained. Yield=64.5 MS=440
Example 15
1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(pyridin-3-
yl)ethen-1-yl]azetidinone hydrochloride
o
' o
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50 mg of the compound of Example 14 was dissolved in
2 ml ethyl acetate. 0.5 ml of 1N hydrochloric acid in ether
was added. The mixture was stirred for 1 hour at room
temperature. A white solid was filtered from the mixture.
44 mg of product were obtained. oYield=81.3 MS=440
Example 16
cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-(2-
(phenyl)ethyl]azetidinone
O
Materials FW Amt Mole E iv
Intermed. 316 -- 0.4716mM 1
PCF 156.6 0.118m1 0.9432mM 2
TEA 101.2 0.66m1 4.716mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.), PCF and DMAP were combined in 10
ml dichloromethane at room temperature under nitrogen. A
solution of TEA in 10m1 dichloromethane was added dropwise
under nitrogen. The mixture was stirred at room temperature
until the reaction appeared complete. The mixture was then
quenched with 1N hydrochloric acid and the organics were
separated and purified over silica gel. 130mg of a white
solid were obtained. Yield=63 MS=440
Theory Found
C 70.94 70.64
H 4.58 4.53
N 6.36 6.07
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Example 17
trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-
(carboxy)ethen-1-yl]azetidinone
OH
0 ~
50mg of (t) trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-
4-[2-(carboxybenzyl)ethen-1-yl]azetidinone (Intermed.) in
3m1 dichloromethane was combined at room temperature with
lOmg of 5% Pd-c. The mixture was stirred under a balloon
hydrogen. Thin layer chromatography indicated a new spot
forming. The mixture was stirred overnight under hydrogen.
Organics were separated and purified over silica gel.
25.5mg of a white solid were obtained. %Yield=62 MS=408
Example 18
1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2,2-
(diphenyl)ethen-1-yl]azetidinone
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Materials FW Amt Mole Eauiv
Intermed. 394 125mg 0.3172mM 1
PCF 156.6 0.08m1 0.6344mM 2
TEA 101.2 0.442m1 3.172mM 10
DMAP 222.2 CAT
5m1 of 3-(phthalimid-2-o)-4-[2,2-(diphenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in dichloromethane
at room temperature. TEA and DMAP were added all at once.
Phenyl chloroformate (PCF) was added dropwise to the mixture
at room temperature and stirred overnight. The mixture was
then quenched with 1N hydrochloric acid. Organics were
separated and purified over silica gel. 104mg of a white
solid were obtained. oYield=63.7 MS=514
Examt~le 19
cis-1-[4-(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-2-
0)-4-[2-(phenyl)ethen-1-yl]azetidinone
O ~v
O
O
Materials FW Amt Mole E iv
Intermed. 318 0.1g 0.3144mM 1
MCP 152 96mg 0.6288mM 2
Phosgene 1.93M 0.326m1 0.6288mM 2
Pyridine 79.10 0.069m1 0.6288mM 2
4-methoxyc arbonylphenol was combined
(MCP) with
dichloromethane at room temperature. solution of
A 1.93M
phosgene was added via syringe under nitrogen. The solution
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was cooled to -60°C. Pyridine was added dropwise via
syringe. The mixture was stirred at -60°C for 15 minutes
and then warmed to -10°C for 1 hour. 3-(phthalimidin-2-o)-
4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was added
via syringe all at once. The mixture was warmed to room
temperature. No reaction by TLC. 10 eq. RA was added all
at once. The mixture was then stirred at room temperature
overnight. Complete reaction by TLC was then observed. The
reaction mixture was quenched with 1N hydrochloric acid.
Organics were separated and purified over silica gel. 84 mg
of a white solid were obtained. Yield=54 MS=496
Example 20
cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yI]azetidinone
20mg of 3-(phthalimid-2-o)-4-[2-(phenyl)ethyn-1-yl
(Intermed.) azetidinone were dissolved in ethanol in a Parr
bottle. 5~ Pd on calcium carbonate poisoned with lead
(Lindar's Catalyst-CAT) was added. The mixture was placed
on a Parr shaker at 20 psig/room temperature for 2 hours.
The solid was purified over silica gel. l6mg of product
were obtained. Yield=79.6 MS=438.
O
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Example 21
cis-1-[4-(chloro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
CI
Materials FW Amt Mole E iv
Intermed. 318 0.1168 0.3647mM 1
TEA 101.2 0.508m1 3.647mM 10
PC1PCF 190 O.lml 0.7194mM 2
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 5m1
dichloromethane under nitrogen. TEA and DMAP were added all
at once. A solution of 4-chlorophenyl chloroformate
(PC1PCF) in 5m1 dichloromethane was added dropwise at room
temperature under nitrogen. The mixture was stirred at room
temperature for 24 hours. The reaction mixture was then
quenched with 1N hydrochloric acid. The organics were
separated and purified over silica gel for a total yield of
79~. 68mg of the desired were obtained. MS=472.1
Theorv Found
66.04 66.21
3.62 3.60
N 5.92 6.04
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Examt~ 1 a 2 2
traps-1-[4-(chloro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-
[2-(phenyl)ethen-1-yl]azetidinone
CI
The product was obtained in the same manner as
Example 21 with the exception that the traps isomer was
isolated from the silica gel. 68 mg were obtained.
MS=472.1
Theorv Found
C 66.04 66.19
H 3.62 3.57
N 5.92 6.04
Example 23
cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethen-1-yl]azetidinone
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Materials FW Amt Mole E iv
Intermed. 318 0.2g 0.629mM 1
PCF 156.6 0.16m1 1.26mM 2
LHI~IDS 1.OM 0.63m1 0.629mM 1
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was combined in 6m1 dry
tetrahydrofuran. The mixture was cooled to -75°C. 1. OM
LHI~S (lithium bis(trimethylsilyl) amide) in tetrahydrofuran
was added to the reaction dropwise under nitrogen via
syringe. The mixture was stirred at -75°C for 30 minutes.
Phenyl chloroformate (PCF) was added all at once and the
mixture stirred at room temperature for 1 hour. The
reaction was then quenched with NH4C1 solution followed by
extraction with ethyl acetate. The organics were purified
over silica gel. 0.1058 of a white solid were obtained.
Yield=38.1 MS=438
Theorv Found
C 71.23 71.53
H 4.14 4.27
N 6.39 6.49
Exam>Jle 24
cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-
(phenyl)ethyn-1-yl]azetidinone
~N
O ~O
O
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Materials FW Amt Mole Ecruiv
Intermed. 316 0.1g 0.3164mM 2
PCF 156.6 0.08m1 0.6328mM 2
TEA 101.2 0.441m1 3.164mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-j2-(phenyl)ethyn-1-
yl]azetidinone (Intermed.) was dissolved in dichloromethane
at room temperature. TEA and DMAP were added all at once.
A solution of phenyl chloroformate (PCF) in dichloromethane
was added to the reaction dropwise at room temperature under
nitrogen. The reaction mixture was stirred at room
temperature for 72 hours. The reaction mixture was quenched
with 1N hydrochloric acid. The organics were purified over
silica gel. 83mg of a white solid were obtained.
%Yield=60.1 MS=436
Example 25
cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-
phenylazetidinone
o
/r
0
-N
~O
//O
Materials FW Amt Mole E iv
Intermed. 296 0.1g 0.3424mM 1
TEA 101.2 0.48m1 3.424mM 10
PCF 156.6 0.085m1 0.6848mM 2
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-phenylazetidinone
(Intermed.)
was dissolved in 5ml dichloromethane at room
temperature.
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TEA and DMAP were added all at once. Phenyl chloroformate
(PCF) was then added dropwise and the mixture was stirred at
room temperature overnight. The reaction mixture was then
quenched with 1N hydrochloric acid. The organics were
separated and purified over silica gel. 48mg of a white
solid were obtained. Yield=33.9 MS=412
Example 26
1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone
0~,,~~~~
N \ ~N
ii., ~/ v
O
~--N
O ~O
O
Materials FW Amt Mole E iv
Intermed. 333 0.1g 0.6006mM 1
TEA 101.2 0.167mM 1.2012mM 2
PCF 156.6 0.150m1 1.2012mM 2
DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-
3-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in
dichloromethane. The mixture was cooled to -10°C under
nitrogen. DMAP was added followed by TEA at -10°C. The
mixture was stirred for 5 minutes. Phenyl chloroformate was
added dropwise via syringe. TLC 1 hour after addition
showed complete reaction. The mixture was stirred for an
additional hour at +10°C. The reaction was quenched with
saturated NH4C1. Organics were dried over magnesium sulfate
and concentrated under vacuum to residue. The residue was
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then slurried in ether at room temperature. The mixture was
filtered and 87mg of off white solid were collected.
Theorv Found
C 68.56 68.45
H 4.65 4.74
N 9.23 9.04
Example 27
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride
O~,,w\
N
Nip., \ /
O I
O~-N
O
O
87mg of free-base Example 26 were dissolved in ethyl
acetate. 5 eq. of 1N hydrochloric acid in ether was added
at room temperature dropwise. An immediate precipitant was
noted. The mixture was stirred at room temperature for 30
minutes. Solvents were removed under vacuum to give 105mg
of a white solid. MS=455.
Theorv Found
C 63.48 63.27
H 4.51 4.46
N 8.54 8.44
C1 7.22 6.91
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Example 28
1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride
/
O ~ /N
N
O
O
Materials FW Amt Mole E iv
Intermed. 333 0.1g 0.3003mM 1
PCF 156.6 0.075m1 0.6006mM 2
TEA 101.2 0.4186m1 3.003mM 10
DMAP 122.2 CAT
The 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-
3-yl}ethen-1-yl]azetidinone (Intermed.} was dissolved in
dichloromethane at room temperature under nitrogen. TEA and
DMAP were added all at once. A solution of phenyl
chloroformate (PCF) in dichloromethane was added to the
reaction dropwise under nitrogen. The reaction mixture was
stirred at room temperature overnight. The reaction mixture
was then quenched with 1N hydrochloric acid. The organics
were separated and purified over silica gel. 43mg of a 1:1
cis/trans product were obtained.
Example 29
1-phenoxycarbonyl-3S-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride
O
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l~
'1
O , /N
N
_ O
N
O ~O
O
I~
The product was obtained in the same manner as
Example 28 with the exception that the cis isomer was
isolated. 30mg were obtained. 'MS=491
Examt~le 30
1-phenaxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(quinoline)ethen-1-yl)azetidinone hydrochloride
O
O
Materials FW Amt Mole Ecruiv
Intermed. 335 0.1578 0.4686mM 1
PCF 156.6 0.118m1 0.9377mM 2
TEA 101.2 0.635m1 4.686mM 10
DMAP 122.2 CAT
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The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(quinoline)ethen-1-yl]azetidinone (Intermed.) was dissolved
in 5 ml dichloromethane at room temperature. TEA and DMAP
were added all at once followed by the dropwise addition of
phenylchloroformate (PCF) at room temperature. The mixture
was stirred at room temperature for 16 hours. The reaction
mixture was then quenched with 1N hydrochloric acid.
Organics were separated and 5 eq 1N hydrochloric acid in
ether was added to the organics. 43 mg of a white solid
were obtained. %Yield=16.3% MS=528
Examble 31
1-phenoxycarbonyl-3R-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(phenyl)ethen-1-yl]azetidinone
\
O~,.wv
N~~. \
O I
O/r N
~O
O//
Materials FW Amt Mole Ecruiv
Intermed. 334 0.1668 0.497mM 1
TEA 101.2 0.416m1 2.98mM 6
PCF 156.6 0.125m1 0.994mM 2
DMAP 122.2 CAT
3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in
5m1 dichloromethane at room temperature. TEA and DMAP were
added all at once followed by phenyl chloroformate (PCF)
dropwise. The reaction mixture was stirred at room
temperature for 24 hours. The mixture was then quenched
with 1N hydrochloric acid. The organics were separated and
purified over silica gel. 60mg trans were obtained.
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Example 32
1-phenoxycarbonyl-35-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
. (phenyl)ethen-1-yl)azetidinone
off,,,,,, ,
N \ \
O I
-N
O ~O
O
The same procedure was used as in Example 30 with the
exception that 55mg of the cis isomer was obtained from the
silica gel.
Example 33
1-phenoxycarbonyl-3-(phthalimid-2-o)-4-(3-buten-1-
yl)azetidinone
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Materials FW Amt Mole E iv
Intermed. 270 0.2g 0.741mM 1
PCF 156.6 0.186m1 1.48mM 2
TEA 101.2 1.03m1 7.407mM 10
DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-(3-buten-1-yl)azetidinone
(Intermed.) was combined in 20m1 dichloromethane at room
temperature. TEA and DMAP were added all at once. A
solution of PCF in 10 ml dichloromethane was added under
nitrogen to the reaction dropwise at room temperature. The
mixture was stirred for 24 hours and then quenched with 1N
hydrochloric acid. The mixture was purified over silica gel
to obtain a pure product. lO8mg of a white solid (a 1:1
cis/trans mixture) was obtained. oYield=37o MS=390
Example 34
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-3-yl)ethen-1-yl']azetidinone acetate
l~
o ,
/N
N~'
O I
O~--N
O O
O \ H3C OH
1 g of the azetidinone of Example 26 was dissolved in
10 ml ethyl acetate. 1 ml of acetic acid was then added.
The mixture Was stirred at room temperature for 5 hours.
The mixture was then filtered and 0.758 of a white solid was
collected. Yield=66.2 MS=455
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Examble 35
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-2-yl)ethen-1-yl]azetidinone
(,,W\ ~ /
O
N~. \ ~ N
O
~--. N
O ~O
/O
Materials FW Amt Mole E iv
Intermed. 333 0.1g 0.6006mM 1
TEA 101.2 0.167m1 1.2012mM 2
PCF 156.6 0.150m1 1.2012mM 2
DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-
2-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5ml
dichloromethane at room temperature. TEA and DMAP were
added all at once followed by phenyl chloroformate dropwise.
The reaction mixture was stirred at room temperature for 16
hours. The reaction was then quenched with 1N hydrochloric
acid. The organics were separated and 5 eq. 1N hydrochloric
acid in ether. The mixture was filtered and 63mg of a white
solid was obtained. Yield=21.4 MS=455.
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Example 36
1-phenyloxycarbonyl-3R-[4R-phenyl-oxazolidin-2-on-3-yl]-4S-
[2-(phenyl)ethen-1-yl]azetidinone
O
Nii., \
O I
O
i'
Materials FW Amt Mole E iv
Intermed. 334 32.9mg 0.0985mM 1
PCF 157 0.025m1 0.197mM 2
TEA 101.2 0.137m1 0.985mM 10
DMAP 122.2 CAT
The 3R-[4R-phenyl-oxazolidin-2-on-3-yl]-45-[2-
(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in
2 ml dichloromethane at room temperature. The reaction was
protected with a dry tube. DMAP and TEA were added all at
once. PCF was then added via syringe and the reaction was
stirred at room temperature. TLC showed a complete reaction
within minutes. The reaction was quenched with NH4C1. The
product was purified over a silica gel to obtain a pure
trans product. 28 mg of a white solid was obtained.
Yield=63 MS=454
Example 37
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(n-oxide-pyridin-3-yl)ethen-1-yl]azetidinone
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off.....,, , \
N \ ~ / N
ice,, ~ O
O
--N
O ~O
/O
Materials FW Amt Mole E iv
Intermed. 455 0.138 g 0.3032 mmole 1
MCPBA 172.6 0.115 g 0.6670 mmole 2.2
The 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(n-oxide-pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.)
was dissolved in 10 ml dichloromethane at room temperature.
MCPBA (3-chloroperoxybenzoic acid) was added all at once and the
mixture was stirred at room temperature for 16 hours. The
reaction was quenched with a solution of 10°s Na2S203. The
organics were removed and the resulting mixture was dried over
MgS04, filtered. The organics were concentrated to a white foam.
1H-NMR and TLC indicate the N-oxide. Obtained 105mg of a white
powder. Yield=73.5 MS=471
Example 38
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(pyridin-4-yl)ethen-1-yl]azetidinone hydrochloride
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l
p ,,,,,~~
..,,
o i
O~N O ~ Hci
O
Materials FW Amt Mole Ectuiv
Intermed. 333 606 mg 1.82 mM 1
PCF 156.6 0.457m1 3.64 mM 2
TEA 101.2 0.507 ml 3.64 mM 2
DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-
4-yl)ethen-1-yl]azetidinone (Intermed.) was combined with
10m1 of dichloromethane at room temperature. TEA and DMAP
were then added all at once. A solution of phenyl
chloroformate (PCF) in approximately 10 ml dichloromethane
was slowly added dropwise to the mixture at room temperature
(protected with dry tube). TLC analysis showed a complete
reaction. The mixture was adsorbed directly onto a silica
gel and purified using hexane (1:1 hex/ethyl acetate) The
solid was dissolved in ethyl acetate and 5 equivalents of 1N
hydrochloric acid in ether was added dropwise. The mixture
was stirred at room temperature for 1 hour. The mixture was
then filtered. 202 mg of an off white solid were collected.
Ms=455
Theory Found
C 68.56 68.80
H 4.65 ' 4.70
N 9.23 9.48
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Example 39
1-[4-methoxycarbonylphenoxycarbonyl]-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone
y
,.,,,~
N,,,,
0
--N
° ~O
O
O
O~
Materials FW Amt Mole- Eauiv
Intermed. 334 248mg 0.7425mM 1
MCPCF 214.6 175mg 0.817mM 1.1
TEA 101.2 0.207m1 1.485mM 2
DMAP 122.2 CAT
3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-phenyl)ethen-
1-yl]azetidinone (Intermed.) was dissolved in 5m1
dichloromethane at room temperature. DMAP followed by TEA
was added to the mixture. A solution of 4-methoxy
carbonylphenyl chloroformate (MCPCF) in 10m1 dichloromethane
was added dropwise at room temperature. The reaction
mixture was stirred at room temperature overnight with dry
tube. The reaction mixture was then quenched with 1N
hydrochloric acid. The organics were separated and purified
over silica gel. 274mg of a white solid was obtained.
Yield=72 MS=512
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Examble 40
1-j(4-chlorobutyl)oxycarbonyl]-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone
O ,,~~~\
Nip.. \
O I
~O
O~
/0
CI
Materials FW Amt Mole E iv
Intermed. 334 43.2mg 0.1293mM 1
TEA 101.2 0.18m1 1.293mM 10
4-BCF 171 0.035m1 0.2586mM 2
DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-
(phenyl)ethen-1-yl)azetidinone (Intermed.) was dissolved in
dichloromethane at room temperature. DMAP and TEA were
added via syringe followed by the dropwise addition of
chlorobutylchloroformate (4-BCF). The mixture was stirred
at room temperature with dry ice. The reaction mixture was
then quenched with 1N hydrochloric acid and the organics
separated. The organics were purified over silica gel.
38.77mg was obtained. %Yield=64 MS=468
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Example 41
1-phenoxycarbonyl-3-[4R-phenyl-oxaxolidin-2-on-3-yl)-4S-[2-
(phenyl)ethen-1-yl]azetidinone
- O
N
\~~~ \
O
~N~
O ~~ O
O
Materials FW Amt Mole Ecruiv
Intermed. 334 0.1g 0.244mM 1
PCF 157 0.075m1 0.599mM 2
TEA 101.2 0.42m1 2.994mM 10
DMAP 112.2 CAT
The 3R-[4R-phenyl-oxaxolidin-2-on-3-yl]-4S-[2-
(phenyl)ethen-1-yl]azetidinone (Intermed.) was combined with
TEA and DMAP in 10 ml dichloromethane at room temperature
under nitrogen. PCF in 5m1 of dichloromethane was added to
the reaction dropwise at room temperature. Completion of
the reaction was tested by TLC. The reaction was quenched
with 1N hydrochloric acid. The mixture was purified over
silica gel. 4lmg of a 1:1 mixture of trans:cis
product was
obtained. MS=454
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Example 42
1-phenoxycarbonyl-3-[4R-phenyl-oxaxolidin-2-on-3-yl]-4S-[2-
(phenyl)ethen-1-yl]azetidinone
O
N~~
O
--N
O ~O
I/O
23mg of the cis chiral product was obtained from the
silica gel of Example 41. MS=454
Example 43
cis-1-phenoxycarbonyl-3-(phthalimid-2-o?-4-buten-1-
ylazetidinone
0 ~v
l5mg of the pure cis isomer was isolated from the
silica gel of Example 33. MS=390
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Example 44
cis-1-phenoxycarbonyl-3-[oxazolidin-2-on-3-yl]-4-[2-
(phenyl)ethen-1-yl]azetidinone
Materials FW Amt ( Mole E iv
Intermed. 258 0.448 0.0017M 1
LHMDS/THF 1N 1.7m1 0.00187M 1.1
PCF 156.6 0.32m1 0.00255M 1.5
The 3-(2-oxazolidirione-3-yl)-4-[2-(phenyl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 17 ml of
tetrahydrofuran. The mixture was kept cool in a dry ice acetone
bath (at a temperature of from about -73°C to about -78°C).
l.7ml of 1N LHMDS/THF was added dropwise via syringe to the
mixture. 0.32 ml PCF was added all at once and the mixture was
stirred until all of the components of the reaction were
consumed. The reaction mixture was quenched with 20m1 of 0.5N
hydrochloric acid and extracted with 20 ml of diethyl ether and
30m1 of dichloromethane. A solid formed. The solid was
dissolved in 50m1 of dichloromethane. The combined organic
layers were washed with 50 ml of 10°s sodium bicarbonate, washed
with 50 ml of 12.5 sodium chloride and dried over magnesium
sulfate. The mixture was then filtered concentrated. The
residue was dissolved in 20 mL of dichloromethane and added to
20m1 of ice cold Diethyl ether. The white solid was vacuum
filtered, washed with 10 mL of diethyl ether, and vacuum dried.
MS=378.38
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Example 45
trans-1-phenoxycarbonyl-3R-[5-(isopropyl)-oxazolidin-2-on-
3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone
O O \
N~~~) ~ /
N
O ~O
O
Materials FW Amt Mole Ecruiv
Intermed. 300.36 0.118 0.00036M 1
LHMDS/THF 1N 0.40m1 0.0004M 1.1
PCF 156.6 0.07m1 0.005M 1.5
The 3-[(5-isopropyl)oxazolidin-2-on-3-yl]-4-[2-
(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved
in
10m1 of tetrahydrofuran. The mixture was kept cool in a dry
ice acetone bath (at a temperature of from about -73 C to
about -78 C). 1N LHMDS/THF (0.40m1) was added dropwise via
syringe to the solution. PCF (0.07m1) was added all at once
and the mixture was stirred until all of the components of
the reaction were consumed. The reaction mixture was
removed from the ice bath and quenched with 20m1 of 0.5N
hydrochloric acid and extracted twice with 20m1 of
dichloromethane. The dichloromethane extract was washed
with 20m1 of 10~ sodium bicarbonate, washed with 20m1 of
12.5% sodium chloride and dried over magnesium sulfate. The
mixture was then filtered and concentrated. The product was
obtained by subjecting the dichloromethane solution of
residue to silica gel chromatography.
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Example 46
cis-1-phenoxycarbonyl-3-[(5-isopropyl)oxazolidin-2-on-3-
yl]-4-[2-(phenyl)ethen-1-yl]azetidinone
Q O
N%'. ,~~y \
i
N
Q ~O
/O
Materials FW Amt Mole E iv
Intermed. 300.36 0.1g 0.00033M 1
LF~DS/THF 1N 0.37m1 0.00036M 1.1
PCF 156.6 0.06m1 0.005M 1.5
The 3-[(5-isopropyl)oxazolidin-2-on-3-yl]-4-[2-
(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 10 ml
of tetrahydrofuran. The mixture was kept cool in a dry ice
acetone bath (at a temperature of from about -73° C to about -
78° C). 1N LHIKDS/THF (.37 ml) was added dropwise via syringe to
the solution. PCF (.06 ml) was added all at once and the mixture
was stirred until all of the components of the reaction were
consumed. The reaction mixture was removed from the ice bath and
quenched with 20 ml.of 0.5N hydrochloric acid and extracted with
ml of dichloromethane. The dichloromethane extract was washed
20 with 20 ml of 10~ sodium bicarbonate, washed with 20 ml of 12.5%
sodium chloride and dried over magnesium sulfate. The mixture
was then filtered and concentrated. The residue was dissolved in
20 ml of dichloromethane and was added dropwise to a mixture of
10 ml of diethyl ether and 10 ml of hexane in an ice bath. A
white solid formed. The white solid was vacuum filtered.
MS=420.3
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Scheme II depicted below illustrates the general method
used to synthesize the compounds of Examples 47-50.
SCHEME II
O
STEP 1 ~ R,2
\ ~ \ ~/
H Wittig or Horner-Emmons Rxn
BaseISolvent ~ / N
o / \ o / \
(i) ~- (ii)
o,- o,
CAN
O / ~ Solvent STEP 2
,2 ~
\ \ R CI" O
\ R,2
/ O N~O BaseIDMAP
O \ Sovent . / N
/ O ~H
(iv) STEP 3 (iii)
The bases and solvents useful for the reactions
described in Synthetic Scheme II are the same as those
described as useful for Synthetic Scheme I.
The following is a more detailed description of the
steps described in Synthetic Scheme II. Those of ordinary
skill in the art will recognize that the chemistry is
merely a slight variation of the chemistry described for
Synthetic Scheme I. The following descriptions and
examples are intended to further illustrate the synthesis
of the compounds of the present invention and are not meant
to limit the invention in any manner. Other methods for
preparing the compounds of the present invention, although
not explicitly described are contemplated within the scope
of the present invention.
The starting aldehyde (i) is prepared according to the
procedures detailed in Tet. Lett., 32 (5), 803-6 (1991). An
acid chloride is dissolved in solvent and added dropwise to
a mixture of an appropriately substituted imine, solvent and
amine to produce the starting aldehyde (i). The reaction
mixture is stirred at room temperature under inert gas until
the reaction was completed. 5~ hydrochloric acid is added
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and the reaction mixture is allowed to stir for about 1.5
hours. Solvent is added to the organic layer and the layer
is washed with 5~ hydrochloric acid, followed by water and
. brine. The resulting product is then dried and the solvent
is removed by evaporation under reduced pressure. The
preferred solvent used is toluene and the preferred amine is
TEA. The appropriately substituted olefin can then be
prepared from the starting aldehyde (i) by either the Wittig
Reaction or the Horner-Emmons Reaction as outlined in Orcr.
React., 14, 270 (1965) and Acc. Chem. Res., 16, 411 (1983).
[STEP 1] Alkenes are synthesized from carbonyl compounds by
the Wittig Reaction by reacting the starting compounds by
the base treatment of an alkyl triphenylphosphanium salt or
alternatively by the Wadsworth-Emmons Reaction (Horner-
Emmons modification of the Wittig Reaction) in which
phosphonate esters are reacted with carbonyl compounds in
the present of base to form alkenes. The CAN Oxidation
[STEP 2] and Acylation [STEP 3] procedures are the same as
described in Synthetic Scheme I, Steps 5A and 6A or Steps 4B
and 5B.
Examr~le 47
1-phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-
yl]azetidinone
0 ~v
O/
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Materials FW Amt Mole Ecruiv
Intermed. 263 223mg 0.8479mM 1
LI~75/THF 1.OM 0.8479m1 0.8479mM 1
PCF 156.6 0.212m1 1.6953mM 3
The 3-benzyl-4-[2-(phenyl)ethen-1-yl]azetidinone
(Intermed.) was dissolved in 8m1 dry tetrahydrofuran. The
mixture was cooled to -78°C. 1. OM LHIKDS in tetrahydrofuran
was added to the reaction dropwise via syringe under
nitrogen. The reaction mixture was stirred at -78°C for 30
minutes. PCF was added at -78°C. The mixture was stirred
for 30 minutes. The external cooling was removed and the
reaction was quenched with saturated NH4C1. The reaction
mixture was stirred at room temperature. The mixture was
purified over silica gel. 237mg of a white solid was
obtained. %Yield=73
Theorv Found
C 78.31 78.05
H 5.52 5.68
N 3.65 3.46
Example 48
cis-1-phenoxycarbonyl-3-benzyl-4-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone hydrochloride
O
O
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Materials FW Amt Mole E iv
Intermed. 264 O.lg 0.379mM 1
TEA 101.2 0.53m1 3.787mM 10
PCF 156.6 0.095m1 0.7574mM 2
DMAP 122.2 CAT
The cis-1-benzyl-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone (Intermed.) was dissolved in 5ml
dichloromethane at room temperature. TEA and DMAP were
added all at once. A solution of phenyl chloroformate was
then added dropwise. The solution was stirred overnight at
room temperature. The reaction was quenched with 1N
hydrochloric acid. The organics were separated and the
resulting product was purified over silica gel. 78mg of a
white solid was obtained. Yield=48.9 MS=421
Example 49
cis-2-phenoxycarbonyl-3-benzyl-4-[2-(cyano)ethen-1-
yl]azetidinone
/ N
/ ~ /
N
O ~O
O
Materials FW Amt Mole E iv
Intermed. 212 O.lg 0.4716mM 1
PCF 156.6 0.118m1 0.9432mM 2
LHI4I77S 1.OM 0.4716m1 0.4716mM 1
The 3-benzyl-4-[2-(cyano)ethen-1-yl)azetidinone
_ 25 (Intermed.) was combined in 4 ml dry tetrahydrofuran at
around -70°C under nitrogen. 1. OM LHIKDS in tetrahydrofuran
was added to the ruction mixture dropwise via syringe. The
reaction mixture was then stirred at around -70°C for 30
minutes. PCF was added to the mixture. The mixture was
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stirred for another 30 minutes at around -70°C. The
reaction mixture was then quenched with 1N hydrochloric
acid. The organics were separated and purified over silica
gel. 105mg was obtained. aYield=67 MS=332
Theorv Found
C 72.28 72.02
H 4.85 5.05
N 8.43 8.38
Example 50
trans-1-phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-
yl]azetidinone
The trans isomer was isolated from Example 47.
The present invention also provides the following novel
and favored process for preparing certain azetidinones
within the scope of Formula I and provides intermediates
useful in preparing azetidinones. More specifically, an
invention is directed to the individual steps and the entire
process for preparing a compound of the formula Ia
O ~.,.v~ /
R~s
O
NwRm
O
U
O
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Ia
wherein R16 represents: phenyl, 2-nitrophenyl, 4-
nitrophenyl, naphthyl, 3-nitro-1-naphthyl, 4-nitro-2-
_ naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-
isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-
benzothiazolyl, 2-benzoxazolyl, 2-thienyl, 3-furanyl, 3-
pyridinyl, 3-pyridin-1-N-oxide) 5-pyrimidinyl, or 3,5-
dimethylphenyl; and
R1~ represents: 1-phenoxycarbonyl, 4-chlorophenoxycarbonyl,
4-fluorophenoxycarbonyl, benzyloxycarbonyl, 4-
nitrobenzyloxycarbonyl, 4-chlorobutyloxycarbonyl, 4-
methoxycarbonylphenoxycarbonyl, 4-methoxyphenoxycarbonyl or
1-propyleneoxycarbonyl; or a pharmaceutically acceptable
salt or solvate thereof, which comprises:
reacting an aldehyde of the formula II
O
H
R' B
II
wherein R18 is a trialkylsilane,
with an N-protected amine of the formula III
2 5 H2N R'9
III
wherein R19 is a nitrogen-protecting group,
to afford an N-protected imine of the formula IV
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R,s
i
N
H
R' 8
IV
reacting the N-protected imine of the formula IV, with 4S-
phenyloxazolidin-2-on-3-ylacetyl chloride V
.~~~~ \
O
O~N~CI
V
to afford an N-protected azetidinone VI
I \ Rsa
~ /
O N
~~
O i
N
~R~s
;
VI
desilylating and epimerizing the N-protected azetidinone VI
to afford a desilylated 4-acetylenic azetidinone
intermediate of the formula VII
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_ C
VII
reducing and N-deprotecting the 4-acetylenic azetidinone
intermediate of the formula VII to afford a 3-(4S-phenyl-
oxazolidin-2-on-3-yl)-4-ethenylazetidinone of the formula IX
,,,
O I'
N~,.
O NH
O
Ix
functionalizing the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-
ethenylazetidinone (IX), in the presence of a catalyst, with
an electrophile selected from the group X-R16 wherein X is a
leaving group, to give the alkenyl substituted azetidinone
of the formula XI
N \ R~s
O NH
and
XI
0
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acylating the alkenyl substituted azetidinone XI, to produce
the substituted oxycarbonylazetidinone of the formula Ia.
Preferred intermediates of the invention have the
formulas VIII and IX:
O~,,av\\
N
O
N~R,s
O
VIII
where R19 is a nitrogen-protecting group; and
lw
0~.,,,,v /
N
~i~,. \
O
NH
O
IX
Scheme III depicted below further illustrates this
preferred process for preparing certain azetidinones of this
invention.
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SCHEME III
STEP 1
R' 9
i
O N
H .i.. H2N R'9 ---~~ ~H
R, a R
II III IV
STEP 2
/ I R,9 \
N i (''\\\ I / R, 8
,~~~~~ \
O + ( bas
O
O N~ . ~ H N~
CI
R, s O
O ~ N
O ~R,s
V IV VI
STEP 3
R, a H
O R~n
VI VII
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STEP 4
H .,.~~\ /
O
~N,
!O/~~ I
N
o R~y ~ ~R,s
VII VIII
STEP 5
O O~~w\ /
II Ni lI Ni
O N O NH
O vR,e O
VIII IX
STEP 6
\ ~ \
/ ~,,.v\
O \ Rys
'/N, ~N~
NH ~,O ~ NH
O p
IX XI
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STEP 7
C R,s O~ R,s
~ 1,/Ni
O
O ~ ~R,~
XI Ia
where R16, R17 R18 and R19 are as previously defined.
The N-protected imine (IV) is prepared by methods known
in the art, for example by treating the aldehyde (II) with
an N-protected primary amine (III), for example, Q-
anisidine, in the presence of a solvent, preferably
methylene chloride or dichloromethane [STEP 1]. The
aldehyde (II) can be made by methods known in the art, for
example, according to the method of Hauptman, H. and Mader,
M., Svnthesis, 307 (1978). Suitable R18 groups include, for
example, trimethylsilane or other alkylsilanes. In
addition, various nitrogen-protecting groups (R19) familiar
to one skilled in the art can be used. A drying agent,
typically magnesium sulfate, sodium sulfate, silica gel or
the like, is preferably added to the reaction mixture. The
reaction is stirred overnight at room temperature until all
of the reactants are consumed as measured by readily
available techniques. The mixture is then filtered and the
solvent removed by vacuum to provide the desired N-protected
imine (IV).
2+2 cycloaddition of 4S-phenyloxazolidin-2-on-3-
ylacetyl chloride (V) with the N-protected imine (IV) yields
the N-protected azetidinone (VI), primarily as the cis
isomer [Step 2]. The process of 2+2 cycloaddition is
' generally well known in the art. See: G.I. Georg, Ed.; The
Organic Chemistry of (3-lactams, Chapter 6, Verlag Chemie,
New York, (1992); U.S. Patent No. 4,751,299; and, U.S.
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Patent No. 4,665,171, each incorporated herein by reference.
One equivalent of 4S-phenyloxazolidin-2-on-3-ylacetyl
chloride (V) and a solvent, for example, dichloromethane are
charged into a reaction vessel and the mixture is cooled to
about -78 °C. An appropriate base, for example,
tri(C1-C4)amine, typically triethylamine, is then added to
the mixture while keeping the temperature around -70 °C.
The reaction mixture is stirred thoroughly. The imine,
dissolved in solvent, is slowly added keeping the
temperature around -70 °C. While the addition time is not
critical, best results are achieved when the addition takes
place dropwise over a period of from about 1 to about 6
hours followed by stirring the reaction mixture for 2 to
about 4 hours. The reaction is carried out at a temperature
25 from about -78 °C to about 25 °C, preferably from about -
78 °C to about 0 °C and even more preferably from about -
78 °C to about -75 °C, in a solvent in the presence of
tri(C1-C4)amine.
4S-phenyloxazolidin-2-on-3-ylacetyl chloride (V) may be
prepared by methods known in the art such as the method
disclosed in U.S. Patent No. 4,665,171, incorporated herein
by reference. For example, 1.8 equivalents of an oxalyl
chloride is reacted with one equivalent of the appropriately
substituted acid in the presence of a solvent, preferably
toluene or benzene, to produce the acid chloride.
Preferably, the reaction is heated to about 60°C for about
3-4 hours under inert gas, for example, nitrogen gas, helium
gas or argon gas. The reaction mixture is cooled to room
temperature and the solvent removed by vacuum.
The N-protected azetidinone (VI) is then desilylated
and epimerized at the 3 position to give an approximately
4:1 mixture of a trans:cis N-protected, desilylated 4-
acetylenic azetidinone intermediate [STEP 3]. The N-
protected azetidinone (VI) can be desilylated and epimerized
by various methods known in the art. However, the N-
protected azetidinone (VI) is preferably desilylated and
epimerized by employing tetrabutylammonium fluoride (TBAF)
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at reaction temperatures below -50°C. Tetrahydrofuran is a
preferred solvent.
The trans desilylated 4-acetylenic azetidinone
- intermediate (VII) is partially reduced and N-deprotected to
yield the ~i-lactam trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-
4-ethenylazetidinone (IX) [STEPS 4 and 5]. The partial
reduction is preferably accomplished by hydrogenation of
trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-
ethenylazetidinone (vii) with Lindlar's catalyst and
quinoline. The deprotection is preferably accomplished
employing cerric ammonium nitrate in the presence of
acetonitrile, for example, according to the method outlined
at J. Ora. Chem., 47, 2765-68 (1982). One skilled in the
art would understand that either the partial reduction or
the deprotection may be accomplished first.
The resulting trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-
4-ethenylazetidinone (IX) is functionalized by reaction with
an electrophile, X-R16, in the presence of a solvent, and is
acylated to produce the substituted oxycarbonylazetidinone
of the formula I [STEPS 6 and 7]. In the formula X-R16, X
is a leaving group such as halogen, sulfonate or the like
and R16 is as previously defined. Functionalization is best
accomplished employing a catalyst, such as, palladium
acetate, and preferably in the presence of potassium acetate
and tetrabutylammonium chloride hydrate dissolved in
dimethylformamide. See: A. Satake, et al., Synlett, 839
(1994). The following R16 groups are preferred: 2-vitro-4-
phenyl, 4-vitro-2-phenyl, 3-vitro-1-naphthyl, 4-vitro-2-
naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-
isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-
benzothiazolyl, 2-benzoxazolyl. More preferred R groups
include: 2-thienyl, 3-furanyl, 5-pyrimidinyl, and 3,5-
dimethylphenyl. One skilled in the art would understand
that either the functionalization or the acylation of trans
3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX)
may be accomplished first, although the functionalization
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with X-R16 to yield the alkenyl substituted azetidinone (XI)
preferably precedes the acylation.
Acylation is preferably accomplished with an
appropriate chloroformate to produce the substituted
oxycarbonylazetidinone of the formula Ia. Examples of
appropriate chloroformates include: phenyl chloroformate, 4-
chlorophenyl chloroformate, 4-fluorophenyl chloroformate,
benzyl chloroformate, 4-nitrobenzyl chloroformate, 4-
chlorobutyl chloroformate, 4-methoxy carbonylphenyl
chloroformate, 4-methoxyphenyl chloroformate, and allyl
chloroformate.
Scheme III provides an illustration of the preferred
sequence of steps for the present invention. However, the
order of certain steps may be altered and still afford the
compounds of formula Ia. For example, the compounds of
formula Ia may be prepared from the 4-acetylenic azetidinone
intermediate VII by reduction to the compound VIII, followed
by: 1-deprotecting compound VIII to the compound IX,
followed by functionalizing with an electrophile, X-R16 and
acylating (in either order); or 2-functionalizing compound
VIII with an electrophile, X-R16, followed by deprotecting
the compound, followed by acylating. The 4-acetylenic
azetidinone intermediate VII may also be deprotected first,
followed by reduction to the compound IX, followed by
functionalizing with an electrophile, X-R16 and acylation
(in either order).
The following Preparations and Examples further
illustrate the synthesis of the compounds of the present
invention and are not meant to limit the invention in any
manner.
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Preparation of IVa
OCH3
~ OCH3
. ~ H + I / Mg~
TMS H2N ~% H
TMS
IIa IIIa IVa
The aldehyde IIa (4.89 g) was dissolved in 10 ml
methylene chloride. Anhydrous magnesium sulfate (9.43 g)
was added, followed by a solution of g-anisidine (4.77 g) in
20 ml methylene chloride. After stirring at room
temperature for 90 minutes, the mixture was filtered and the
solvent evaporated to give a brown liquid. The material was
dissolved in hexane. The hexane solution was decanted from
the insolubles and then washed with 1% hydrochloric acid
solution. After drying over anhydrous sodium sulfate, the
solvent was evaporated to give the imine (7.36 g) as an
orange liquid.
TLC 0.74 (3/1 hexane/ethyl acetate); 1H NMR (CDC13, 500
Rf
MFiz) 7.73 (s, 1 H), 7.20 (d, 1 H, J 8.9 Hz), &.91 (d,
8 = 1
H, J 8.9 Hz), 3.83 (s, 3 H), 0.29 (s, 9 H).
=
Preparation of V
4S-phenyloxazolidin-2-on-3-ylacetyl chloride
o
cl
I
0 o v
o N~ IC-OH Solvent
~O p~ C-CI
~~O
Va V
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The acid Va (100 g) was slurried in toluene at room
temperature. Oxalyl chloride (103.6 g) was added all at
once. The solution was heated to 60°C for 4 hours under a
nitrogen purge. The mixture was then cooled to room
temperature and the toluene was removed by vacuum to give an
oil. The oil solidified upon standing at a sub-zero
temperature. The acid chloride V (113 g) was produced.
Pret~aration of VIa
1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-
trimethylsilyl)ethyn-1-yl]azetidinone.
~ ~OCH3 TMS
O~'
~ O + >
O N O N
CI ~ H O v/~
TMS I ,
O
OCH3
V IVa VIa
The 2+2 Cycloaddition was performed by dissolving 3.4g
of the acid chloride V in 40 ml dichloromethane and cooling
the solution with a dry ice/acetone bath. Triethylamine
(3.0 ml) was added dropwise, giving a lavender solution.
After 15 minutes) the imine IVa (3.6g in 24 ml toluene) was
added dropwise. After 15 minutes, the dry ice/acetone bath
was replaced with an ice bath. After 3 hours, the solution
was warmed to room temperature. The reaction mixture was
diluted with ethyl acetate and washed with 10a hydrochloric
acid solution (3x), brine (1x), saturated sodium bicarbonate
(2x) and brine (1x). The organic solution was dried over
sodium sulfate and concentrated by rotary evaporation. The
amber solid (5.5g) was recrystallized with 60% ethyl
acetate/40~ hexane to give 3.72 g of the ~i-lactam 1-
methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-
trimethylsilyl)ethyn-1-yl]azetidinone.
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TLC Rf 0.25 (2/1 ethyl acetate/hexane); 1H NMR (CDC13, 500
MHz) 8 7.51-7.40 (m, 7 H), 6.90-6.87 (m, 2 H), 4.99 (t, 1 H,
J = 8.8 Hz), 4.72-4.68 (m, 2 H), 4.42 (d, 1 H, J = 5.0 Hz),
4.21 (t, 1 H, J' = 8.9 Hz), 3.81 (s, 3 H), 0.26 (s, 9 H).
Preparation of VIIa
1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-
trimethylsilyl)ethyn-1-yl]azetidinone.
,.
.W TAA H
O TBAF
0
o O
OCH3 OCH3
VIa VIIa
6.0 g of 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-
3-yl]-4-[(2-trimethylsilyl)ethyn-1-yl]azetidinone was
dissolved in 150 ml tetrahydrofuran and the solution was
cooled with a dry ice/acetone bath. TBAF (4.34g) was added
in three portions. The reaction mixture was allowed to warm
slowly to room temperature in the presence of the cold bath
overnight. The volume of the reaction solution was reduced
by two-thirds by rotary evaporation. The solution was
diluted with ethyl acetate and washed with 10~ hydrochloric
acid solution (2x), brine (1x), saturated sodium bicarbonate
(2x) and brine (lx). The organic solution was dried over
sodium sulfate and concentrated by rotary evaporation to
give 4.43 g of a 4.3:1 trans:cis mixture of the desired (3-
lactam 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-ylJ-4-
ethyn-1-yl]azetidinone. This material was carried on
without further purification.
TLC Rf 0.45 (trans); 0.37 (C1S) (1/1 ethyl acetate/hexane);
spectral data recorded from a 4.3:1 trans:cis mixture,
integrations include corrected values for coincident
resonances; 1H NMR (CDC13, 500 MHz) trans isomer 8 7.48-7.37
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(m, 7 H), 6.87 (d, 2 H, J = 8.9 Hz), 5.03-4.99 (m, 1 H),
4.91 (t, 1 H, J = 2.1 Hz), 4.75 (t, 1 H, J = 8.8 Hz), 4.42
(d, 1 H, J = 2.5 Hz), 4.30-4.24 (m, 1 H), 3.78 (s, 3 H),
2.38 (d, 1 H, J = 1.6 Hz); unobscured resonances for cis
isomer $ 4.53 (d, 1 H, J = 4.8 Hz), 2.67 (d, 1 H, J =
1.8 Hz).
Pret~aration of VIIIa
1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-
trimethylsilyl)ethyn-1-yl]azetidinone.
.,, ~ 1 ,,,~ 1
H
o~ ~~ H2 o
--.-s
o Lindlar
quinoline
O ~ O
/ /
OCH3 OCH3
VIIa VIIIa
1-Methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-
ethyn-1-ylazetidinone (2.0 g) was dissolved in methanol/60
ml dichloromethane (140 ml). Quinoline (0.55m1) and
Lindlar~s catalyst (0.15 g) were added. The mixture was
stirred under hydrogen atmosphere for 5 hours. The mixture
was then filtered through a pad of Celite and the solvent
removed by rotary evaporation. The residue was dissolved in
ethyl acetate and washed with 10~ hydrochloric acid solution
(3x) and brine (1x). The organic solution was dried over
sodium sulfate and concentrated by rotary evaporation to
give 2.00 g of a 4.3:1 trans:cis mixture of the desired (3-
lactam 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-
ethenylazetidinone. This material was carried on without
further purification.
TLC Rf 0.41 (trans); 0.45 (cis) (1/1 ethyl acetate/hexane);
spectral data recorded from a 4.3:1 trans:cis mixture,
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integrations include corrected values for coincident
resonances; 1H NMR (CDC13, 500 MHz) traps isomer 8 7.45-7.30
(m, 7 H), 6.85 (m, 2 H), 5.57-5.47 (m, 1 H), 5.23 (d, 1 H, J
- 17.1 Hz), 5.12 (d, 1 H, J = 10.3 Hz), 4.95-4.91 (m, 1 H),
4.76 (dd, 1 H, J = 2.3, 7.8 Hz), 4.69 (t, 1 H, J = 8.7 Hz),
4.26-4.19 (m, 1 H), 4.06 (d, 1 H, J = 2.5 Hz) 3.78 (s, 3 H);
unobscured resonances for cis isomer S 5.75-5.67 (m, 1 H),
5.5 (d) 1 H, J = 17 Hz) , 5.39 (d, 1 H, J = 10.4 Hz) .
Preparation of IX
3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone
o~~ ., \ o
~ ~ ~!
N o i
O ~~ NH
O
OCH3
VIIIa IX
1-Methoxyphenyl-3-[4S-phenyl-axazolidin-2-on-3-yl]-4-
ethenylazetidinone (0.92 g) was dissolved in acetonitrile
(70 ml) and the solution was cooled with an ice/acetonitrile
bath. Ceric ammonium nitrate (5.50g) in 70 ml water was
added dropwise. Thirty minutes after addition was complete,
ethyl acetate (100 ml) was added. Saturated sodium
bicarbonate solution was added to raise the pH of the
reaction mixture to 7. The reaction mixture was stirred for
1 hour and then filtered through a pad of Celite. The
solution was diluted with ethyl acetate and washed with 100
sodium sulfite solution (3x), brine (lx), saturated sodium
bicarbonate (2x) and brine (1x). The organic solution was
dried over sodium sulfate and concentrated by rotary
evaporation to give a 4.6:1 trans:cis mixture of the desired
~3-lactam 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-
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ethenylazetidinone. Trituration with ethyl acetate/hexane
gave 0.47 g of a yellow solid.
TLC Rf 0.16 (4/1 CHC13/ethyl acetate); spectral data
recorded from a 4.6:1 trans:cis mixture, integrations
include corrected values for coincident resonances; 1H NMR
(CDC13, 500 MHz) trans isomer 8 7.47-7.38 (m, 5 H), 6.24 (m,
1 H), 5.49-5.43 (m, 1 H), 5.15 (d, 1 H, J = 17.1 Hz), 5.02
(d, 1 H, J = 10.3 Hz), 4.94-4.87 (m, 1 H), 4.74 (t, 1 H, J =
8.8 Hz), 4.47 (d, 1 H, J = 2.5 Hz), 4.30-4.20 (m, 1 H), 3.88
(d, 1 H, J = 2.7 Hz); unobscured resonances for cis isomer S
6.37 (m, 1 H), 5.85-5.78 (m, 1 H), 5.33-5.27 (m, 2 H), 4.69
(t, 1 H, J = 8.9 Hz).
Preparation of 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(1-
naphthyl)ethen-1-ylazetidinone
,,
0
w ---~ o~..
1r N,..
O
~NH
O /~NH
O
O
IX
1-Iodonaphthalene (0.1625g), palladium acetate
(0.019 g), potassium acetate (0.125 g) and
tetrabutylammonium chloride hydrate (0.142 g) were dissolved
in 1 ml dimethylformamide. 3-[4S-Phenyl-oxazolidin-2-on-3-
yl]-4-ethenylazetidinone (0.11 g) in dimethylformamide
(2 ml) was added. The solution was heated at 80°C for 2.5
hours. After cooling to room temperature, the mixture was
filtered through a pad of Celite and washed with ethyl
acetate. The organic solution was washed with brine (lx),
saturated ammonium chloride (3x), brine (1x) and saturated
sodium bicarbonate (3x). The organic solution was dried over
sodium sulfate and concentrated by rotary evaporation to
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give a black oil. The product was purified by a silica
plug with chloroform to remove residual 1-iodonaphthalene
then ethyl acetate to remove the product. Further
. purification with column chromatography (chloroform, then
1/1 chloroform/ethyl acetate, then ethyl acetate) gave 0.052
g of a 10:1 trans:cis mixture of the desired ~i-lactam [3-
[4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-(1-naphthyl)ethen-1-
ylazetidinone.
TLC Rf 0.36 (1/1 ethyl acetate/hexane); spectral data
recorded from a 10:1 trans:cis mixture, integrations include
corrected values for coincident resonances; 1H NMR (CDC13,
500 MHz) trans isomer 8 7.99-7.96 (m, 1 H), 7.87-7.85 (m, 1
H), 7.81-7.79 (m, 1 H), 7.58-7.52 (m, 2 H), 7.43-7.23 (m, 7
H), 6.75 (s, 1 H), 6.50 (s, 1 H), 5.82-5.76 (m, 1 H), 4.96-
4.92 (m, 1 H), 4.79-4.70 (m, 2 H), 4.30-4.25 (m, 1 H), 4.15-
4.13 (m, 1 H); unobscured resonances for cis isomer S 8.10-
8.07 (m, 1 H), 6.55 (s, 1 H), 6.15-6.10 (m, 1 H).
Example 51
1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl)-4-j2-
(1-naphthyl)ethen-1-yl]azetidinone
~w 0
~ 1. LiHMDS
~,,av\\ ~N~~,
2. CICOOPh O
... _ O~-N
~O
NH
O O
3-[45-Phenyl-oxazolidin-2-on-3-yl)-4-[2-(1-
naphthyl)ethen-1-ylazetidinone (0.062 g) was dissolved in
3 ml tetrahydrofuran and the solution was cooled with a dry
ice/acetone bath. Lithium bis (trimethylsilyl) amide
solution (0.15, 1 M in tetrahydrofuran) was added. After 15
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minutes, 22 ul phenyl chloroformate in 1 ml tetrahydrofuran
was added. After 20 minutes, saturated ammonium chloride
solution was added. The reaction mixture was allowed to
warm to room temperature. The reaction mixture was
extracted with chloroform (2x) and the organic fraction
washed with brine (1x). The organic solution was dried over
sodium sulfate and concentrated by rotary evaporation to
give 0.11 g of a trans:cis mixture of the desired (3-lactam.
Column chromatography with 8/1 chloroform /ethyl acetate
gave 0.018 g of the desired trans ~i-lactam.
TLC Rf 0.42 (1/1 ethyl acetate/hexane); 1 H NMR (CDC13, 500
MHz) 8 7.94-7.91 (m, 1 H), 7.89-7.86 (m, 1 H) 7.82 (d, 1 H,
J=88.2 Hz), 7.56-7.47 (m, 3 H), 7.45-7.34 (m, 9H), 7.32-7.23
(m, 1 H) 7.19 (d, 2H, J=7.9Hz), 5.90 (dd, 1 H, J=8.2, 15.4
Hz), 5.23 (dd, 1 H, J=3.5, 8.2 Hz), 5.05-5.02 (m, 1 H), 4.82
(t, 1 H, J= 8.7 Hz) , 4.38-4.34 (m, 1 H) ~ 4.25 (d, 1 H,
J=3.7).
Preparation of 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-
methoxyphenyl)ethen-1-yl]azetidinone
W W
w
0
I \ -
~Ni~, ~Ni, ~ ~ OCH3
O I O'/
NH NH
O O
3-Iodoanisole (0.203g), palladium acetate (0.026g),
potassium acetate (0.171g) and tetrabutylammonium chloride
hydrate (0.244g) were dissolved in 1 ml dimethylformamide.
3-[4S-Phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone
(0.15g) in 2 ml dimethylformamide was added. The solution
was heated at 80°C for 3 hours. After cooling to room
temperature, the mixture was filtered through a pad of
Celite and washed with ethyl acetate. The organic solution
was washed with brine (1x), saturated ammonium chloride
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(3x), brine (1x) and saturated sodium bicarbonate (3x). The
organic solution was dried over sodium sulfate and
concentrated by rotary evaporation to give a black oil. The
product was purified by column chromatography (chloroform,
then 1/1 chloroform/ethyl acetate, then ethyl acetate) gave
0.068 g of the desired (3-lactam [3-[4S-phenyl-oxazolidin-2-
on-3-yl]-4-[(3-methoxyphenyl)ethen-1-yl]azetidinone].
Example 52
1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-
(naphthyl)ethen-1-yl]azetidinone
0~,,.vv
N ~ /
O
N
O ~O
O
The procedure of Example 51 resulted in 0.007 g of the
(3-lactam of Example 52 in the cis configuration.
TLC Rf 0.3 (1/1 ethyl acetate/hexane); 1 H NMR (CDC13, 500
MHz) b 8.11 (d, 1 H, J=7.71 1Iz), 7.96-7.80 (m, 2H), 7.65-
7.19 (m, I5 H), 6.32 (dd, 1 H, J=8.6, 15.7 Hz) 5.08 (dd, 1
H, J=6.2, 8.5 Hz), 4.93 (t, 1 H, J=8.1 Hz), 4.73-4.65 (m, 2
H), 4.27-4.24 (m, 1 H).
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Example 53
1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl}-4R-
[2-(3-methoxyphenyl)ethen-1-yl]azetidinone
\ \
-1. LiHMDS O~'~~~,\\ /
~NG \ ~ OCH 2. CICOOPh ~Ni~, \ ~ OCH3
3
O N
NH O O
O
O
3-[45-phenyl-oxazolidin-2-on-3-yl]-4-[(3-
methoxyphenyl)ethen-1-yl]azetidinone (0.068 g) was dissolved
in tetrahydrofuran {3 ml) and the solution was cooled with a
dry ice/acetone bath. Lithium bis (trimethylsilyl) amide
solution {0.19 ml, 1 M in tetrahydrofuran) was added. After
minutes, 27 ul phenyl chloroformate in 1 ml
tetrahydrofuran was added. After 20 minutes, saturated
ammonium chloride solution was added. The reaction mixture
was allowed to warm to room temperature. The reaction
15 mixture was extracted with chloroform (2x) and the organic
fraction washed with brine (1x). The organic solution was
dried over sodium sulfate and concentrated by rotary
evaporation to give 0.082 g of the desired ~i-lactam. Column
chromatography with 9/1 chloroform/ethyl acetate gave
0.0321 g.
TLC Rf 0.38 ((9/1 chloroform/ethyl acetate); 1H NMR (CDC13,
500 MHz) $ 7.38 - 7.29 {m, 7H), 7.25-7.21 (m, 2 H), 7.18-
7.16 (m, 2 H), 6.85-6.80 (m, 2H), 6.78 (s, 1 H), 6.42 (d, 1
H, J=15.8 Hz), 5.85 (dd, 1 H, J=7.7, 15.8 Hz)) 5.05-5.03 (m,
1 H), 5.00-4.97 (m, 1 II), 4.80 {t, 1 H, J=8.8 Hz), 4.37-
4.34 {m, 1 H), 4.20 (d, 1 H, J=3.5 Hz), 3.82 (s, 3 H).
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Preparation of 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-
nitrophenyl)ethen-1-yl]azetidinone
y y
o~,,,,,,,
0
I
~N ~N /
i,,~, i,~ a
~ No2
O O
NH NH
O O
1-Iodo-3-nitrobenzene (0.217 g), palladium acetate
(0.026g), potassium acetate (0.171g) and tetrabutylammonium
chloride hydrate (0.244g) were dissolved in 1 ml
dimethylformamide. 3-[4S-Phenyl-oxazolidin-2-on-3-yl]-4-
ethenylazetidinone (0.15 g) in dimethylformamide (2 ml) was
added. The solution was heated at 80°C for 3 hours. After
cooling to room temperature, the mixture was filtered
through a pad of Celite and washed with ethyl acetate. The
organic solution was washed with brine (1x), saturated
ammonium chloride (3x), brine (1x) and saturated sodium
bicarbonate (3x). The organic solution was dried over
sodium sulfate and concentrated by rotary evaporation to
give a black oil. The product was purified by column
chromatography (chloroform, then 1/1 chloroform/ethyl
acetate, then ethyl acetate) gave 0.033 g of the desired (3-
lactam [3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-
nitrophenyl)ethen-1-yl]azetidinone].
TLC Rf 0.28 (1/1 CHC13/ethyl acetate); 1H NMR (CDC13, 500
I~iz) b 8.13-8.11 (m, 1 H), 8.02 (s, 1 H), 7.49 (d, 2 H, J =
5.1 Hz), 7.46-7.33 (m, 5 H), 6.45 (d, 1 H, J = 15.9 Hz),
6.17 (s, 1 H), 5.75 (dd, 1 H, J = 6.6, 15.9 Hz), 4.94-4.89
(m, 1 H), 4.80 (t, 1 H, J = 8.8 Hz), 4.61 (dd, 1 H, J = 2.2,
6.5 Hz), 4.39 (dd, 1 H, J = 5.5, 8.9 Hz), 3.98 (d, 1 H, J =
2.6 Hz).
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Example 54
1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl)-4R-
(2-(3-nitrophenyl)ethen-1-yl]azetidinone
\ \
,,,v\
/ ~ N~ \
\ ~N02 ~', v N02
O
-NH ~N O
O O ~ \
O /
3-(4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-
nitrophenyl)ethen-1-yl)azetidinone (0.033 g) was dissolved
in tetrahydrofuran (3 ml) and the solution was cooled with a
dry ice/acetone bath. Lithium bis (trimethylsilyl) amide
solution (0.10 ml, 1 M in tetrahydrofuran) was added. After
minutes, phenyl chloroformate (12.7 ul in 1 ml
tetrahydrofuran) was added. After 20 minutes, saturated
ammonium chloride solution was added. The reaction mixture
15 was allowed to warm to room temperature. The reaction
mixture was extracted with chloroform (2x) and the organic
fraction washed with brine (1x). The organic solution was
dried over sodium sulfate and concentrated by rotary
evaporation to the desired (3-lactam. Trituration with
chloroform, and a water wash gave 0.0078.
TLC Rf 0.52 (4/1 chloroform/ethyl acetate); 1 H NMR (CDC 13,
500 MHz) b 8.12-8.09 (m, 2H), 7.72 (d, 1 H, J=7.7 Hz), 7.63
(t, 1 H, J=7.9 Hz), 7.46-7.42 (m, 4H), 7.34-7.28 (m, 3 H),
7.21-7.17 (m, 3 H), 6.66 (d, 1 H, J=15.9 Hz) 6.30 (dd, 1 H,
J=8.3, 15.9 Hz), 5.13 (dd, 1 H, J=5.6, 8.6 Hz), 4.93 (dd, 1
H, J= 3.4, 8.3 Hz), 4.86 (t, 1 H, J=8.8 Hz), 4.73 (d, 1 H,
J=3.6 Hz), 4.32 (dd, 1 H, J=5.6, 8.9 Hz)
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Example 55
1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
ethen-1-ylazetidinone
O ~,,,~~~~ /
N~i~,.
O
N
O ~O
O
0.168 of [3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-
ethenylazetidinone was dissolved in 10 ml tetrahydrofuran
and the solution was cooled with a dry ice/acetone bath.
Lithium bis (trimethylsilyl) amide solution (0.62 ml, 1 M in
tetrahydrofuran) was added. After 15 minutes, phenyl
chloroformate (90 ul) in 1 ml tetrahydrofuran was added.
After 15 minutes, saturated ammonium chloride solution was
added. The reaction mixture was allowed to warm to room
temperature. The reaction mixture was extracted with
chloroform (2x) and the organic fraction washed with brine
(1x). The organic solution was dried over sodium sulfate
and concentrated by rotary evaporation to the desired ~i-
lactam. Column chromatography with 9/1 chloroform/ethyl
acetate followed by recrystallization with hexane/ethyl
acetate gave 0.07 g. (31~)
TLCRf 0.42 (9/1 chloroform/ethyl acetate); 1H NMR (CDC13,
500 MHz) b 7.49-7.43 (m, 3H), 7.40-7.36 (m, 4 H), 7.29-7.24
(m, 1 H), 7.20-7.18 (m, 2 H), 5.65-5.57 (m, 1 H), 5.22 (d, 1
H, J=17.OHz), 5.17 (d, 1 H, J=10.5 Hz), 4.98-4.92 (m, 2H),
4.80 (t, 1 H, J=8.8,Hz), 4.34 (dd, 1 H, J= 6.7, 8.8 Hz),
4.07 (d, 1 H, J=3.5Hz).
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The present invention also provides an additional novel
and favored process for preparing azetidinones and provides
intermediates useful in preparing azetidinones. More
specifically, an invention is directed to the individual
steps and a process for preparing a compound of the formula
Ia
!~
0~,,,,~~~ /
R, s
N, \
i~,
O
NwR,~
O
Ia
wherein R16 and Rl~ are as previously defined, which
comprises:
reacting an aldehyde of the formula II
O
H
R, a
II
wherein R18 is a trialkylsilane,
with an N-protected amine of the formula III
H2N R's
III
wherein R19 is a nitrogen-protecting group,
to afford an N-protected imine of the formula IV
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R' 9
i
N
'H
R,e
IV
reacting the N-protected imine of the formula IV, with 4S-
phenyloxazolidin-2-on-3-ylacetyl chloride V
fl
O
V
to afford an N-protected azetidinone VI
~ R,
O N~
O I
N
O ~R~s
VI;
desilylating and epimerizing the N-protected azetidinone VI
to afford a desilylated 4-acetylenic azetidinone
intermediate of the formula VII
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\
H
O Ni
O I
N
O ~R,e
VII;
reducing and N-deprotecting the 4-acetylenic azetidinone
intermediate of the formula VII to afford a 3-(4S-phenyl-
oxazolidin-2-on-3-yl)-4-ethenylazetidinone of the formula IX
,~~\\ /
O~ R2o
i
O
NH
O
IX'
wherein R20 is SnBu3 or B(OH)2;
functionalizing the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-
ethen-1-yl]azetidinone (IX'), in the presence of a catalyst,
with an electrophile selected from the group X-R16 wherein X
is a leaving group, and
acylating the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-
1-yl]azetidinone (IX'), to produce the substituted
oxycarbonylazetidinone of the formula Ia.
The preferred intermediates of the invention have the
formulas VI, VII, VIII, IX', IXa and IXc:
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(y\ / ~Rie
O N
~~
O I
~ N
~~19
VI
/ H
O
N/
O I
N
~R19
VII
,.v\ / H
O Ni
O I
NH
O
VIII
Rzo
O.
IX'
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0~.; ,
SnBu3
O
NH
O
IXa
i
O
(~y~. ~ B(OHk
O
/~NH
0
IXc
wherein R16, R1~, R18, R19 and R20 are as previously
de f fined .
Scheme IV depicted below further illustrates a
preferred sequence of steps for this process which is a
subject of this invention.
scHEME Iv
STEP 1
R' 9
N~
H + H2N R'9 -.
H
Rie
II III IV
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STEP 2
i
\ Ni ,'\\\\~ ,e
i
base
O ~' ~ --~,- O
O N~ ~ H N1
CI
R, a O
O / N
O ~R,s
V IV VI
STEP 3
R, 8 \
H
C O- 1
~N~
O~ I
N
U R,J ~ ~R,s
VI VII
STEP 4
\ \
~,v\ / H
/
O O
II Ni II Ni
O N O I
N
O
VII VIII
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STEP 5
/ ~~~\~ /
O N p~ Rzo
i i
O
/ N O / NH
O \R,s O
VIII IX'
STEP 6
.N R2o p. N R,s
/ NH O / NH
O O
IX' XI
STEP 7
/~ .~~\~ / ,w\\ /
O~ R, s O. 1 R
,6
i ~ N~
O NH O I
O 0 \Rn
XI Ia
where R16, R1~, R18, R19, and R20 are as previously defined.
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The traps desilylated 4-acetylenic azetidinone
intermediate (VII), prepared according to Scheme III, is
partially reduced and N-deprotected to yield the ~3-lactam
traps 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-
yl]azetidinone (IX) [STEPS 4 and 5]. Preferably, the
desilylated 4-acetylenic azetidinone intermediate (VII) is
first N-deprotected to yield the (3-lactam traps 3-(4S-
phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (VIII),
followed by the partial reduction to afford the 3-(4S-
phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone
(IX). The deprotection is preferably accomplished
employing cerric ammonium nitrate in the presence of
acetonitrile, for example, according to the method outlined
at J. Ora. Chem., 47, 2765-68 (1982).
The partial reduction of the desilylated 4-acetylenic
azetidinone intermediate (VII) or the 3-(4S-phenyl-
oxazolidin-2-on-3-yl)-4-ethynylazetidinone (VIII), is
accomplished with, for example, an organotin hydride, such
as, tributyltin hydride to furnish the desired vinyl tin
derivative as a mixture of isomers. A catalyst, for
example, a palladium catalyst, such as,
dichlorobis(triphenylphosphine)palladium, may be employed.
Alternatively, hydrostannylation of the triple bond may be
afforded by thermolysis in the presence of, for example,
2,2~-azobisisobutyronitrile (AIBN). Other reducing
reagents may be employed to afford the vinyl boronic acid
intermediate, for example catecholborane or the like. The
isomers may be separated by methods known in the art, for
example, by silica chromatography, to afford the desired 3-
(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-
yl]azetidinone (IX'). One skilled in the art would
understand that either the partial reduction or the
deprotection may be accomplished first.
- 35 The resulting traps 3-(4S-phenyl-oxazolidin-2-on-3-
yl)-4-[2-ethen-1-yl]azetidinone (IX') is functionalized by
reaction with an electrophile, X-R16, in the presence of a
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solvent, and is acylated to produce the substituted
azetidinone of the formula Ia [STEPS 6 and 7]. In the
formula X-R16, X is a leaving group such as halogen,
sulfonate or the like and R16 is as previously defined.
Functionalization is best accomplished employing a
catalyst, such as,
tetrakis(triphenylphosphine)palladium(O), and preferably in
the presence of copper(I)iodide dissolved in
tetrahydrofuran. The following R groups are preferred:
2-nitrophenyl, 4-nitrophenyl, 3-vitro-1-naphthyl, 4-nitro-
2-naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-
isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-
benzothiazolyl, 2-benzoxazolyl. More preferred R groups
include: 2-thienyl, 3-furanyl, 5-pyrimidinyl, and 3,5-
dimethylphenyl. One skilled in the art would understand
that either the partial functionalization or the acylation
of trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-
yl]azetidinone (IX') may be accomplished first, although
the functionalization with X-R16 to yield the alkenyl
substituted azetidinone (XI') preferably precedes the
acylation.
Acylation is preferably accomplished with an
appropriate chloroformate to produce the substituted
azetidinone of the formula Ia. Examples of appropriate
chloroformates include: phenyl chloroformate, 4-
chlorophenyl chloroformate, 4-fluorophenyl chloroformate,
benzyl chloroformate, 4-nitrobenzyl chloroformate,
4-chlorobutylchloroformate, 4-methoxycarbonylphenyl
chloroformate, 4-methoxyphenyl chloroformate, and
allylchloroformate.
Scheme IV provides an illustration of the preferred
sequence of steps for the present invention. However, the
order of certain steps may be altered and still afford the
compounds of formula Ia. For example, the compounds of
formula Ia may be prepared from the 4-acetylenic
azetidinone intermediate (VII) by reduction followed by
deprotection to afford the 3-(4S-phenyl-oxazolidin-2-on-3-
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yl)-4-ethenylazetidinone (IX'), followed by functionalizing
with an electrophile X-R16 and acylating (in either order).
The 4-acetylenic azetidinone intermediate (VII) may also be
deprotected first, followed by reduction to the 3-(4S-
phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX'),
followed by functionalizing with an electrophile, X-R16 and
acylation (in either order).
The following Preparations and Examples are intended
to further illustrate the synthesis of the compounds of the
present invention and are not meant to limit the invention
in any manner.
Preparation of VIII
H
O ,.~~~\
H
N~ CAN O
--
O Nip..
N O I
O
OCH3
O
Vlla VIII
The azetidinone (VIIa) (2.0 g, 5.5 mmol) was dissolved
in 140 mL of acetonitrile and the solution was cooled with
an ice/acetone bath to -15°C. Ceric ammonium nitrate
(12.1 g, 22.0 mmol) in 140 mL water was added dropwise. At
the end of the addition, ethyl acetate (200 mL) was added.
Saturated sodium bicarbonate solution was added to obtain
pH 7. After stirring for 1 hour, the mixture was vacuum
filtered through Celite. The organic layer was separated
_ 25 and the aqueous layer was extracted with ethyl acetate. The
combined organic extracts were washed with 10°s sodium
sulfite solution, brine, and saturated sodium bicarbonate
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solution. The organic solution was dried over anhydrous
sodium sulfate and concentrated by rotary evaporation. The
yellow solid was triturated with ethyl acetate to give 0.55
g of (VIII). The remaining material was purified by column
chromatography to give 0.25 g. Total yield: 0.80 g.
TLC Rf 0.20 (4/1 chloroform/ethyl acetate); 1H NMR (CDC13,
500 MHz) d 7.49-7.44 (m, 3 H), 7.37-7.35 (m, 2 H), 6.05 (s,
1 H), 4.96 (dd, J = 6.9, 8.7 Hz, 1 H), 4.76 (t, J = 8.9 Hz,
1 H), 4.69 (t, J = 2.3 Hz, 1 H), 4.28 (m, 2 H), 2.29 (d, J =
2.1 Hz, 1 H).
Preparation of IXa and IXb
N
O (,vv
O
~N Bu3SnH
ice, --
O PdCl2(PPh3)2 ~N~~, \ Sn8u3
N\ O
O H NH
O
VIII
IXa
The azetidinone VIII (1.78 g, 7.0 mmol) was dissolved
in 70 mL tetrahydrofuran.
dichlorobis(triphenylphosphine)palladium (0.10 g, 0.14 mmol)
was added and the mixture was stirred under nitrogen.
Tributyltin hydride (2.3 mL, 8.4 mmol) was added dropwise.
Near the end of the addition, hydrogen evolution and a
slight exotherm were noted. After addition was complete,
the solvent was evaporated to yield an orange oil. Column
chromatography (3/1 to 1/1 hexane/ethyl acetate) provided
2.54 g (66°s) of the desired tin intermediate (IXa)
contaminated with approximately 7~ of the oc-substituted tin
derivative. The desired tin intermediate (IXa) was carried
forward without further purification.
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TLC Rf 0.38 (1/1 hexane/ethyl acetate); 1H NMR (CDC13, 500
MHz) d 7.40-7.33 (m, 5 H), 6.32 (s, 1 H), 6.12 (m, 1 H),
5.53 (m, 1 H), 4.91 (dd, J = 6.3, 8.6 Hz, 1 H), 4.73 (t, J =
. 8.8 Hz, 1 H), 4.43 (m, 1 H), 4.24 (dd, J = 6.2, 8.8 Hz, 1
H) , 3 . 84 (d, J = 2 . 5 Hz, 1 H) , 1 .41 (m, 6 H) , 1 .27 (m, 6 H) ,
0:85 (m, 15 H).
Example 56
\ \
I ,,a~~ ~ /
S O
~Nl ~ SnBu3 + ~ ~ -Pd(PPh~)a ~N~~'~
v -
Cul o
o NH NH
O O
IXa
The tin intermediate IXa (0.198 g, 0.362 mmol) was
dissolved in 5 mL of deoxygenated tetrahydrofuran
(subsurface nitrogen purge for 1 hour). 2-Iodothiophene
(0.052 mL, 0.471 mmol),
tetrakis(triphenylphosphine)palladium(O) (0.042 g, 0.036
mmol) and copper iodide (0.0138 g, 0.0724) were added.
After stirring for 1.25 hours at room temperature, the
mixture was refluxed under a nitrogen atmosphere for 1.5
hours. Ethyl acetate (200 ml) was added and the solution
was washed with brine, saturated sodium bicarbonate
solution, and water. The organic solution was dried over
anhydrous sodium sulfate and concentrated by rotary
evaporation. The residue was dissolved in acetonitrile and
washed with hexane. Evaporation gave 0.17 g of a yellow
solid. The material was purified by column chromatography
and the desired product was obtained (0.06 g).
TLC Rf 0.24 (3/2 chloroform/ethyl acetate); 1H NMR (CDC13,
500 MHz) $ 7.41-7.32 (m, 5 H), 7.17 (d, J = 5.0 Hz, 1 H),
6.96 (m, 1 H), 6.89 (d, J = 3.4 Hz, 1 H), 6.52 (d, J = 15.7
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Hz, H), 6.23 (s, 1 H), 5.50 (dd, J = 7.1, 15.7 Hz, 1 H),
1
4.90 (dd, J 5.8,8.6 Hz, 1 H), 4.76 (t, J = 8.8 Hz, 1 H),
=
4.54 (dd, J 2.3,7.1 Hz, 1 H), 4.33 (dd, J = 5.8, 8.9 Hz,
=
1 3.96 (d, J 2.6 Hz, I H).
H), =
1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]=4R-
[2-(2-thienyl)ethen-1-yl]azetidinone.
O ~,.v~ /
,.v\\ ~ /
~N -~ 1. LiHMDS ~N \
_, v _
p 2. CICOOPh O
NH N O
O O
O /
The indicated azetidinone (0.06 g, 0.176 mmol) was
dissolved in 5 mL tetrahydrofuran and the solution was
cooled with a dry ice/acetone bath. A 1 M solution of
lithium bis(trimethylsilyl)amide in tetrahydrofuran
(0.18 mL, 0.18 mmol) Was added. After 15 minutes, phenyl
chloroformate (0.024 mL, 0.19 mmol) in 1 mL tetrahydrofuran)
was added. After 30 minutes, saturated ammonium chloride
solution was added. After warming to room temperature, the
reaction mixture was extracted with chloroform (2x) and the
organic fraction was washed with brine (lx). The organic
solution was dried over anhydrous sodium sulfate and
concentrated by rotary evaporation to give 0.09 g of a
yellow solid. Column chromatography with 9/1
chloroform/ethyl acetate gave 0.055 g (68°s) of the trans
(3-lactam, contaminated with approximately 70 of the cis
~3-lactam.
TLC Rf 0.38 (9/1 chloroform/ethyl acetate); 1H NMR (CDC13,
500 MHz) $ 7.33 (m, 11 H), 6.96 (m, 1 H), 6.90 (d, J = 3.3
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Hz, 1 H), 6.53 (d, J = 15.6 Hz, 1 H), 5.65 (dd, J = 7.8,
15.6 Hz, 1 H), 4.97 (m, 2 H), 4.81 (t, J = 8.8 Hz, 1 H),
4.37 (dd, J = 6.3, 8.9 Hz, 1 H), 4.16 (d, J = 3.5 Hz, 1 H).
Examt~le 57
\ \
O (,~~~~ i'
C Pd2(dba)3 O ,,,,w ~ / O
S Br TFP
nBu3-1- ~ /
is N,,~ \
O ~ Cul O
NH NH
O O
The compound was prepared by reacting the indicated tin
derivative IXa (0.20 g, 0.37 mmol) with 3-bromofuran
(0.042 mL, 0.475 mmol) according to the same method of
Example 7A. Tetrakis(triphenylphosphine)palladium(0) was
replaced with IO mold tris(dibenzylideneacetone)dipalladium
and 80 mold tri-2-furylphosphine. After stirring for 1 hour
at room temperature, the reaction mixture was refluxed for
16 hours. The material obtained after workup was purified
by silica plug (1/1 chloroform/ethyl acetate, then ethyl
acetate). The product collected was dissolved in
acetonitrile and washed with hexane. Evaporation gave a
yellow solid (14 mg).
TLC Rf 0.23 (ethyl acetate); 1H NMR (CDC13, 500 l~iz) 8 7.70
(m, 1 H) , 7 .35 H) , 7.00 (m,1 H) , 6 .55 (m, 1 H) , 6.25
(m, 6
(m, 1 H), 5.81 (m, H), 5.17 (m,1 H), 4.88 (m, 1 H), 4.42
1
(m, 1 H), 4.25 (m, H), 3.88 (m,1 H).
1
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1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(3-furanyl)ethen-1-yl]azetidinone.
\ ~\
0
o~.,,,,v i
o~,,,~~~ i
l 0
\ ~ ~ TEA N~~,, \
CICOOPh
NH
O \
O
The indicated azetidinone (14 mg, 0.043 mmol) was
dissolved in methylene chloride (1 mL). A catalytic amount
of 4-dimethylaminopyridine was added, followed by
triethylamine (0.06 mL, 0.43 mmol). After 5 minutes, phenyl
chloroformate (0.022 mL, 0.17 mmol) was added. After 30
minutes, chloroform was added and the solution was washed
with saturated ammonium chloride solution (3x) and brine
(1x). The organic solution was dried over anhydrous sodium
sulfate and concentrated by rotary evaporation to give 0.039
g of an orange solid. Trituration with hexane/ethyl acetate
followed by a silica plug with 1/2 hexane/ethyl acetate gave
the desired compound (5.5 mg).
TLC Rf 0.27 (2/1 chloroform/ethyl acetate); 1H NMR (CDC13,
500 MHz)8 7.31 13 H), 5.87 (d, J = 14.1 Hz, 1 H), 5.33
(m,
(m, 1 H), 4.93 2 H), 4.79 (t, J = 8.8 Hz, 1 H), 4.35
(m,
(dd, J = 6.6, 8.5 Hz, 1 H), 4.07 (d, J = 3.3 Hz, I H).
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Example 58
O ,,w ~ /
Pd2(dba)3 .,~~~~ J , N
g~ ASPH3 O~' ~ N
~N~~ ~ SnBu3~-
N ~ N~,
. o ~ ~ Cul
NH o
O N NH
O
!Xa
The indicated azetidinone was prepared by reacting the
indicated tin derivative IXa (0.30 g, 0.55 mmol) with
5-bromopyrimidine (0.11 g, 0.71 mmol) according to the
method of Example 7A.
Tetrakis(triphenylphosphine)palladium(0) was replaced with
mol% tris(dibenzylideneacetone)dipalladium and 80 mold
triphenylarsine. The reaction mixture was refluxed for 4
hours. The material obtained was dissolved in ethyl acetate
and washed with 1 N hydrochloric acid solution (4x). The pH
of the aqueous fractions was adjusted to 6 with 5 N sodium
hydroxide solution, then to 8.5 with saturated sodium
15 bicarbonate solution. The product was extracted from the
basic aqueous fraction with ethyl acetate (3x). The organic
solution was dried over anhydrous sodium sulfate and
concentrated by rotary evaporation to yield the desired
product as a white solid (28 mg).
TLC Rf 0.23 (ethyl acetate); 1H NMR (CDC13, 500 MHz) 8 9.09
(s, 1 H), 8.55 (s, 2 H), 7.35 (m, 5 H), 6.54 (s, 1 H), 6.31
(d, J = 16.1 Hz, 1 H), 5.80 (dd, J = 6.5, 16.0 Hz, 1 H),
4, 90 (dd, J = 5.4, 8.7 Hz, 1 H) , 4.79 (t, J = 8.9 Hz, 1 H) ,
4.59 (dd, J = 2.1, 6.6 Hz, 1 H), 4.37 (dd, J = 5.3, 8.9 Hz,
1 H)) 3.98 (d, J = 2.7 Hz, 1 H).
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1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(5-pyrimidinyl)ethen-1-yl]azetidinone.
N
O ~,,~w / / N ~ / N
O ~,.,~~~~ / N
N~~~, ~ TEA
N~~~
I CICOOPh
NH ~
O N
p
(ix) fix) O,
i
The indicated azetidinone compound (28 mg) was utilized
to prepare compound 1-phenyloxycarbonyl-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(5-pyrimidinyl)ethen-1-
yl]azetidinone. by the same method as Example 8B.
Recrystallization with diethyl ether/ethyl acetate provided
the desired compound (18 mg).
TLC Rf 0.52 (ethyl acetate); 1H NMR (CDC13, 500 Ngiz) b 9.15
(s, 1 H), 8.59 (s, 2 H), 7.35 (m, 8 H), 7.19 (d, J = 7.9 Hz,
1 H), 6.33 (d, J = 16.1 Hz, 1 H), 5.98 (dd, J = 7.5, 16.1
Hz, 1 H), 5.02 (dd, J = 3.5, 7.4 Hz, 1 H), 4.95 (dd, J =
5.8, 8.5 Hz, 1 H) , 4.84 (t, J = 8.8 Hz, 1 H) , 4.43 (dd, J =
5.8, 8.9 Hz,l H), 4.18 (d, J = 3.6 Hz, 1 H).
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Examt~le 59
\ \ HsC
~ o~,aAV
I CH3 Pd2{dba)s ,,w
N~~ ~ SnBu3-~- ~ ASPh3 C~ CH3
I ~N,,.
o ( \ Cul ~
NH NH
CH3 O
IXa
The indicated azetidinone compound was prepared by
reacting the indicated tin derivative IXa (0.20 g,
0.37 mmol) with 5-iodo-m-xylene (0.11 g, 0.48 mmol)
according to the same method as Example 7A.
Tetrakis(triphenylphosphine) palladium(0) was replaced with
10 mol% tris(dibenzylideneacetone)dipalladium and 80 mol%
triphenylarsine. The reaction mixture was refluxed for 1.5
hours. The material obtained after workup was purified by
silica plug (1/1 chloroform/ethyl acetate). The product
collected was dissolved in acetonitrile and washed with
hexane (4x). Evaporation gave a yellow solid (0.044 g)
which was further purified by radial chromatography (1/1
hexane/ethyl acetate) to provide >90o pure product by NMR.
TLC Rf 0.20 (1/1 hexane/ethyl acetate); 1H NMR (CDC13, 500
MHz) 8 7.35 (m, 5 H), 6.91 (s, 1 H), 6.82 (s, 2 H), 6.45 (s,
1 H), 6.35 (d, J = 15.8 Hz, 1 H), 5.66 (dd, J = 7.1, 15.8
Hz, 1 H), 4,90 (dd, J = 6.0, 8.5 Hz, 1 H), 4.75 (t, J = 8.8
Hz, 1 H), 4.57 (dd, J = 1.6, 6.9 Hz, 1 H), 4.29 (dd, J =
6.0, 8.8 Hz, 1 H), 3.98 (d, J = 2.4 Hz, 1 H).
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I-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-
[2-(3,5-dimethylphenyl)ethen-1-yl]azetidinone.
H3C
~ HsC
cH ° .,,,,,, l
N 3 CH3
ice. \ \
TEA ~N''~
O -
NH CICOOPh O N
O ~° \
O
The indicated compound (0.044 g) was utilized to
prepare 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(3,5-dimethylphenyl)ethen-1-yl]azetidinone by the
same method as Example 8B. Recrystallization with diethyl
ether/ethyl acetate provided the desired compound (0.032 g).
TLC Rf (CDC13, 500
0.65
(1/1
hexane/ethyl
acetate);
1H
NMR
MHz) 8 7 H), 7.24 (m, H), 7.18 (d, = 7.9 Hz,
7.38 1 J 2
(m,
H) , 6 (s, H) , 6 .84 (s, 6.43 (d, J = 15 . 8 Hz,
.93 1 2 H) , 1
H), 5.85 (dd, = 7.7, 15.8 Hz, H), 5.07 (dd, J = 3.6, 7.6
J 1
Hz, 1 4.98 (dd, J = 6.7, 8.5 Hz, 1 H), 4.81 (t, J = 8.8
H),
Hz, 1 4.36 (dd, J = 6.7, 8.8 Hz, 1 H), 4.16 (d, J = 3.6
H),
Hz, 1
H)
.
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Example 50
trans-1-isopropoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
(,~~~~~ , / Solvent
O DMAP ,..~~~ ~ / /
O
TEA
\ \ N
\ \ N
O O .,,
O
O ~ ~R N O-CH(CH )
3 2
O
The trans deprotected azetidinorie (vi) (0.1 g, 0.3003 mmol)
was dissolved in 5 ml methylene chloride at room
temperature. Triethylamine (0.084 ml, 0.6006 mmol) and DMAP
(catalytic) were added all at once. Isopropyl chloroformate
(1.0 M soln. in toluene, 0.6 ml) was added dropwise at room
temperature. The resulting solution was stirred overnight
at room temperature, and then purified over silica gel to
provide 73 mg product. FD-MS=420.9
Theory Found
C 65.55 65.67
H 5.50 5.36
N 9.97 9.86
The compounds of Examples 61 through 73 were prepared
according to the procedure of EXAMPLE 60, employing 5
equivalents of the appropriate chloroformate.
Exam>Jle 61
trans-1-sec-butoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
- 25 yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
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Nip \ / N
,, ,.
O
N
O ~O
// CH3
O
CH3
Yield: 41 mg white solid: MS=435
Example 62
traps-1-g-nitrobenzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
0~,~,~\1\
/ \
Nip \ / N
,, ,.
O
--N
O ~O
O
O~N
O
Yield: 75 mg product off-white solid: MS=
Theorv Found
C 58.56 59.09
H 4.21 3.96
N 10.17 10.14
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Example 63
traps-1-ethoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
N \ ~ /N
~i~~ ~/ v
O
O
O
HsC
Yield: 52 mg product; MS=406
Example 64
traps-1-[2-(2-isopropyl-5-methyl)cyclohexyl]oxycarbonyl-3R-
[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-
1-yl]azetidinone
Nor \ / N
,, ,.
O
H3
Yield: 34 mg product; M5=517.6
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Example 65
trans-1-methoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
0
Nip \ / N
,,
O
-N
O ~O
/O
~CH3
Yield: 61 mg white solid; MS=393.1
Example 66
trans-1-benzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl,)ethen-1-yl]azetidinone
0
Nip \ / N
,,
O
~---N
O ~O
O
Yield: 69 mg solid; MS=469
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Example 67
trans-1-cyclohexyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
O
/ N
v
O
O
Yield: 24 mg solid; MS=461.5
Example 68
trans-1-cyclobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
I~
O ~,,,,~~
Nip ~ / N
O
-N
O ~O
O
Yield: 31 mg white solid; MS=433.4
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Examble 69
trans-1-cyclopentyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
l~
0
Nip \ / N
,,
0
~- N
O ~O
O
Yield: 27 mg foam; MS=447.5
Examble 70
trans-1-allyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl}ethen-1-yl]azetidinone
O ~,,~w\\
Nip \ / N
0
~~--N
O ~O
O
1o CH2
Yield: 63 mg white foam; MS=419
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Example 71
trans-1-n-butoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
O ~,,.~~\\
/ ~ \~
N~~ \ / N
,,
O
Yield: 71 mg yellow solid; MS=435.2
Example 72
trans-1-isobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
/ \
O ~,..~\\\
Nip \ / N
,,
O
O
H3C
CHs
Yield: 50 mg white solid; MS=435.2
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Example 73
traps-1-vinyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
lw
0
I
N~. \ / N
O
O
O
H2C
Yield: 17 mg solid; MS=405.4
Example 74
traps-1-[benzoxazol-2-yl)-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (vii)
\ \
(,,.w / \~ O ,,.w / \
\ ~ N ~ ~ ~~CI ~N~~ \ ~ N
U ~ N ~ U
O N CH2C12,Et3N O N
O H DMAP p ~O
(vi) (vii)
To a solution of the traps deprotected azetidinone (vi)
(0.23 g, 0.67 mmol) in 4 mL of dichloromethane were added
triethylamine (0.68 g, 6.7 mmol), catalytic
dimethylaminopyridine (DMAP) and 2-chlorobenzoxazole
(0.21 g). The resulting mixture was stirred for 5 hours
then diluted with ethyl acetate. The organic solution was
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extracted with one portion each of a 0.5 N hydrochloric acid
and 1 N hydrochloric acid aqueous solution. The aqueous
extracts were combined and the pH was adjusted to
approximately 7 by the addition of a saturated sodium
bicarbonate solution. The mixture was extracted with ethyl
acetate and the organic solution was dried over sodium
sulfate, filtered and concentrated by rotary evaporation.
The residue was purified by silica gel chromatography (ethyl
acetate). The product was concentrated from chloroform (2X)
and dried at 40 °C to give 0.12 g of the compound of Formula
(vii) (34~ yield).
Spectral data were collected from two lots of material
prepared in similar fashion which contained approximately
0.5 equivalents of water.
TLC Rf (EtOAc) 0.44; 1H NMR (CDC13, 300 MHz) 8 8.5 (br s,
1H), 8.4 (br s, 1H), 7.57-7,21 (m, 21H), 6.45 (d, 1H,
J=15.9Hz), 5.94 (dd, 1H, J=7.5, 15.9Hz), 5.19 (dd, 1H,
J=3.15, 7.5Hz), 4.97 (dd, 1H, J=5.8, 8.6 Hz), 4.82 (t, 1H,
J=8.8 Hz), 4.40 (dd, 1H, J=5.8, 8.8 Hz), 4.35 (d, 1H, J=3.3
Hz); IR (CHC13) 1799, 1760, 1624, 1574 cm 1; MS (FD+) 452;
Anal. Calcd. for C17H15N105 (1/2 H20): C, 67.67; H, 4.59; N,
12.14; Found: C, 67.88; H, 4.57; N, 11.96.
Examt~le 7 5
trans-1-[4,6-dimethoxy-1,3,5-triazin-2-yl]-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone (viii)
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\ CI \ OCH3
N /N ~ /
N~ ~ /N ~ O N~~ ~ /N
OCH,, ~ ~ _
O N CH2CI2,i-Pr2NEt O
O H DMAP O N
OCH
N ~ s
>=N
H3C0
(vi) (viii)
To a solution of the trans deprotected azetidinone (vi)
(0.18 g, 0.53 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-
triazine (0.19 g, 1.1 mmol) in 5 mL dichloromethane, was
added N,N-diisopropylethylamine (0.34 g, 2.63 mmol) and a
catalytic amount of dimethylaminopyridine (DMAP). The
contents were stirred under a nitrogen atmosphere for 3
hours. The mixture was diluted with dichloromethane and
washed with a saturated ammonium chloride solution. The
organic layer was dried over sodium sulfate, filtered and
concentrated. The residue was purified by silica gel
chromatography (gradient 100% hexane to 75% ethyl acetate in
hexane) to give 0.04 grams of the desired compound (viii)
(16~ yield).
TLC Rf (EtOAc) 0.26; 1H NMR (CDC13, 300 MHz) b 8.4 (br s,
2H), 7.5-7.3 (m, 7H), 6.31 (d, 1H, J=15.9 Hz), 5.90 (dd, 1H,
J=7.2, 15.9 Hz), 5.08 (dd, 1H " J=2.5, 6.8 Hz), 4.95 (m,
1H), 4.80 (t, 1H, J=8.6 Hz), 4.37 (dd, 1H, J=5.4, 8.6 Hz),
4.17 (d, 1H, J=3.1 Hz), 3.96 (s, 5H).
The compounds of Examples 76, 77 and 78 (trans-1-[4-
trifluoromethylpyrimid-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (ix);
trans-1-[6-nitropyridin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (x); and
trans-1-[2-phenylquinazol-4-yl]-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yI)ethen-1-yl]azetidinone (xi))
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were prepared by dissolving the traps deprotected
azetidinone (vi, 100 mg, 0.3003 mmole) in methylene chloride
(5 ml) at room temperature. Triethylamine (0.21 ml, 4.5
mmole) and catalytic DMAP were added all at once and the
mixture was stirred. The appropriate chlorinated
heterocycle (5 equivalents) (2-chloro-4-
(trifluoromethyl)pyrimidine; 2-chloro-5-nitropyridine; or 4-
chloro-2-phenylquinazoline) was added to the stirred
reaction mixture and the reaction was stirred over night at
room temperature. The resulting residue was purified using
silica gel to give the desired product.
Example 76
traps-1-[4-trifluoromethylpyrimid-2-yl]-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone (ix)
!~
,,
,N
O
CF3
(ix)
Yield: 27 mg; MS=481.1
Example 77
traps-1-[5-nitropyridin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (x)
' 25
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O
N
O
N~
N02
!w
o ,,,,,\\
i
N
N~
(x)
Yield: 33 mg; MS=457.1
Examble 78
trans-1-[2-phenylquinazol-4-yl]- 3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (xi)
O
N
N~~~) ~ wr
O
O N ~N
r
N
i
(xi)
Yield: 18 mg; MS=539
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Example 79
trans-1-[benzoxazol-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone
(~~~\\ ~ /
N~,
O
N
O O
N
To a solution of (vi) (0.134 g, 0.40 mmol) in 10 mL
dichloromethane. Diisopropylethylamine (0.2 g, 1.2 mmol)
was added followed by 2-chlorobenzoxazole. The resulting
mixture was stirred overnight. Dimethylaminopyridine
(0.098 g, 0.8 mmol) was added and stirring was continued for
4 h. The mixture was diluted with ethyl acetate and washed
with brine. The organic layer was dried over sodium
sulfate, filtered and concentrated to an oil. The residue
was purified by silica gel chromatography (1:1 hexane: ethyl
acetate). Further purification was accomplished by
recrystallization from acetonitrile to give 20 mg of the
desired product.
1H NMR (CDC13, 300 MHz) 8 7.59 - 7.19 (m, 14 H), 6.54 (d,
1H, J=15.9Hz), 5.88 (dd, 1H, J=7.7, J=15.8 Hz), 5.22 (dd,
1H, J=3.0, J=7.6 Hz), 4.96 (dd, 1H, J=6.3, J=8.6 Hz), 4.80
(t, 1H, J=8.8Hz), 4.36 (dd, 1H, J=6.3, J=8.9 Hz), 4.32 (d,
1H, J=3.3 Hz).
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Example 80
cis-1-[benzoxazol-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(phenyl)ethen-1-yl]azetidinone
o n
0
0
To a solution of the indicated 3,4-cis-~3-lactam isomer (0.4
g, 1.2 mmol) in 4 mL dichloromethane was added triethylamine
(1.2 g, 11 mmol) followed by 2-chlorobenzoxazole (0.36 g,
2.4 mmol). Dimethylaminopyridine (--0.05 g, 0.4 mmol). The
resulting mixture was stirred overnight. The mixture was
diluted with ether and washed with 0.5 N HC1 followed by
sequential washes with a saturated solution of sodium
bicarbonate then brine. The organic phase was dried over
sodium sulfate, filtered and concentrated to an oil. The
residue was purified by silica gel chromatography (1:1
hexane: ethyl acetate).
TLC Rf (1:1 hexane:ethyl acetate) 0.64; 1H NMR (CDC13, 300
MHz) d 7.56-7.20 (m, 14H), 6.90 (d, 1H, J=l6Hz), 6.31 (dd,
1H, J=8.6, J=l6Hz), 5.10 (dd, 1H, J=5.8) J=8.7 Hz), 4.90 (t,
1H, J=8.4 Hz), 4.76 (d, 1H, J=5.7 Hz), 4.68 (t, 1H,
J=8.9Hz), 4.23 (t, 1H, J=8.0 Hz).
The thioamidoazetidinone compounds of the present
invention may be prepared by various methods known in the
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art. Scheme V is a preferred method for preparing certain
preferred thioamidoazetidinone compounds of the formula Ib:
_ /
,,~~ \
O /
w \ N
p t H
O N~N.R2s
S
Ib
where R23 is phenyl, benzyl, naphthyl or furfuryl;
where the phenyl, naphthyl or aromatic ring of benzyl may be
substituted with one to four halo, trifluoromethyl or
C1-C6 alkyl groups; or a pharmaceutically acceptable salt or
solvate thereof.
SCHEME V
/ S=C=N-R2a O N,, ~ (N
O~N~, ~ N LiHMDS O N N-R2s
THF p
N. S
O H
(vi) (Ib)
where R23 is as previously defined.
Preparation of the compound of Formula Ib is carried
out by dissolving the trans deprotected azetidinone (250 mg,
0.7462 mmole, vi) in dry tetrahydrofuran. The mixture is
' cooled to around -78 °C using an ice/acetone bath. Lithium
(bis(triethylsilyl)amide (125 mg, 0.7462 mmole) in
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tetrahydrofurnan (0.75 ml, 1M) is then slowly added to the
reaction mixture. The reaction is stirred for 30 minutes.
The appropriate isothiocyanate (2 equivalents) is then added
and the reaction is stirred for 30 minutes. The appropriate
isothiocyanate is commercially available and can be made by
methods known in the art. The reaction is allowed to warm
to room temperature. The reaction is then purified over
silica gel to give the compound of Formula Ic.
The following Examples are intended to further
illustrate the synthesis of the compounds of the present
invention and are not meant to limit the invention in any
manner.
Example 81
traps-1-phenylthioamido-3R-[45-phenyl-oxazolidin-2-on-3-yl]-
4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
(,, ~ il
\
O O
~. ~ N ~-N N
O N O S I \
O vH /
(vi )
The traps deprotected azetidinone (vi) (250 mg, 0.7462 mmol)
was dissolved in 125 ml of dry tetrahydrofuran and cooled to
-78 °C using an ice/acetone bath. Lithium
bis(triethylsilyl)amide (125 mg, 0.7462 mmole) in 0.75 ml of
tetrahydrofuran (1M) was slowly added to the mixture. The
mixture was stirred for 30 minutes. Phenyl isothiocyanate
(263 mg) was added and the reaction mixture was stirred for
minutes. The resulting solution was stirred overnight,
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allowed to reach room temperature, and then purified over
silica gel to provide the desired product. MS=470
The compounds of Examples 82 through 89 were prepared
according to the procedure of EXAMPLE 81, employing 2
equivalents of the appropriate isothiocyanate.
Example 82
trans-1-[2-bromophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
~~ /
O~N
O
0
(2-bromophenyl isothiocyanate)
Yield: 266 mg white solid: MS=549
Example 83
trans-1-[3-fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin
2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
~~ /
N
O
N'/'S
~O
HN
_ /
(3-fluorophenyl isothiocyanate)
Yield: 210 mg white solid: MS=488
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Example 84
trans-[2-fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-
on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
.~ /
N
O
O N '~S F
HN
i~
(2-fluorophenyl isothiocyanate)
Yield: 100 mg product; MS=488
Example 85
trans-1-[4-fluorophenylthioamido]oxycarbonyl-3R-(4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone
~~ /
,, \ N
O
N ( /'S
O
HN
/)
F
(4-fluorophenyl isothiocyanate)
Yield: 40 mg tan solid; MS=488
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Examble 86
trans-1-[2,3,5,6-tetrafluorophenylthioamido]-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone
\ N
O ~-N S
O ~ F
HN F
i~
F
F
(2,3,5,6-tetrafluorophenyl isothiocyanate)
Yield: 20 mg white solid; MS=541.8
Example 87
trans-1-[3-furfurylthioamido-3R-[4S-phenyl-oxazolidin-2-on-
3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
O
\N
o ~
N~S
O
HN
O
(3-furfuryl isothiocyanate)
. Yield: 70 mg tan solid; MS=473.9
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Example 88
trans-2-naphthylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-
yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone
~~ /
I
\N
o I
0
(2-naphthyl isothiocyanate)
Yield: 55 mg white solid; MS=520
Examt~le 89
trans-1-[4-trifluoromethylphenylthioamido]-3R-[4S-phenyl-
oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-
yl]azetidinone
\
.~ /
~ I
0 N
wN
o I
N~S
O
HN
CF3
(4-trifluoromethylphenyl isothiocyanate)
Yield: 30 mg yellow foam; MS=538.0
The biological activity of the compounds of the present
invention was evaluated by an initial screening assay which
measures the inhibition of the proteolytic activity of PSA
by the compound being tested.
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Colorimetric Assav for PSA Inhibitors
Compounds were tested to determine the IC50 value
(inhibitory concentration 50~) of PSA inhibition following a 2
hour pre-incubation of compound with PSA [prostate-specific
antigen-protein concentration 0.72 mg/ml (25.3 uM) in 50
PBS/Glycerol stored at -20°C; molecular weight = 28,433 g/mole;
specific activity of PSA was determined experimentally to be 155
mmol/hr/mg protein using the Beer-Lambert Law]. Two different
PBS/BSA Buffers were used: Buffer A which comprised PBS + 0.7 mg
BSA/ml used for dilution of PSA and Buffer B which comprised PBS
+ 6.3 mg BSA/ml used in the reaction mixture to prevent non-
specific binding of the PSA to the microtiter plate. Both
buffers were stored at 4°C. Disposable, non-sterile, polystyrene
(not treated), 96 well, flat-bottom, microtiter assay plates from
Corning (Catalog #25880-96) were used. A Bio-Tek Instruments,
Inc. Microtiter Plate Reader, CERES W900HDi, was used to read
the colorimetric changes. Dual wavelengths reading at 405 nm with
a reference wavelength of 450 nm were utilized when assessing
optical density changes.
The peptide substrate (Me0-Suc-Arg-Pro-Tyr-pNA) was
commercially obtained from Pharmacia Hepar [Chromogenix S-2586 [a
chromogenic substrate for chymotrypsin; Catalog no. S-2586 (25 mg
vials); molecular weight =705.3; stored at room temperature (kept
dry) until reconstituted; reconstituted in PBS at 10 mM (7.05
mg/ml) and stored at 4°C as described by the product insert].
The PBS was Gibco BRL Dulbecco's Phosphate-Buffered Saline 1X (D-
PBS) (Catalog No. 14040-026) stored at 4°C. The BSA (Bovine
Serum Albumin) was obtained from Sigma (Catalog No. #A-7511),
stored at 4°C.
PBS/BSA solutions, and the substrate solution (3546 ml
PBS/25 mg substrate) were removed from the refrigerator and
warmed to 37°C for at least 30 minutes. 1-5 mg of PSA test
compound (in the form of a solid or oil) was weighed out and
diluted with DMSO to obtain an inhibitor stock solution of 300
uM. Serial dilutions of the inhibitor stock solution were
carried out in a 96 well microtiter plate using DMSO to obtain
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the following inhibitor concentrations in the final reaction
mixture. The final concentrations were 100; 33; 10; 3; 1; 0.3;
0.1; 0.03; and 0.01 uM. The outer wells of the plates were not
used. The plates consisted of rows A-H and columns 1-12. Well
B2 served as an experimental blank in all experiments.
ul of PBS buffer B Was added to all reaction wells
including well B2. 10 ul of DMSO was added to well B2 as well as
to "no inhibitor control" wells) (B10, C10, D10, E10, F10, G10,
H10).
10 10 ul of test compound (final cons. 100; 33; 10; 3; 1; 0.3;
0.1;0.03; 0.01 uM) was added in singlicate, to remaining wells
(B1-9, C1-9, D1-9, E1-9, F1-9, G1-9 and H1-9).
10 ul of stock PSA was diluted with 610 ul PBS Buffer A.
10 ul of PBS + 0.7 mg BSA/ml was added to well B2. 10 ul of
diluted PSA (40 nM final concentration) was added to all wells
containing inhibitor and to the "no inhibitor control" well(s).
The microtiter plate was gently shaken (manually) to ensure
adequate mixing of well contents, wells were sealed with parafilm
and preincubated for 2 hours at 37°C. Following pre-incubation,
70 ul of substrate stock solution (1 mM final concentration) was
added to all wells. Reaction progress, PSA cleavage of g-
nitroaniline (g-NA) from the substrate resulting in appearance of
yellow color, was monitored for the ensuing 10 minutes. Twenty
optical density readings on each well were automatically taken
and stored by the instrument.
Following completion of data accumulation, printouts of the
reaction profile in all wells were obtained. Reaction velocities
(slope in terms of mO.D./minutes) were plotted against inhibitor
concentrations to determine the inhibitory concentration at 50~
inhibition (IC50).
The IC50 values were determined using non-linear analysis.
Compounds demonstrating less than 50o inhibition at the highest
inhibitor concentration (generally 100 uM) were assigned an IC50
value of ">~~ the highest concentration. Compounds demonstrating
greater than 50~ inhibition at the highest inhibitor
concentration were modeled with non-linear analysis and assigned
an ICSp value.
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Colorimetric assav results:
Example # IC50 uM
1 o.2a
2 0.24
3 0.30
4 0.69
5 0.39
6 0.28
7 0.44
8 0.52
0.51
10 0.64
11 0.68
12 1.71
13 1.72
14 1.92
15 1.85
16 2.49
17 3.85
18 3.07
19 4.28
20 9.29
21 0.21
22 17.50
23 18.5
24 19.1
25 23.7
27 0.13
28 0.21
29 0.31
30 0.14
31 0.34
32 0.95
33 13.03
34 0.13
35 1.27
36 0.38
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37 1.59
38 1.04
39 >100
40 >100
41 36.61
42 >100
43 49.69
44 22.13
45 1.19
46 2.87
47 4.43
48 4.99
49 6.56
50 1.2
51 0.62
52 1.62
53 0.18
54 0.24
55 11.08
56 0.7
57 15.47
58 0.33
59 0.15
60 11
61 20.32
62 27.95
63 5.4
64 >3 0
65 6.68
66 >30
67 12 . 3
68 3.78
69 19.4
70 7.48
71 23.4
72 38.5
73 1.07
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74 0.20
75 0.035-0.045
76 8.1
77 2.31
78 10.12
79
81 .0583
82 .0353
10 83 19.1
84 0.275
0.832
86 20.85
87 >22.6
15 88 >100
89 >100
HPLC Assav Far PSA Inhibitors
Compounds were tested to determine the IC50 value
20 (inhibitory concentration 50~) of potential PSA inhibitors
following a 2 hour pre-incubation of the potential inhibitor
with PSA. The substrate used was a 10 amino acid peptide
synthesized on an ABI 433 peptide synthesizer using FMOC
chemistry with HBTU activation. Standard cycles supplied
25 with the instrument were used. The peptide was cleaved from
the resin and deprotected using 80~ Trifluoroacetic acid
(TFA), 5~ thioanisol, 7.5~ phenol, and 2.5°s ethanedithiol.
Crude peptide was purified by C-18 reversed phase HPLC and
characterized by amino acid analysis and electrospray mass
30 spectrometry. The amino acid sequence for the peptide
substrate was modeled from the experimentally proposed
interaction of PSA with bovine milk casein. The peptide has
the following sequence: SGAWYYVPLG [SEQ ID N0:1] (serine-
glycine-alanine-tryptophan-tyrosine-tyrosine-valine-proline-
35 leucine-giycine) and a molecular weight of 1111.1 g/mol.
The substrate was stored as a lyophilized solid at -20°C
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until reconstituted. Prior to the assay, the substrate was
reconstituted in phosphate buffer saline (PBS) at 0.1 mg/ml.
The lyophilized substrate and PBS were removed from the
freezer and warmed to room temperature for at least 30
minutes before use.
1-5 mg of each compound to be tested (in the form of a
solid or oil) was weighed out and diluted (DMSO) to obtain a
compound primary stock solution of 300 uM. Serial dilutions
(1:10)of each PSA inhibitor test compound primary stock
solution were carried out using DMSO to obtain the following
additional stock solution concentrations 30, 3, 0.3 uM. The
primary stock solution was labelled "A". The remaining
stock solutions were labelled "B", "C", and "D"
(corresponding to 30, 3 and 0.3 mM). The final
concentrations of the compound to be tested in the reaction
vials were 30, 3, 0.3, and 0.03 uM respectively.
The following depicts how the samples were tested,
including the volumes of each component utilized. Amounts
are in ul. I1 through I8 are the test samples. C1 through
C3 are the controls with enzyme and substrate only. S1 is
substrate only. P1 is enzyme only.
30ouM 3ouM 3uN! .3uM
A B C D DMSO Substrate PSA Tot.Vol
I1 10 0 0 0 0 80 10 100
I2 &.6 0 0 0 3.4 80 10 100
I3 0 10 0 0 0 80 10 100
I4 0 6.4 0 0 3.4 80 10 100
I5 0 0 10 0 0 80 10 100
I6 0 0 6.4 0 3.4 80 10 100
I7 0 0 0 10 0 80 10 100
I8 0 0 0 6.4 3.4 80 10 100
C1 0 0 0 0 10 80 10 100
C2 0 0 0 0 10 80 10 100
C3 0 0 0 0 10 80 10 100
S1 0 0 0 0 10 80 0 100
P1 0 0 0 0 10 0 10 100
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80 ul of substrate (with a final concentration of
72 uM) was added to all vials) except P1. 100 ul of stock
prostate-specific antigen [PSA-protein concentration 0.72
mg/ml (25.3 uM) in 50% PBS/Glycerol stored at -20 C;
molecular weight 28,433 g/mole; the specific activity of PSA
was determined experimentally to be I55 mmol/hr/mg protein]
was diluted with 620 ul 50% PBS/glycerol. 10 ul of diluted
PSA (357 nM final concentration) was added to all HPLC
vials, except S1 to start the reaction. All vials were
gently vortexed to ensure adequate mixing, capped, and
incubated for 2 hours at 37° C .
The reaction was terminated by adding 100 ul of 0.2%
TFA/water (trifluoroacetic acid/water) to all reaction
vials.
HPLC was used to analyze the samples. The analysis was
carried out using the following equipment and parameters:
Beckman autosampler model #507; Programmable solvent module
model #116; Diode array detector model #168; System Gold
software v.7.0; Injection volume:100 ml; Column:Vydac
Company, Cat. # 214TP5415 (4.6 mm X 250 mm) for protein and
peptide separation C-4 solid phase; Particle size: 5 um;
Pore diameter: 300 A; Detection Parameters: System Gold
Diode array scanner (model #168) detection at 210 and 280
nm.
Mobile Phase:
Solvent A = 0.1% TFA in water
Solvent B = 0.1% TFA in Acetonitrile
Gradient elution as follows:
Time %B
0 minutes 10%
5 minutes 10%
minutes 30%
36 minutes 10%
minutes 10%
35 Elution times:
peak 1 (YVPLG) . 8.5 + 0.3 minutes
peak 2 (SGAWY) . 13 ~ 0.3 minutes
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peak 3 (SGAWYY) . 19 ~ 0.3 minutes
Whole substrate peak 4 (SGAWYYVPLG) . 30 ~ 0.3 minutes
See Figure 1 for graph.
Data Analysis
The initial evaluation of each compound was carried out
at final concentrations of 30, 10, 3 and 1 uM inhibitor.
Inhibitors that demonstrated an ICSp estimate < lOUM were
re-evaluated in an 8 point concentration response (30, 10,
3, 1, 0.3, 0.1, 0.03, 0.01 uM). The System Gold software
integrated all chromatographic peaks and calculated the peak
area to be used for statistical analysis. All controls were
checked for intra-assay consistency. ~ inhibition was
plotted as a function of inhibitor concentration and
analyzed by non-linear regression. Compounds demonstrating
less than 50% inhibition at the highest inhibitor
concentration (generally 30 uM) were assigned an IC50 value
of ">" the highest concentration. Compounds demonstrating
greater than 50% inhibition at the highest inhibitor
concentration were modeled with JMPTN' [SAS Institute, Cary,
N.C.] non-linear analysis and assigned an IC50 value.
Compounds that did not inhibit PSA cleavage of the substrate
were designated as not active (NA).
HPLC assav results:
Examflle # IC50 uM
2 0.91
7 1.12
21 >30
22 0.45
23 20.10
26 0.70
27 0.84
Several of the compounds of the present invention were
tested to determine whether they inhibited other serine
proteases. The method used for testing for PSA inhibition
is the colorimetric method disclosed above. The method used
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for thrombin and tissue plasminogen activator (t-PA)
inhibition is disclosed in "A Family of Arginal Thrombin
Inhibitors Related to Efegatran", Seminars in Thrombosis and
( Hemostasis, Vol. 22, No. 2, 1996.
Example # PSA Thrombin t-PA
23 1.2 NA NA
As noted supra, the compounds of the present invention
are useful in inhibiting the proteolytic activity of PSA.
Thus, the present invention also provides a method for
inhibiting the proteolytic activity of PSA in mammals
comprising administering to a mammal in need thereof a PSA
proteoiytic activity-inhibiting dose of a compound of the
present invention.
The compounds of the present invention are useful for
inhibiting the proteolytic activity of prostate-specific
antigen and thereby for use in treating prostatic cancer in
mammals. It is preferred that the mammal to be treated by
the administration of compounds of this invention is human.
Measurements of the serum concentration of PSA have now
found widespread use in monitoring patients with PCa, as
well as in diagnosing or predicting the probability of a
patient having PCa. In normal males, PSA is present at less
than 4 ng/ml. In males, suspicions about the presence of
PCa surface once the level of PSA reaches from about 4 to
about 10 ng/ml or the change in PSA concentration over time
increases. In those males having a level of greater than
10 ng/ml, there is almost certain diagnosis of PCa.
Accordingly, the present compounds can be used to prevent
the onset of prostatic cancer, delay the onset of prostatic
cancer or decrease the likelihood of the onset of prostatic
cancer in males with elevated PSA levels, for example, in
males with a family history of the disease.
' 35 Administration of the PSA inhibitors of the present
invention alone may provide an effective course of treatment
for prostatic cancer. Still another embodiment of the
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present invention comprises the administration of PSA
inhibitors of the present invention in combination with
other known treatments to provide an effective course of
treatment for prostatic cancer.
While it is possible to administer a compound employed
in the methods of this invention directly without any
formulation, the compounds are usually administered in the
form of pharmaceutical compositions comprising a
pharmaceutically acceptable excipient and at least one
active ingredient (the compound of the present invention).
Such compositions contain from about 0.2% by weight to about
90.0% by weight of the present compound. These compositions
can be administered by a variety of routes including oral,
rectal, topical) transdermal, buccally, subcutaneous,
intravenous, intramuscular, and intranasal. Many of the
compounds employed in the methods of this invention are
effective as both injectable, oral and topical compositions.
Such compositions are prepared in a manner well known in the
pharmaceutical art and comprise at least one active
compound. See, e.a., Remincrton's Pharmaceutical Sciences,
(16th ed. 1980).
In making the compositions employed in the present
invention the active ingredient is usually mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier which can be in the form of a capsule, sachet, paper
or other container. When the excipient serves as a diluent,
it can be a solid, semi-solid, or liquid material, which
acts as a vehicle, carrier or medium for the active
ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols
(as a solid or in a liquid medium), ointments containing for
example up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable
solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill
the active compound to provide the appropriate particle size
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prior to combining with the other ingredients. If the
active compound is substantially insoluble, it ordinarily is
milled to a particle size of less than 200 mesh. If the
active compound is substantially water soluble, the particle
size is normally adjusted by milling to provide a
substantially uniform distribution in the formulation.
Some examples of suitable carriers, excipients and
diluents include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone, cellulose,
alcohol, water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents
such as talc, magnesium stearate, and mineral oil; wetting
agents; emulsifying and suspending agents; preserving agents
such as methyl- and propylhydroxybenzoates; sweetening
agents; and flavoring agents. The compositions of the
invention can be formulated so as to provide quick,
sustained or delayed release of the active ingredient after
administration to the patient by employing procedures known
in the art.
The compounds of this invention may be delivered
transdermally using known transdermal delivery systems and
excipients. Most preferably, a compound of this invention
may be admixed with permeation enhancers including, but not
limited to, propylene glycol, polyethylene glycol
monolaurate, and azacycloalkan-2-ones, and incorporated into
a patch or similar delivery system. Additional excipients
including gelling agents, emulsifiers, and buffers may be
added to the transdermal formulation as desired.
For topical administration, the compound of this
invention ideally can be admixed with any variety of
excipients in order to form a viscous liquid or cream-like
preparation.
For oral administration, a compound of this invention
ideally can be admixed with carriers and diluents and molded
into tablets or enclosed in gelatin capsules.
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The compositions are preferably formulated in a unit
dosage form, each dosage containing from about 0.05 to about
500 mg, usually about 1.0 to about 100 mg, more usually
about 1.0 to about 50 mg, of the active ingredient. The
term "unit dosage form" refers to physically discrete units
suitable as unitary dosages for human subjects and other
mammals, each unit containing a predetermined quantity of
active material calculated to produce the desired
therapeutic effect, in association with a suitable
pharmaceutical excipient.
The active compounds are generally effective over a
wide dosage range. For examples, dosages per day normally
fall within the range of about 0.01 to about 500 mg/kg of
body weight, preferably within the range of about 0.01 to
about 30 mg/kg, more preferably within the range of about
0.01 to about 10 mg/kg. In the treatment of adult humans,
the range of about 0.1 to about 5 mg/kg/day, in single or
divided dose, is especially preferred. However, it will be
understood that the amount of the compound actually
administered will be determined by a physician) in the light
of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual
compound or compounds administered, the age, weight, and
response of the individual patient, and the severity of the
patient's symptoms, and therefore the above dosage ranges
are not intended to limit the scope of the invention in any
way. In some instances dosage levels below the lower limit
of the aforesaid range may be more than adequate, while in
other cases still larger doses may be employed without
causing any harmful side effect) provided that such larger
doses are first divided into several smaller doses for
administration throughout the day.
In order to more fully illustrate the operation of the
present invention, the following formulation examples are
provided. The examples are illustrative only, and are not
intended to limit the scope of the invention in any manner.
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The formulations may employ as active ingredients
(compounds) any of the compounds of the present invention.
Formulation Preparation 1
Hard gelatin capsules containing the following
ingredients are prepared:
Quantity
Ingredient (ma/capsule)
Active Ingredient 10.0
Starch 325.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard
gelatin capsules in 340 mg quantities.
Formulation Preparation 2
A tablet formula is prepared using the ingredients
below:
Quantity
Ingredient (ma/tablet)
Active Ingredient 100.0
Cellulose, microcrystalline 125.0
Colloidal silicon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form
tablets, each weighing 240 mg.
Formulation Preparation 3
A dry powder inhaler formulation is prepared containing
the following components:
Ingredient Weight
Active Ingredient 5
Lactose g5
'' 3 5
The active mixture is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.
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Formulation Preparation 4
Tablets, each containing 30 mg of active ingredient,
are prepared as follows:
Quantity
Ingredient (ma/tablet)
Active Ingredient 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone
(as 10% solution in water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1.0 ma
1
Total 120 mg
The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The
solution of polyvinylpyrrolidone is mixed with the resultant
powders, which are then passed through a 16 mesh U.S. sieve.
The granules so produced are dried at 50-60°C and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl
starch, magnesium stearate, and talc, previously passed
through a No. 30 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet
machine to yield tablets each weighing 120 mg.
Formulation Preparation 5
Capsules, each containing 40 mg of medicament are made
as follows:
Quantity
Ingredient (ma/capsule)
Active Ingredient 40.0 mg
Starch , 109.0 mg
Magnesium stearate 1.0 ma
Total 150.0 mg
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The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 20 mesh U.S.
sieve, and filled into hard gelatin capsules in 150 mg
quantities.
Formulation Preparation 6
Suppositories, each containing 25 mg of active
ingredient are made as follows:
Ingredient Amount
Active Ingredient 25 mg
Saturated fatty acid glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh
U.S. sieve and suspended in the saturated fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2.0 g capacity and allowed to cool.
Formulation Preparation 7
Suspensions, each containing 50 mg of medicament per
5.0 ml dose are made as follows:
Ingredient Amount
Active Ingredient 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11~)
Microcrystalline cellulose (89~) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10
0
. mg
Flavor and Color
q. v.
Purified water to 5.0 ml
The medicament, sucrose and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed with
' 35 a previously made solution of the microcrystalline cellulose
and sodium carboxymethyl cellulose in water. The sodium
benzoate, flavor, and color are diluted with some of the
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water and added with stirring. Sufficient water is then
added to produce the required volume.
Formulation Preparation 8
Capsules, each containing 15 mg of medicament, are made
as follows:
Quantity
Inaredient 1ma/capsule>
Active Ingredient 15.0 mg
Starch 407.0 mg
Magnesium stearate 3.0 ma
Total 425.0 mg
The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 20 mesh U.S.
sieve, and filled into hard gelatin capsules in 425 mg
quantities.
Formulation Pret~aration 9
An intravenous formulation may be prepared as follows:
Inaredient Ouantity
Active Ingredient 250.0 mg
Isotonic saline 1000 ml
Formulation Preparation 20
A topical formulation may be prepared as follows:
Inaredient Ouantitv
Active Ingredient 1-10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
The white soft paraffin is heated until molten. The liquid
paraffin and emulsifying wax are incorporated and stirred
until dissolved. The active ingredient is added and
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stirring is continued until dispersed. The mixture is then
cooled until solid.
Formulation Preparation 11
, Sublingual or buccal tablets, each containing 10 mg of
active ingredient, may be prepared as follows:
Quantity
Ingredient Per Tablet
Active Ingredient 10.0 mg
Glycerol 210.5 mg
Water 143.0 mg
Sodium Citrate 4.5 mg
Polyvinyl Alcohol 26.5 mg
Polyvinylpyrrolidone 15.5 ma
Total 410.0 mg
The glycerol, water, sodium citrate, polyvinyl alcohol, and
polyvinylpyrrolidone are admixed together by continuous
stirring and maintaining the temperature at about 90°C.
When the polymers have gone into solution, the solution is
cooled to about 50-55°C and the medicament is slowly
admixed. The homogenous mixture is poured into forms made
of an inert material to produce a drug-containing diffusion
matrix having a thickness of about 2-4 mm. This diffusion
matrix is then cut to form individual tablets having the
appropriate size.
Another preferred formulation employed in the methods
of the present invention employs transdermal delivery
devices ("patches"). Such transdermal patches may be used
to provide continuous or discontinuous infusion of the
compounds of the present invention in controlled amounts.
The construction and use of transdermal patches for the
delivery of pharmaceutical agents is well known in the art.
See, e.cr., U.S. Patent 5,023,252, issued June 11, 1991,
herein incorporated by reference. Such patches may be
constructed for continuous, pulsatile, or on demand delivery
of pharmaceutical agents.
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Indirect techniques, which are generally preferred,
usually involve formulating the compositions to provide for
drug latentiation by the conversion of hydrophilic drugs
into lipid-soluble drugs or prodrugs. Latentiation is
generally achieved through blocking of the hydroxy,
carbonyl, sulfate, and primary amine groups present on the
drug to render the drug more lipid soluble and amenable to
transportation across the blood-brain barrier.
Alternatively, the delivery of hydrophilic drugs may be
enhanced by intra-arterial infusion of hypertonic solutions
which can transiently open the blood-brain barrier.
The type of formulation employed for the administration
of the compounds employed in the methods of the present
invention may be dictated by the particular compounds
employed, the type of pharmacokinetic profile desired from
the route of administration and the compound(s), and the
state of the patient.
