Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2002-10-10
2004-11-02
Desai, Rita (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S414000
Reexamination Certificate
active
06812362
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of synthesizing organic compounds, and more particularly to methods of synthesizing pharmaceutical compounds and their derivatives.
BACKGROUND OF THE INVENTION
Androgen deprivation is a common treatment for persons with prostate cancer. Various non-steroidal antiandrogens are known for use in the treatment of prostate cancer. For example, bicalutamide is often used in the treatment of prostate cancer. Bicalutamide is commercially available as Casodex® (bicalutamide) from AstraZeneca Pharmaceuticals.
The chemical name of bicalutamide is N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl ]-2-hydroxy-2-methyl-propanamide(+−). The structural formula of bicalutamide is:
The &bgr;-carbon atom in the propanamide is a chiral carbon. As a result, bicalutamide is an optically active compound.
Such optically active compounds exist as a pair of stereoisomers that are identical with the notable exception that they are non-superimposable mirror images of one another. A specific stereoisomer, such as the R isomer, may be referred to as an enantiomer. A mixture of R and S enantiomers may be referred to as a racemic mixture.
U.S. Pat. No. 4,636,505 to Tucker proposes various methods of synthesizing racemic mixtures of bicalutamide and/or its derivatives.
In Tucker et al.,
Nonsteroidal Antiandrogens. Synthesis and Structure-Activity Relationships of
3
-Substituted Derivatives of
2
-Hydroxypropionanilides
, 31 J. MED. CHEM. 954-959 (1988), the authors propose two general synthetic routes, Scheme I and Scheme II, that may be used to prepare acylanilides.
U.S. Pat. No. 5,985,868 to Gray proposes synthesizing racemic mixtures of bicalutamide using methods as described in U.S. Pat. No. 4,636,505 to Tucker, and obtaining the (−) isomer of bicalutamide by resolution of the enantiomers of bicalutamide or of intermediates thereto using fractional crystallization or chromatography of diastereomeric esters of chiral acids. Gray notes that other standard methods of resolution such as simple crystallization and chromatographic resolution can also be used.
In Howard Tucker et al.,
Resolution of the Nonsteroidal Antiandrogen
4′-Cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3′-(trifluoromethyl)-propioanilide and
the Determination of the Absolute Configuration of the Active Enantiomer
, 31 J. MED. CHEM. 885-887 (1988), the authors propose an asymmetric synthesis of (S)-bicalutamide using the N-methacrylamide of (S)-proline as a starting material. The authors state that this approach is not suitable for the general synthesis of the active enantiomers of analogous anti-androgens, which would require the inaccessible and expensive (R)-proline as a starting material.
U.S. Pat. No. 6,019,957 to Miller et al. proposes an asymmetric synthesis of (R)-bicalutamide using (R)-proline as a starting material.
It would be desirable to provide more effective methods for synthesizing bicalutamide and/or its derivatives and/or intermediates.
SUMMARY OF THE INVENTION
Embodiments of the present invention provide improved methods for synthesizing acylanilides, particularly bicalutamide and/or its functional derivatives. Methods according to embodiments of the present invention may provide a racemic mixture of bicalutamide using commercially available reagents in fewer steps than the conventional methods described above, which may reduce the overall synthesis time by more than 50 percent compared to these methods. Methods according to embodiments of the present invention may result in yields greater than 50 percent, 60 percent, 70 percent or more. Moreover, methods according to embodiments of the present invention may be performed at or near room temperature. These reaction conditions may provide an energy savings when compared to the conventional methods described above, which involve, for example, refluxing conditions and cooling to 5° C.
According to embodiments of the present invention, methods of synthesizing an acylanilide such as bicalutamide or its functional derivatives are provided. The methods include contacting a compound having the structure of Formula I:
wherein
R
1
is substituted or unsubstituted alkyl or haloalkyl; with a compound having the structure of Formula II:
wherein
R
2
is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen; or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulfinyl, or perfluoroalkylsulfonyl each being substituted or unsubstituted and having up to 4 carbon atoms; or phenyl, phenylthio, phenylsulfinyl or phenylsulfonyl each being susbstituted or unsubstituted;
R
3
is cyano, carbamoyl, nitro, fluoro, chloro, bromo or iodo; or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulfinyl or perfluoroalkylsulfonyl each being substituted or unsubstituted and having up to 4 carbon atoms; or phenyl, phenylthio, phenylsulfinyl or phenylsulfonyl each being substituted or unsubstituted; and
R
4
is hydrogen or halogen;
under conditions sufficient to provide a compound having the structure of Formula III:
and treating the compound of Formula III under conditions sufficient to provide an acylanilide. The compound of Formula I is most preferably pyruvic acid.
In embodiments of the present invention, the compound of Formula III is additionally reacted with a compound having the structure of Formula IV:
R
5
—X
1
—R
6
—R
7
Formula IV
wherein
R
5
is substituted or unsubstituted alkyl having up to 6 carbon atoms;
R
6
is a direct link, or substituted or unsubstituted alkyl having up to 6 carbon atoms;
R
7
is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each being substituted or unsubstituted and having up to 6 carbons; or R
7
is phenyl which bears one, two or three substituents independently selected from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, perfluoroalkylsulfinyl, perfluoroalkylsulfonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulfinyl and phenylsulfonyl; or R
7
is naphthyl; or R
7
is a 5- or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each of up to 4 carbon atoms, or oxy or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents; and
X
1
is oxygen, sulfur, sulfinyl (—SO—), sulfonyl (—SO
2
—), imino (—NH—) or alkylimino (—NR
8
—) where R
8
is alkyl having up to 6 carbon atoms;
under conditions sufficient to provide an acylanilide having the structure of Formula V:
The acylanilide is most preferably bicalutamide or a functional derivative thereof. While methods according to embodiments of the present invention generally yield acylanilide compositions having both R and S enantiomers in substantially equal quantities, embodiments of the present invention resolve these acylanilide compositions (e.g., bicalutamide products) to provide compositions comprising more than about 60 percent R enantiomer.
Methods according to embodiments of the present invention provide a more efficient synthesis route for acylanilides, particularly bicalutamide and/or its functional derivatives. Methods of the present invention may reduce the number of steps as well as the overall synthesis time compared to conventional methods of synthesizing bicalutamide. Moreover, methods of the present invention may provide an overall yield that is greater than 50 percent and preferably even greater than 70 percent, which is higher than the overall yield provided by conventional methods of s
Ekwuribe Nnochiri N.
James, Jr. Kenneth D.
Barrett William A.
Desai Rita
Moore & Van Allen PLLC
Nobex Corporation
Shiao Robert
LandOfFree
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