Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2000-10-18
2003-06-24
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S397000, C349S200000
Reexamination Certificate
active
06583306
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of synthesizing organic compounds, and more particularly to methods of asymmetrically synthesizing optically active pharmaceutical compounds and their intermediates.
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, which may be among the most commonly used non-steroidal antiandrogens in the world, is typically used in the treatment of prostate cancer. Bicalutamide is commercially available as Casodex® (bicalutamide) from Zeneca 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.
Optically active compounds have the ability to rotate the plane of polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are used to denote the optical rotation of the compound (i.e., the direction in which a plane of polarized light is rotated by the optically active compound). The l or (−) prefix indicates that the compound is levorotatory (i.e., rotates the plane of polarized light to the left or counterclockwise) while the d or (+) prefix means that the compound is dextrarotatory (i.e., rotates the plane of polarized, light to the right or clockwise). The sign of optical rotation, (−) and (+), is not related to the absolute configuration of the molecule, R and S.
Optically active compounds, such as bicalutamide, 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.
Bicalutamide, is presently commercially available as a racemic mixture. The racemic mixture of bicalutamide may be synthesized by various methods including, for example, the methods described in U.S. Pat. No. 4,636,505 to Tucker. Tucker further describes various derivatives and analogs of bicalutamide having antiandrogenic properties. Tucker, however, does not disclose or suggest methods for asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its intermediates.
U.S. Pat. No. 5,985,868 to Gray proposes synthesizing racemic mixtures of Casidex® (bicalutamide) using methods as described in U.S. Pat. No. 4,636,505 to Tucker, and obtaining the (−) isomer of Casidex® (bicalutamide) by resolution of the enantiomers of Casidex® (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. Gray does not disclose or suggest methods of asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its derivatives and/or intermediates.
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)-Casodex® (bicalutamide) using the N-methacrylamide of (S)-proline as a starting material. The proposed reaction scheme is as follows:
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)-Casodex® (bicalutamide) using (R)-proline as a starting material. The proposed reaction scheme is as follows:
As noted above, (R)-proline is an inaccessible and expensive starting material. It would be desirable to provide more cost effective methods for asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its derivatives and/or intermediates that do not rely on (R)-proline as a starting material.
SUMMARY OF THE INVENTION
Embodiments of the present invention provide methods for asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its intermediates. Asymmetric synthesis methods according to embodiments of the present invention are more cost effective than conventional methods. For example, asymmetric synthesis methods according to embodiments of the present invention react 4-fluorobenzenethiol with the bromolactone of Formula 1 or 2 above. By reacting the 4-fluorobenzenethiol with the bromolactone prior to hydrolyzing the bromolactone instead of hydrolyzing the bromolactone and then reacting the 4-fluorobenzenethiol with the resulting acid as proposed above, improved separation of the reaction products and thus higher yields may be provided. Furthermore, asymmetric synthesis methods according to embodiments of the present invention produce (R)-Casodex® (bicalutamide) and/or its intermediates using (S)-citramalic acid (2-hydroxy-2-methylbutanedioic acid) as a starting material, which may be more cost effective than the conventional scheme, which uses the inaccessible and expensive (R)-proline as a starting material.
According to embodiments of the present invention, methods of asymmetrically synthesizing an enantiomer of an acylanalide such as Casodex® (bicalutamide) or its derivatives are provided. The methods include contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I:
wherein
R
1
is alkyl or haloalkyl having up to 4 carbons;
R
2
is alkyl having up to 6 carbon atoms; and
R
3
is CH
2
OR
4
where R
4
is hydrogen or benzyl, C(O)CH
3
, or C(O)OR
5
where R
5
is hydrogen or alkyl;
with a compound having a structure of Formula II:
R
7
—R
6
—X
1
H Formula II
wherein
R
6
is a direct link or alkyl having up to 6 carbon atoms;
R
7
is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of 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, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl; 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, alkylsulphinyl or alkylsulphonyl 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, sulphinyl (—SO—), sulphonyl (—SO
2
—), imino (—NH—) or alkylimino (—NR
8
—) where R
8
is alkyl having up to 6 carbon atoms;
under conditions sufficient to provide a compound having the structure of Formula III:
wherein X
2
is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO
2
—), imino (—NH—), oxidized imino alkylimino (—NR
8
—) where R
8
is alkyl having up to 6 carbon atoms, or oxidized alkylimino. The method further includes treating the compound of Formula III under conditions sufficient to provide a pure enantiomer of Casodex® (bicalutamide) or
Barrett, Esq. William A.
McKenzie Thomas C
Myers Bigel Sibley & Sajovec P.A.
Nobex Corporation
Raymond Richard L.
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