Methods of asymmetrically synthesizing enantiomers of casodex, its derivatives and intermediates thereof
First Claim
1. A method of asymmetrically synthesizing an enantiomer of an acylanilide or a derivative thereof comprising:
- (a) contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I;
wherein R1 is alkyl or haloalkyl having up to 4 carbons;
R2 is alkyl having up to 6 carbon atoms; and
R3 is CH2OR4 where R4 is hydrogen or benzyl, C(O)CH3, or C(O)OR5 where R5 is hydrogen or alkyl;
with a compound having a structure of Formula II;
R7—
R6—
X1H
Formula II wherein R6 is a direct link or alkyl having up to 6 carbon atoms;
R7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons;
or R7 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 R7 is naphthyl;
or R7 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
X1 is oxygen, sulfur, sulphinyl (—
SO—
), sulphonyl (—
SO2—
), imino (—
NH—
) or alkylimino (—
NR8—
) where R8 is alkyl having up to 6 carbon atoms;
under conditions sufficient to provide a compound having the structure of Formula III;
wherein X2 is oxygen, sulfur, sulphinyl (—
SO—
), sulphonyl (—
SO2—
), imino (—
NH—
), oxidized imino alkylimino (—
NR8—
) where R8 is alkyl having up to 6 carbon atoms, or oxidized alkylimino; and
(b) treating the compound of Formula III under conditions sufficient to provide a pure enantiomer of an acylanilide or a derivative thereof.
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Abstract
A method of synthesizing pure enantiomers of acylanalides such as Casodex® (bicalutamide) and its derivatives includes contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I:
wherein
R1 is alkyl or haloalkyl having up to 4 carbons;
R2 is alkyl having up to 6 carbon atoms; and
R3 is CH2OR4 where R4 is hydrogen or benzyl, C(O)CH3, or C(O)OR5 where R5 is hydrogen or alkyl;
with a compound having a structure of Formula II:
R7—R6—X1H Formula II
wherein
R6 is a direct link or alkyl having up to 6 carbon atoms;
R7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons; or R7 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 R7 is naphthyl; or R7 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
X1 is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO2—), imino (—NH—) or alkylimino (—NR8—) where R8 is alkyl having up to 6 carbon atoms;
under conditions sufficient to provide a compound having the structure of Formula III:
wherein X2 is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO2—), imino (—NH—), oxidized imino alkylimino (—NR8—) where R8 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 acylanalides such as Casodex® (bicalutamide) and/or derivatives thereof. In preferred embodiments, R1 is methyl, R2 is methylene, R6 is a direct link, R7 is 4-fluorophenyl, X1 is sulfur, the compound of Formula II is 4-fluorobenzenethiol, and X2 is sulphonyl. Methods of synthesizing acylanalides such as Casodex® (bicalutamide) and/or derivatives thereof from a starting material of citramalic acid are also provided.
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Citations
38 Claims
-
1. A method of asymmetrically synthesizing an enantiomer of an acylanilide or a derivative thereof comprising:
-
(a) contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I;
wherein R1 is alkyl or haloalkyl having up to 4 carbons;
R2 is alkyl having up to 6 carbon atoms; and
R3 is CH2OR4 where R4 is hydrogen or benzyl, C(O)CH3, or C(O)OR5 where R5 is hydrogen or alkyl;
with a compound having a structure of Formula II;
R7—
R6—
X1H
Formula IIwherein R6 is a direct link or alkyl having up to 6 carbon atoms;
R7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons;
or R7 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 R7 is naphthyl;
or R7 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
X1 is oxygen, sulfur, sulphinyl (—
SO—
), sulphonyl (—
SO2—
), imino (—
NH—
) or alkylimino (—
NR8—
) where R8 is alkyl having up to 6 carbon atoms;
under conditions sufficient to provide a compound having the structure of Formula III;
wherein X2 is oxygen, sulfur, sulphinyl (—
SO—
), sulphonyl (—
SO2—
), imino (—
NH—
), oxidized imino alkylimino (—
NR8—
) where R8 is alkyl having up to 6 carbon atoms, or oxidized alkylimino; and
(b) treating the compound of Formula III under conditions sufficient to provide a pure enantiomer of an acylanilide or a derivative thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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- 10. A method of forming an optically active compound having the structure of Formula III:
- 17. A method of forming an optically active compound having the structure of Formula III:
- 25. A method of forming an optically active compound having the structure of Formula III:
- 31. A method of synthesizing an optically active compound having the structure of Formula XVI:
-
36. A compound having a chemical structure of Formula IV:
Specification