Methods of asymmetrically synthesizing enantiomers of Casodex, its derivatives and intermediates thereof

A method of asymmetrically synthesizing a pure enantiomer of an acylanilide having the structure of Formula XX:

• wherein
• R6 is a direct link or alkyl having up to 6 carbon atoms;
• 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;
• 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;
• R13 is cyano, fluoro, chloro, bromo, or iodo;
• R14 is perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms;
• and
• R15 is hydrogen or halogen;
• the method comprising:
• adding a protecting group to the citramalic acid to provide a dioxolanone, wherein the protecting group protects the hydroxy acid of the citramalic acid from decarboxylation;
• then
• decarboxylating the dioxolanone to replace the carboxyl group of the dioxolanone with a leaving group;
• then
• removing the protecting group from the dioxolanone to provide a free carboxylic acid group;
• replacing the leaving group with the group —X2R6R7;
• and
• reacting the free carboxylic acid group with a compound having the structure of

A method of asymmetrically synthesizing a pure enantiomer of an acylanilide having the structure of Formula XX:

• wherein
• R6 is a direct link or alkyl having up to 6 carbon atoms;
• R7 is phenyl which bears one, two or three substituents independently selected from hydrogen and halogen;
• 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;
• R13 is cyano, fluoro, chloro, bromo, or iodo;
• R14 is perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms;
• and
• R15 is hydrogen or halogen;
• the method comprising:
• adding a protecting group to the citramalic acid to provide a dioxolanone, wherein the protecting group protects the hydroxy acid of the citramalic acid from decarboxylation;
• then
• decarboxylating the dioxolanone to replace the carboxyl group of the dioxolanone with a leaving group;
• then
• removing the protecting group from the dioxolanone to provide a free carboxylic acid group;
• replacing the leaving group with the group —X2R6R7;
• and
• reacting the free carboxylic acid group with a compound having the structure of Formula XIII:

A method of asymmetrically synthesizing a pure enantiomer of an acylanilide comprising:

• reacting citramalic acid with a compound having the structure R9C(O)R10 to provide a compound having the structure of Formula XV:
• wherein
• R9 is hydrogen, or straight, branched or cyclic alkyl;
• and
• R10 is straight or branched alkyl, aryl, or R11X34, where R11 is alkylene and X4 is alkyl, halogen or aryl;
• decarboxylating the compound of Formula XV to provide a compound having the structure of Formula XVI:
• wherein X3 is a leaving group;
• hydrolyzing the compound of Formula XVI to provide a compound having the structure of Formula XXIII:
• reacting the compound of Formula XXIII with a compound having the following structure:
• R7—R6—X2H
• wherein
• X2 is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO2—), imino (—NH—) or alkylimino (—NR8—) where R8 is alkyl having up to 6 carbon atoms;
• 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;
• to provide a compound having the following structure:
• reacting the free carboxylic acid group of the compound with a compound having the structure of Formula XIII:
• wherein
• R13 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;
• R14 is cyano, cabamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms;
• or phenylthio, phenylsulphinyl or phenylsulphonyl;
• and
• R15 is hydrogen or halogen;
• to provide a compound having the structure of Formula XX:

A method of asymmetrically synthesizing a pure enantiomer of an acylanilide or a derivative thereof comprising:

• reacting citramalic acid with a compound having the structure R9C(O)R10 to provide a compound having the structure of Formula XV:
• wherein
• R9 is hydrogen, or straight, branched or cyclic alkyl;
• and
• R10 is straight or branched alkyl, aryl, or R11X34, where R11 is alkylene and X4 is alkyl, halogen or aryl;
• decarboxylating the compound of Formula XV to provide a compound having the structure of Formula XVI:
• wherein X3 is a leaving group;
• hydrolyzing the compound of Formula XVI to provide a compound having the structure of Formula XXIII:
• reacting the compound of Formula XXIII with a compound having the structure of Formula XIII:
• wherein
• R13 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;
• R14 is cyano, cabamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms;
• or phenylthio, phenylsulphinyl or phenylsulphonyl;
• and
• R15 is hydrogen or halogen;
• to provide an aniline compound having the following structure:
• reacting the aniline compound with a compound having the following structure:
• R7—R6—X2H
• wherein
• X2 is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO2—), imino (—NH—) or alkylimino (—NR8—) where R8 is alkyl having up to 6 carbon atoms;
• 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;
• to provide a compound having the structure of Formula XX:

A method of asymmetrically synthesizing a pure enantiomer of an acylanilide or a derivative thereof comprising:

• reacting citramalic acid with a compound having the structure R9C(O)R10 to provide a compound having the structure of Formula XV:
• wherein
• R9 is hydrogen, or straight, branched or cyclic alkyl;
• and
• R10 is straight or branched alkyl, aryl, or R11X34, where R11 is alkylene and X4 is alkyl, halogen or aryl;
• decarboxylating the compound of Formula XV to provide a compound having the structure of Formula XVI:
• wherein X3 is a leaving group;
• reacting the compound of Formula XVI with a compound having the following structure:
• R7—R6—X2H
• wherein
• X2 is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO2—), imino (—NH—) or alkylimino (—NR8—) where R8 is alkyl having up to 6 carbon atoms;
• 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;
• to provide a substituted dioxolanone having the following formula:
• hydrolyzing the substituted dioxolanone to provide a free carboxylic acid compound having the following structure:
• reacting the free carboxylic acid compound with a compound having the structure of Formula XIII:
• wherein
• R13 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;
• R14 is cyano, cabamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms;
• or phenylthio, phenylsulphinyl or phenylsulphonyl;
• and
• R15 is hydrogen or halogen;
• to provide a compound having the structure of Formula XX: