Patent EA-004934-B1 (EA)
Title: Asymmetric synthesis of pregabalin
Inventor: BURK MARK JOSEPH
IPC: C07C227/10
Filed: 2001-01-11
Abstract: 1. A method for preparing an (S)-3-cyano-5-methylhexanoic acid derivative of the formula wherein X is CO2H or CO2<->Y, and where Y is a cation; the method comprising asymmetric catalytic hydrogenation of an alkene of the formula in the presence of a chiral catalyst, wherein the chiral catalyst is a rhodium complex with a chiral ligand. 2. A method according to Claim 1 wherein X is CO2<->Y. 3. A method according to Claim 1 wherein the chiral catalyst is a rhodium complex of an (R,R)-DuPHOS ligand, the ligand having the formula wherein R is straight or branched alkyl having 1 to 6 carbon atom. 4. A method according to Claim 3, wherein the chiral catalyst is [Rh (ligand)(COD)] BF4. (COD-1,5-cyclooctadien). 5. A method according to Claim 3, wherein R is methyl or ethyl. 6. A method according to Claim 1, wherein the alkene is the E isomer or the Z isomer or is a mixture of said isomers. 7. A method according to Claim 1, wherein the cation is an alkali metal or alkaline earth metal. 8. A method according to Claim 7, wherein the alkali metal is potassium. 9. A method according to Claim 1, wherein the cation is a salt of a primary amine or a salt of secondary amine. 10. A method according to Claim 9, wherein the amine is tert-butylamine. 11. A method according to Claim 1, which further comprises first converting a carboxylic ester of the formula wherein R<1> is alkyl to the carboxylate salt of the formula where Y is a cation. 12. A method according to Claim 11, wherein R<1> is ethyl. 13. A method according to Claim 11, wherein the carboxylate salt is isolated prior to hydrogenation. 14. A method according to Claim 11, wherein the carboxylate salt is prepared in situ prior to hydrogenation. 15. A method according to Claim 8, further comprising acidifying the (S)-3-cyano-5-methylhexanoic acid carboxylate salt to form (S)-3-cyano-5-methylhexanoic acid. 16. A compound of the formula wherein X is CO2H or CO2<->Y, and where Y is a cation. 17. A compound of the formula wherein R<1> is straight or branched alkyl having 1 to 6 carbon atom. 18. A method for preparing a compound of the formula wherein R<1> is straight or branched alkyl having 1 to 6 carbon atom the method comprising asymmetric catalytic hydrogenation of an alkene of the formula in the presence of a chiral catalyst, wherein the chiral catalyst is a rhodium complex with a chiral ligand. 19. A method according to Claim 18, wherein the chiral catalyst is a rhodium complex of an (S,S)-DuPHOS ligand, the ligand having the formula wherein R is straight or branched alkyl having 1 to 6 carbon atom. 20. A method according to Claim 19, wherein the chiral catalyst is [Rh (ligand) (COD)] BF4 (COD-1,5-cyclooctadien). 21. A method according to Claim 19, wherein R is methyl or ethyl. 22. A method according to Claim 21 wherein R<1> is ethyl. 23. A method according to Claim 1 wherein the cation Y is selected from the group consisting of H+, the salt formed by reaction with a protonated primary or secondary amine, an alkaline earth metal, and an alkali metal. 24. A compound of the formula wherein Y is a cation. 25. A method according to Claim 1 which further comprises the reduction of the cyano group to form an amino group, and when Y is other than H+, protonation by reaction with an acid to produce pregabalin. 26. A process for preparing pregabalin comprising asymmetrically hydrogenating in the presence of a chiral catalyst, followed by reduction of the cyano group, and protonation to the free acid, where Y is a cation and the chiral catalyst is a rhodium complex with a chiral ligand.