Patent ID: 6605723
Filing Date: 2003-08-12
Classification: A61P,C07D

Abstract:
A process for the preparation of compounds of formulae whereinR1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts; which process comprisesa) reacting a protected amino acid ester (1) with a 4-substituted butyric acid derivative (2) whereinR9 is an amino protecting group, preferably benzyl; R10 and R10â€² are independently a carboxylic acid protecting group; and Y represents a leaving group; in the presence of a base to obtain the protected alkoxycarbonylmethyl amino butyric acid derivative (3);b) cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3) wherein the symbols are as defined above to obtain the protected alkyl 3-oxo-piperidine carboxylate salt (4);c) benzylating the protected alkyl 3-oxo-piperidine carboxylate salt (4) whereinAZ signifies a mineral acid or a strong organic acid to obtain the benzylated protected alkyl 3-oxo-piperidine carboxylate (5); d) decarboxylating the benzylated protected alkyl 3-oxo-piperidine carboxylate (5) wherein the symbols are as defined above;in presence of a strong acid to obtain the salt of formula (6);e) asymmetrically hydrogenating the salt of formula (6) wherein R9 is an amino protecting group;in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and an organic or inorganic base, to obtain the compound of formula (7a) or (7b); and deprotecting the compound of formula (7a) or (7b) wherein the symbols are as defined above; ordeprotecting the compound of formula (6); andasymmetrically hydrogenating the salt of formula (6bis) in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and a organic or an inorganic base,to obtain the piperidine derivative of formula III-a or III-b; andf) reacting the piperidine derivative of formula III-a or III-b wherein the symbols are as defined above; with the reactive vinyl sulfone intermediate which is obtained by treating the sulfone derivative of formula II whereinR1-R4 are as defined above; and X is a leaving group; with a base; in the presence of a base to form the desired compound of formula I-a or I-b.