C1-SYMMETRIC BISPHOSPHINE LIGANDS AND THEIR APPLICATION IN ASYMMETRIC SYNTHESIS OF PREGABALIN

摘要

1. A method of obtaining the desired enantiomer of a compound of formula 2 or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, wherein R 1 is C1-6alkyl, alkanoylamino, alkoxycarbonyl, alkoxycarbonylamino, amino, amino-C1-6alkyl, C1-6alkylamino, cyano, cyano-C1-6alkyl, carboxy or —CO — Y; R is Salkanoyl, Salkoxycarbonyl, carboxy or —CO — Y; R and R are independently a hydrogen atom, C1-6alkyl, Cycloalkyl, aryl, aryl-C1-6alkyl or R and R together are Salkanediyl; X is —NH—, —O—, —CH— or a bond and Y denotes a cation; the method includes: reacting a compound of formula 3 with hydrogen in the presence of a chiral catalyst to form a compound of formula 2 and optionally converting a compound of formula 2 to a pharmaceutically acceptable salt, complex, solvate or hydrate; wherein the chiral catalyst comprises a chiral ligand bound to the transition metal via phosphorus atoms, wherein the chiral ligand has the structure represented by formula 4 and where the substituents R, R, R, R and X in formula 3 are the same as those defined in formula 2.2. A method for producing a compound of formula 1 or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, the method comprising: reacting a compound of formula 6 with the corresponding Z-isomer of a compound of formula 6 or a mixture thereof with hydrogen in the presence of a chiral catalyst to form a compound of formula 7, where R represents a carboxyl group or —CO — Y, Y is a cation, and the chiral catalyst comprises a chiral ligand bound to the transition metal via phosphorus atoms, wherein the chiral ligand has the structure represented by the formula 4 restoration of cyan fr