Patent ID: 9090539
Filing Date: 2015-07-28
Classification: C07B,C07C

Abstract:
1. A method of preparing a substantially optically pure (R,R) stereoisomer of a compound of formula (V): or a pharmaceutically acceptable salt thereof, the method comprising: (i) reacting a compound of formula (II): or a pharmaceutically acceptable salt thereof, with a cyanoethyl phosphonic acid derivative of formula (III): to produce a mixture comprising the E-isomer and Z-isomer of a compound of formula (I): or a pharmaceutically acceptable salt thereof; and (ii) separating the E-isomer from the Z isomer in the mixture, thereby obtaining a substantially pure E-isomer of the compound of formula (I) or the pharmaceutically acceptable salt thereof; (iii) reacting the substantially pure E-isomer of the compound of formula (I) or the pharmaceutically acceptable salt thereof with one or more reducing agents, and optionally an alkylating agent, thereby obtaining the compound of formula (V) or the pharmaceutically acceptable salt thereof as a mixture of (R,R) and (S,S) stereoisomers that is substantially free of (R,S) and (S,R) stereoisomers; and (iv) separating the (R,R) stereoisomer from the (S,S) stereoisomer in the mixture, thereby obtaining the substantially optically pure stereoisomer of a compound of formula (V), wherein R 1 represents a hydrogen or an aliphatic, aryl, or phenolic oxygen protecting group, each of R2 and R3 independently represents a hydrogen, alkyl or aryl, R 4 represents CN or CH 2 N(R 5 ) 2 , and R 5 represents a hydrogen or alkyl.