J. Xian
2012
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Journal
Journal of Shenyang Pharmaceutical University
Abstract
Objective To synthesize(S)-(+)-3-methyl-[2-(1-piperidinyl)phenyl]butylamine,the key chiral intermediate for the preparation of(S)-repaglinide-an insulin promoting secretion agent.Methods o-Fluoro benzaldehyde(1)was reacted with hydroxylamine hydrochloride to give o-fluorobenzaldoxime(2),followed by the treatment with acetic anhydride to give 2-fluorocyanobenzene(3),which was reacted with piperidine to provide 2-(1-piperidinyl)cyanobenzene(4),and then proceeding Grignard reaction with i-butyl magnesium bromide to afford imine(5),which was followed by reduction reaction with sodium borohydride to give the racemic mixture,then the racemic was saltified with N-acetyl-L-glutamic acid and the resolution procedure was carried out in the mixed-solvents of actetone-methanol,followed by hydrolysis reaction with sodium hydroxide to yield the target S-(6).Results(S)-(+)-3-methyl-[2-(1-piperidinyl)phenyl]butylamine was synthesized through a six-step procedure in a overall yield of 15.4%,and the structure of the target compound was identified by ESI-MS and 1H-NMR.Conclusions The easy availability of the reactants,facile reaction conditions and convenient operation procedures made the process a promising prospect for application in large-scale manufacture.