The Design And Synthesis Of Repaglinide Intermediates

Objective: a) Design and synthesize repaglinide intermediates: intermediates(Ⅰ) 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and intermediates(Ⅱ)(±)3-methyl-1-(2-piperidinyl phenyl) butyl amine;b) lipase novozym435 was employed to resolution the model 1-phenylethylamine and intermediates(Ⅱ).Methods: a) Intermediate(Ⅰ) was prepared by a two step process,first the starting materials 2-hydroxy-4-methylbenzoic acid was alkylated with ethyl bromide,then deprotonation with lithium diisopropylamide(LDA) and quenching the resulting carbanion with carbon dioxide. b) Intermediate(Ⅱ) was also prepared by two step process, using 2-chloro-benzonitrile as starting materials via piperidine substitution, Grignard addition etc. to give the products.c) Intermediate(Ⅱ) and the model 1-benzyl ethylamine were resolutioned by Novozym435, diisopropyl ether as solvent and ethyl acetate as acyl donor,40℃,200rpm.Result: Intermediate(Ⅰ) and Intermediate(Ⅱ) s' chemical structure were conformed by ~1H-NMR, ~1C-NMR, MS.Conclusion: A practical route to synthesize Intermediate(Ⅰ) and Intermediate(Ⅱ) was established and a new way of resolutioning the Intermediate(Ⅱ) by lipase Novozym435 was put forward by the author;but still having some problems to solve.