Study On The Synthesis And Technology Of Repaglinide

Repaglinide,which belongs to non-sulphonylurea oral-administration drug for diabetes treatment,was cooperatively developed by Boehringer Ingelheim company and Novo Nordisk company.Repaglinide was first marketed to USA in 1998 and to China in 2000.Repaglinide stimulates the pancreas of patients suffering type 2 diabetes mellitus to simulate physiologic insulin secretion with higher plasma protein binding.Repaglinide has other advantages such as quick absorption,easy elimination and better security.It can be administered alone or concurrently with other anti-diabetic drugs to promote the curative effect.Repaglinide consists of two important intermediates:(S)-3-methyl-1-[2-(1-piperidiny)phenyl]-butyl amine and 3-et hox y-4-ethox ycarbonyl phenyl acetic acid.(S)-3-methyl-1-[2-(1-piperidiny)phenyl]-butyl amine could be prepared from o-flurobenzaldehyde undergoing Grignard reaction,oxidation,piperidine substitution,oximation,reduction and resolution.3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid was synthesized through several methods and at last the following process was the best choice.p-Methylsalicylic acid was used as raw material and with carboxyl and hydroxyl group were protected by ethyl groups.The obtained compound reacted with ethyl chlorocarbonate to prepare 3-ethoxy-4-ethoxycarbonyl phenyl acetate when LDA was used as base and then the selective hydrolyzation was executed in base aqua.Two obtained intermediates were condensed and hydrolyzed to give Repaglinide.After lots of explorations,the optimal process technological parameter for Repaglinide synthesis was reached.The commercial process showed that the developed technical route has advantages of low cost,high yield and convenient operation.UV?TLC?IR?MS?1H NMR?13C NMR were used to characterize the intermediates of Repaglinide.HPLC testing methods for evaluating of intermediates and for measurement of enantiomeric excess value of(S)-3-methyl-1-[2-(1-piperidiny)phenyl]-butyl amine were set up.Repaglinide product was detected according to United States Pharmacopeia(USP)and the results showed the specifications can pass all the requirements.