Study On Synthesis Of 3-ethoxy-4-ethoxycarbonylphenylacetic Acid

Repaglinide,which is a non-sulfonylurea insulin secretion agent for treatment of type2 diabetes,was jointly developed by Boehringer Ingelheim company and Novo Nordisk company and first marketed to USA in 1998.As a prandial glucose regulator,Repaglinide can rapidly promote insulin secretion and reduce the glycosylated hemoglobin(HbAlc)and postprandial glucose(PBG)in diabetic patients with quick absorption,rapid onset,short effect time,no gain in weight and good safty whether used alone or combined with other anti-diabetic drugs.Therefore,Repaglinide has great prospect in clinics.Repaglinide consists of two important intermediates:3-ethoxy-4-ethoxycarbonyl phenyl acetic acid and(S)-3-methyl-1-[2-(1-piperidiny)phenyl]-butyl amine.In this paper,an industrially efficient new route for manufacturing 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid,which is a key intermediate of antidiabetic drug Reglatadine,is reported by starting from 3-hydroxyphenylacetic acid and undergoing esterification to afford3-hydroxyphenylacetate,and after formylation an intermediate of4-formyl-3-hydroxyphenylacetate is obtained.The obtained compound is further oxided to give 4-acetylethyl-2-hydroxybenzoic acid.Next the esterification and etherification are performed on 4-acetylethyl-2-hydroxybenzoic acid in one step to give3-ethoxy-4-ethoxycarbonyl phenylacetate.The intermediate 3-ethoxy-4-ethoxycarbonyl phenylacetate on seletive hydrolysis get the final product 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid.After lots of experimental explorations,the optimal process for3-ethoxy-4-ethoxycarbonyl phenyl acetic acid was reached.Compared with the reported articles,the reagents and reaction conditions involved are mild,the route is short and industrially feasible,the risk and difficulty of the operation have been greatly reduced.FT-IR,HRMS and ~1H NMR were used to characterize the intermediates of3-ethoxy-4-ethoxycarbonyl phenyl acetic acid.