An Efficient and Cost-Effective Synthesis of 3-Ethoxy-4-ethoxycarbonyl-phenylacetic Acid:  A Key Acid Synthon of Repaglinide

Abstract

This report describes an efficient and commercially viable synthesis of 3-ethoxy-4-ethoxy-carbonyl-phenylacetic acid ( 1 ), a key intermediate for the preparation of repaglinide, an oral hypoglycemic agent, from 2-hydroxy-4-methylbenzoic acid in two steps. Thus, 2-hydroxy-4-methylbenzoic acid was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate; deprotonation with lithium diisopropylamide (LDA) and quenching the resulting carbanion with carbon dioxide provided the desired compound with improved yield and excellent purity. This procedure is significantly better than a previously published synthesis which involves five steps and requires use of expensive and hazardous reagents.