Efficient Preparation of D-Aspartic Acid β-Methyl Ester as an Aspoxicillin Material by Optical Resolution, Epimerization, and Asymmetric Transformation

Abstract

A practical preparation of D-aspartic acid β-methyl ester [D-Asp(OMe)], a raw material for the antibiotic aspoxicillin, has been developed by the use of a second-order asymmetric transformation. The diastereomeric resolution of DL-Asp(OMe) with (-)-1-phenylethanesulfonic acid (PES) resulted in salt formation of less soluble D-·(-) and more soluble L-·(-) in acetonitrile. The soluble L-·(-) was easily epimerized into DL-·(-) by heating it in acetonitrile in the presence of catalysts. Attempted fractional crystallization of DL-·(-) or L-·(-) under such epimerizing conditions led to the desired D-·(-) in 90% yield via equilibrium asymmetric transformation in a solid-liquid heterogeneous system. Details of optimum techniques for the asymmetric transformation are presented.From these results, unique preparation processes of both D-Asp(OMe) and D-p-hydroxyphenylglycine, important intermediate materials for aspoxicillin, have been achieved by asymmetric transformation using chiral PES as the resolving agent.