An Alternative Approach to Achieve Enantiopure (3S)-4-Benzyl-3- (4-fluorophenyl)morpholin-2-one: A Key Intermediate of Aprepitant, an NK1 Receptor Antagonist

Abstract

An efficient and alternative synthesis of enantiomerically pure (3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one (S)-(+)-2), a key intermediate in the synthesis aprepitant (1), is described. The key resolution of N-benzylglycinamide, (±)-9, is achieved via diastereomeric salt crystallization using (+)-di-p-toluoyltartaric acid (DPTTA) as the resolving agent to furnish (S)-(+)-9. Alkylation of (S)-(+)-9 with 2-bromoethanol followed by stereocontrolled cyclization of obtained (S)-(+)-10 afforded the desired enantiomer (S)-(+)-2 with good yields and enantiopurity (>98%). The reaction conditions were optimized to make the process robust in order to implement at the commercial scale.