Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution

Abstract

An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propionate was synthesized from a racemic mixture of α-chloro-β-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl)₂ with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this α-chloro-β-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.

Key words

Diltiazem - drugs - kinetic resolution - asymmetric catalysis - hydrogenations - ruthenium

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1

Centro de Ciências Exatas e Naturais, Universidade Federal de Alagoas, Campus A.C. Simões, Tabuleiro do Martins, 57072-970, Maceió, Brasil.

2

Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, 01 UR 1201, Facultés des Sciences de Monastir, Avenue de l’Environnement, 5019 Monastir, Tunisie.