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Synthesis 2003(15): 2405-2409  
DOI: 10.1055/s-2003-42397
PAPER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution

Céline Mordant, Cristina Caño de Andrade, Ridha Touati, Virginie Ratovelomanana-Vidal*, Bechir Ben Hassine, Jean-Pierre Genêt*
Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR 7573 C.N.R.S., Ecole Nationale Supérieure de Chimie de Paris, 11, rue P. et M. Curie, 75231 Paris Cedex 05, France
Fax: +33(1)44071062; e-Mail: genet@ext.jussieu.fr;
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Publication History

Received 3 July 2003
Publication Date:
29 September 2003 (online)

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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.