Download PDF
Synthesis 2011(4): 553-554  
DOI: 10.1055/s-0030-1258410
SHORTPAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Metabolism of Diltiazem: A Short Efficient Synthesis of N,N-Didesmethyldiltiazem - An Important Product of N-Demethylation

Kantipudi N. Babu, Kent L. Kunze, Wendel L. Nelson*
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA
Fax: +1(206)6853252; e-Mail: wlnelson@u.washington.edu;
Further Information

Publication History

Received 3 November 2010
Publication Date:
12 January 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

An important product of CYP-450 catalyzed N-demethylation of diltiazem is the primary amine didesmethyldiltiazem. An efficient two-step synthesis of this metabolite was developed via N-alkylation of (2S,3S)-cis-3-acetoxy-2,3-dihydro-2-(4-methoxy­phenyl)-1,5-benzothiazepin-4-(5H)-one with 2-(t-Boc-amino)ethyl bromide (K2CO3) followed by removal of the t-Boc protecting group using TFA. This method avoids the use of a nitrogen mustard electrophile (2-bromoethylamine) and the problematic selective O-acetylation of the HCl salt of the intermediate primary amino alcohol, thus providing the necessary metabolic standard.

Key words

diltiazem - didesmethyldiltiazem - amide N-alkylation - t-Boc protecting group