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Synthesis 2005(1): 92-96  
DOI: 10.1055/s-2004-834903
PAPER
© Georg Thieme Verlag Stuttgart · New York

Efficient Preparation of (3S)-3-(4-Fluorobenzyl)piperidinium Mandelate

George C. Emmett, Gary A. Cain, Melissa J. Estrella, Edd R. Holler, James S. Piecara, Andrew M. Blum, Alfred J. Mical, Christopher A. Teleha, Dean A. Wacker*
Bristol-Myers Squibb Co., Pharmaceutical Research Institute, Discovery Chemistry, PO Box 5400, Princeton, NJ 08542-5400, USA
Fax: +1(609)8186570; e-Mail: dean.wacker@bms.com;
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Publication History

Received 8 June 2004
Publication Date:
02 November 2004 (online)

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Abstract

Methods for the preparation of (3S)-3-(4-fluorobenzyl)piperidine (2) and its mandelate salt (9) are described. The first generation synthesis started from 3-benzylpiperidone, and required Boc protection of the nitrogen for efficient separation of the enan­tiomers using chromatography on a chiral stationary phase. Subsequently, a resolution method using (R)-mandelic acid, produced high %ee salt 9 after recrystallization and eliminated the need for Boc protection. The third generation route, starting from pyridine-3-carboxaldehyde, led to a streamlined synthesis of racemate 2 and was optimized for producing multi-hundred gram quantities of the chiral salt.

Key words

piperidines - chiral resolution - enantiomeric resolution - medicinal chemistry

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The absolute stereochemistry was confirmed as shown, and will be addressed in a series of forthcoming papers.