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3,5-Disubstituted Piperidine Derivatives - A Scalable Route to all Four Stereoisomers

Hartwieg, Constanze, Priess, Jan, Schuetz, Heiner, Rufle, Dominik, Valente, Claudio, Bury, Christophe, La Vecchia, Luigi and Francotte, Eric (2014) 3,5-Disubstituted Piperidine Derivatives - A Scalable Route to all Four Stereoisomers. Organic Process Research and Development, 18 (9). pp. 1120-1127. ISSN 1083-61601520-586X


3,5-Disubstituted piperidines are versatile building blocks that find broad application in medicinal chemistry programs. Here we describe how all four diastereoisomers of a 5-aryl-substituted nipecotic acid derivative were prepared on preparative scale in high enantiomeric purity. The piperidine core structure was formed by catalytic hydrogenation of the corresponding pyridine derivatives. After Boc-protection, the resulting cis / trans mixture was separated by preparative normal phase chromatography into the pure cis and pure trans racemates. Subsequent preparative separation of those racemates by Simulated Moving Bed chromatography (SMB) allowed us to obtain all four enantiopure isomers in amounts between 80 g and 140 g. The absolute configuration of all compounds was determined by crystallisation and X-Ray spectroscopy of suitable derivatives.

Item Type: Article
Keywords: 3,5-disubstituted piperidine, cis- and trans- isomers, racemates, pure enantiomers, scale up, preparative chromatography, simulated moving bed chromatography, absolute configuration, X-ray
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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