First practical synthesis of enantiomerically pure ( R)- and ( S)-desmethylsibutramine (DMS) and unambiguous determination of their absolute configuration by single-crystal X-ray analysis

Abstract

A practical synthesis of enantiomerically pure ( R)-desmethylsibutramine [( R)-DMS] and ( S)-desmethylsibutramine [( S)-DMS] is outlined along with an improved synthesis of racemic desmethylsibutramine. This route was used for kilo-scale production of enantiomerically pure ( R)- and ( S)-DMS. Racemic desmethylsibutramine was resolved with either ( R)- or ( S)-mandelic acid, and the absolute stereochemistry of DMS was determined by single X-ray crystallography of its mandelate salt.