Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride

Various approaches to the preparation of enantiomerically pure (2R,2′R)-(+)-threo-methylphenidate hydrochloride (1) are reviewed. These approaches include synthesis using enantiomerically pure precursors obtained by resolution, classical and enzyme-based resolution approaches, enantioselective synthesis approaches, and approaches based on enantioselective synthesis of (2S,2′R)-erythro-methylphenidate followed by epimerization at the 2-position. 1 Introduction 2 Methods for the Enhancement of Enantiomeric Purity of 1 3 Approaches Using Enantiomerically Pure Precursors Obtained by Resolution 4 Classical Resolution Approaches 4.1 Resolution of Amide and Acid Derivatives 4.2 Resolution of (±)-threo-Methylphenidate 5 Enzyme-Based Resolution Approaches 6 Enantioselective Synthesis Approaches 7 Approaches Based on Enantioselective Synthesis of (2S,2′R)-erythro-Methylphenidate and Epimerization 8 Conclusions