STEREOSPECIFIC SYNTHESIS AND ABSOLUTE-CONFIGURATION OF MEXILETINE

Data on the absolute configuration of mexiletine (MEX) do not appear t o have been published, although in several published reports the confi guration is referred to as (-)-(R) and (+)-(S), based on information f rom manufacturers providing the drug stereoisomers. We demonstrate tha t (-)-MEX has the (R)-configuration by mean of a new stereospecific sy nthesis. X-Ray analysis of an optical active sample of (+)-MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mi xture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure-activity relations hips. We also report the NMR analysis in presence of Eu(hfc)(3) as shi ft reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well-known chiral HPLC met hods. (C) 1994 Wiley-Liss, Inc.