Stereospecific synthesis of mexiletine and related compounds: Mitsunobu versus Williamson reaction

Mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral, orally effect ive antiarrhythmic agent, and several analogues substituted on either the s tereogenic centre or the xylyloxy moiety, were prepared in both, highly enr iched, optically active forms. According to the 'chiral pool' approach, the appropriate amino alcohols, protected as the corresponding phthalimide der ivatives, were condensed with the desired phenols under either Mitsunobu (m ethod A) or Williamson (method B) conditions. Generally, method A provided the most efficient route, both in terms of yields and number of steps neces sary. Only when an isopropyl group was present on the stereogenic centre, i .e. when 2-amino-3-methylbutanol was used as the starting alcohol, method B proved to be the only available route, method A giving no product other th an the starting phthalimide derivative. Regardless of the method used, enan tiomeric excesses ranged from 91 to 99%. Given the availability of both var iously substituted phenols and optically active amino alcohols, the two met hods described herein, taken together, may serve as a versatile approach, u seful to meet the needs of new chiral, optically active mexiletine analogue s, possibly endowed with higher potency in exerting a use-dependent block o n sodium channels and/or more resistant to biotransformations. (C) 2000 Els evier Science Ltd. All rights reserved.