Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine, one of the major metabolites of mexiletine

Hydroxymethylmexiletine (HMM), one of the main metabolites of mexiletine, has been synthesized in both racemic and optically active forms following two alternative routes. The ee values for both HMM enantiomers were 98%, as assessed by 1H NMR analysis in the presence of (−)-(R)-(2-naphthyloxy)phenylacetic acid as a chiral solvating agent and electrophoretic analysis using β-cyclodextrine sulfated sodium salt as a chiral auxiliary.

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(−)-(R)-[2-(2-Aminopropoxy)-3-methylphenyl]methanolC11H17NO2Ee = 98%[α]D20=-9.6 (c 2, CHCl3)Source of chirality: chiral poolAbsolute configuration: (R)

(+)-(R)-3,9-Dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochlorideC11H16ClNOEe = 98%[α]D20=+71.0 (c 0.4, CHCl3)Source of chirality: chiral poolAbsolute configuration: (R)