One-step lipase-catalysed preparation of eslicarbazepine

Abstract

The antiepileptic eslicarbazepine (S-licarbazepine) has been prepared in one step from its racemic form RS-licarbazepine via lipase catalysed kinetic resolution. A novel stereoselective simultaneous HPLC separations of RS-licarbazepine (1) and its racemic esters RS-2–5 have been developed on Lux® cellulose-2 column using cyclohexane/ethanol 1/1 v/v as mobile phase. The developed enantioselective HPLC separations have been utilized for monitoring of lipase catalyzed kinetic resolution of RS-licarbazepine (1). Lipase catalysed trans-esterification and hydrolysis reactions have been performed. Four different esters (acetate (2), propionate (3), butyrate (4) and benzoate (5)) have been investigated for both trans-esterification and hydrolysis using ten lipases from versatile origins. The best enantioselectivity was shown by trans-esterification of RS-licarbazepine with vinyl benzoate in MtBE as solvent and lipase from Candida rugosa where the pharmacologically active enantiomer, S-(+)-licarbazepine, has been accomplished [E = 31, ee = 97%, yield 84%, α²⁰_D = +105, c 0.001 g mL⁻¹, CH₃OH]. Molecular docking attributed the high enantioselectivity of the transesterification when using Candida rugosa lipase to unfavorable ligand contacts between the S-enantiomer and phenylalanine 296.