Milnacipran as a challenging example of aminomethyl substrate for lipase-catalyzed kinetic resolution

•CAL-B was effectively employed for kinetic resolution of milnacipran drug.•Biocatalysed aminolysis was optimized by variation of the reaction parameters.•The pharmacologically active levomilnacipran was obtained in enantiopure form.•The reaction products were isolated by simple extraction work-up.

A biocatalysed procedure for the kinetic resolution of milnacipran, (±)-1 was developed and optimized by careful choice of the reaction parameters. The reaction of (±)-1 with methyl iso-butyrate as acyl donor in the presence of Novozyme 435 in tert-butyl methyl ether proceeded with moderate enantioselectivity giving the more pharmacologically active enantiomer of milnacipran (−)-1 as unreacted substrate and the corresponding amide (−)-4 both in optically enriched form. When the enzymatic reaction was prolonged up to 65% substrate conversion enantiopure levomilnacipran (−)-1 (98% ee) was directly recovered from the reaction mixture by simple extraction workup.

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