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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