BIOCATALISI E CRISTALLIZZAZIONE PREFERENZIALE: DUE UTILI APPROCCI PER LA RISOLUZIONE DEL MILNACIPRAN

Enzymatic catalysis is a valuable approach used in organic synthesis to achieve chemical transformations in mild reaction conditions and with a high degree of selectivity. The use of enzymes, especially lipase, in organic solvent is an advantageous way to obtain single stereoisomers of a drug and biotransformations are today accepted as a powerful methodology for the industrial preparation of chiral pharmaceuticals. Enantiomerically pure molecules containing amino functions are important synthons for the preparation of drugs. Primary and secondary amines, where the amino group is directly located on a stereogenic carbon, have been obtained in good yields and optical purity by lipases-catalyzed kinetic resolution of the racemates through a transamination reaction in the presence of carboxylic esters as acyl donors.1 However, aminomethyl compounds are challenging substrates for their high reactivity and distance from the chiral center. Milnacipran, Z-(±)-2-(aminomethyl)-N,N-diethyl-1-phenyilcyiclopropane, is an active antidepressant drug belonging to the class of inhibitors of the reuptake of serotonin and has recently attracted interest for its painkiller effects in the treatment of fibromyalgia.2 Milnacipran is currently marketed in many countries, but not yet in Italy, in racemic form, however, recent pharmacokinetic studies on single enantiomers showed greater activity for (1S, 2R)-levomilnacipran. The aim of this study is the development of a simpler and more economical strategy alternative to the reported an enantioselective synthesis. The kinetic resolution of racemic milnacipran in the presence of lipase was then investigated and optimized by means of a careful choice of the reaction conditions (lipase source and form, temperature, solvent and acyl donor nature). The amide product and the unreacted substrate were obtained in satisfactory chemical yields and enantiomeric purities.3 During this study we identified one of the amides obtained from the enzyme-catalyzed resolution as a conglomerate, whose nature was confirmed by the physical properties (melting points, solubility and X-ray diffraction). The properties of this specific amide of milnacipran were then exploited for its spontaneous resolution by conglomerate crystallization through a sequence of crystallization steps. Starting from a substrate with quite low enantiomeric excess, crystals of both enantiomers were obtained in enantiopure form.