Synthesis of the intermediate of gemifloxacin by the chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrroidine. Part 1. Screening of metal catalysts

Abstract

A novel synthetic route was devised for 4-aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction lof the methyloxime group employing (t-Boc)(2)O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-aminomethyl-3-amino-1-(N-tert-butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in overreduction of the desired intermediate, 4-aminomethyl-3-Z-methoxyimino 1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbon- yl)pyrrolidine (Z-BAMBP) rose to as high as 91% over Raney cobalt by suppressing the over-reduction of Z-AMBP to AABP. On the basis of these observations, a CMBP hydrogenation process over Raney cobalt was proposed. Among noble metal catalysts, only Pd was found to show a high activity. Over Pd catalyst, 4-eyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrroline (CABP) was found to be a major byproduct, while the formation of AABP or 4-(N-tert-butoxycarbonyl)aminomethyl-3-(N-tert-butoxycarbonyl)amino-1-(N-tert-butoxycarbonyl)pyrrolidine (BABABP) was greatly suppressed. The byproduct CABP formed by hydrogenolysis of the methyl group in the methyloxime group in CMBP could be recycled to the original substrate, 1-(N-tert-butoxycarbonyl)-4-cyano-pyrrolidine-3-one (BCPO) by an acid-catalyzed hydrolysis.