Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1 -(N-tert-butoxycarbonyl)pyrrolidine.Part 1.Screening of Metal Catalysts

摘要

A novel synthetic route was devised for 4-aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM),the key intermediate of gemifloxacin,based on chemoselective hydro-genation of the cyano group in 4-cyano-3-methoxyimino-l-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)_2O (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-l-(N-tert-butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP,resulting in over-reduction of the desired intermediate,4-aminomethyl-3-Z-methoxyimino l-(n-tertt-butoxycarbonyl)pyrrolidine (Z-AMBP) all the way to AABP.When in situ BOC protection was performed,the selectivity to the desired 4-(N-tert-butoxycar-bonyl)aminomethyl-S-Z-methoxyimino-l-(N-fert-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-cyano-3-amino-l-(N-tert-butoxycarbonyl)-3,4-pyrro-line (CABP) was found to be a major byproduct,while the formation of AABP or 4-(N-tert-butoxycarbonyl)aminomethyl-3-(N-tert-butoxycarbonyl)amino-l-(N-tert-butoxycarbonyl)pyr-rolidine (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.