197143-34-3Relevant academic research and scientific papers
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
Noh, Hyun Kuk,Lee, Jae Sung,Kim, Yeongdae,Hwang, Gyohyun,Chang, Jay Hyok,Shin, Hyunik,Nam, Do Hyun,Lee, Kyung Hee
, p. 781 - 787 (2004)
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 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-1-(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 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-butoxycarbonyl)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-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.
