Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine. Part 2. The Palladium Catalysts in Acidi

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• 作者：Hyun Kuk Noh ; Jae Sung Lee ; Yeongdae Kim ; Gyohyun Hwang ; Jay Hyok Chang ; Hyunik Shin ; Do Hyun Nam ; and Kyung Hee Lee
• 刊名：Organic Process Research & Development
• 出版年：2004
• 出版时间：September 2004
• 年：2004
• 卷：8
• 期：5
• 页码：788 - 795
• 全文大小：125K
• 年卷期：v.8,no.5(September 2004)
• ISSN：1520-586X

文摘

Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) to 4-aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), thekey intermediate for gemifloxacin, was investigated over Pdcatalysts with in situ acid protection. Addition of more than1.6 equiv of acidic protons for CMBP was found to drasticallyelevate both the reaction rate and selectivity to 4-aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) over Pd catalyst with a complete suppression of themajor side reaction to 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrroline (CABP). Methanol as the organic solventwas found to increase the hydrogenation rate greatly comparedto other solvents with a negligible decrease of selectivity. Theleaching of Pd by acid and consequent accumulation of Pd ionin the reaction mixture was negligible in CMBP hydrogenation.The novel process of chemoselective CMBP hydrogenation inacidic media over Pd catalyst was thus much simpler yet moreefficient compared to the conventional one. The whole AMPMprocess time starting from 1-(N-tert-butoxycarbonyl)-4-cyanopyrrolidine-3-one (BCPO) could be reduced by at least approximately 15 h which would result in a great reduction ofmaterials such as catalysts, (t-Boc)₂O, and solvent. Additionally,reduction of reaction steps improved the overall yield of AMPMsignificantly. Employment of methanesulfonic acid as an acidicagent in the hydrogenation step allowed an environmentallybenign pathway to AMPM by omission of a neutralization stepwith an extra reduction in process time and materials consumed.