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Large Scale Practical Synthesis of Enantiomerically Pure cis-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene

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posted on 10.02.2021, 20:45 by Bo Qu, Anjan Saha, Guisheng Li, Xingzhong Zeng, Xiaojun Wang, Nizar Haddad, Xiaowen Hou, Jon C. Lorenz, Lifen Wu, Scott Pennino, Heewon Lee, Jinhua J. Song, Chris H. Senanayake
The development of multikilogram scale green and economical synthetic route of enantiomerically pure cis-4-amino-3-fluoro-1-methylpiperidine 1 is described. The synthesis features a highly regio-, chemo-, and enantioselective asymmetric hydrogenation of N-benzyl-4-((tert-butoxycarbonyl)­amino)-5-fluoro-tetrahydropyridinium chloride 3. No purification or chiral enrichment is necessary due to the high selectivity resulting from proper selection of the catalyst system Rh­(NBD)2(BF4) and Walphos 003. The crude product N-benzylpiperidine 4 was carried directly to N-methylpiperidine utilizing a highly effective one-pot debenzylation and reductive amination protocol. The target compound 1·2HCl was prepared in 66–68% overall yield with >99% ee and >98.5% purity from available compound 3-fluoropyridin-4-amine 2 with a process mass intensity of 150.

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