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Download fileLarge Scale Practical Synthesis of Enantiomerically Pure cis-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene
journal contribution
posted on 2021-02-10, 20:45 authored 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. SenanayakeThe
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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cis -4-enantioselectivebenzylpiperidine 4Large Scalemultikilogram scalehydrogenationSynthesiprocess mass intensityreductive amination protocolregioTetrasubstituted FluoroalkeneterteeselectivityenantiomericallyEnantiomerically Pure cis -4- Amino...butoxycarbonylsynthesis featuresmethylpiperidineone-pot debenzylationcrude product NHClWalphos 003.150.chloridecompound 3- fluoropyridin -4-amine 2catalystpuritychiral enrichment-3-fluoro 1Rhodium-Catalyzed Asymmetric Hydrog...BF 4purificationchemo