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

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.