Stereocomplementary Synthesis of a Key Intermediate for Tofacitinib via Enzymatic Dynamic Kinetic Resolution-Reductive Amination

Tofacitinib is an oral protein tyrosine kinase inhibitor approved for the treatment of rheumatoid arthritis, active psoriatic arthritis and ulcerative colitis. Its efficient production remains a challenge due to the two consecutive stereogenic centers associated to the piperidine ring. In this study, an enzymatic dynamic kinetic resolution-asymmetric reductive amination was developed to prepare enantiomerically complementary cis-1-benzyl-N,4- dimethylpiperidin-3-amine and its analogues. Two enantiocomplementary imine reductases (IREDs) were identified for the synthesis of (3R,4R)- and (3S,4S)-1-benzyl-N,4-dimethylpiperidin-3-amine in high isolated yields (83% and 91%) with excellent stereoselectivity (97% and >99% ee values) and diastereoselectivity (>99:1 dr), providing a green methodology for the production of the key intermediate of tofacitinib.

Automated summary

In this study, an enzymatic dynamic kinetic resolution-asymmetric reductive amination was developed for the production of the key intermediate of tofacitinib. The method successfully synthesized cis-1-benzyl-N,4-dimethylpiperidin-3-amine with high stereoselectivity and diastereoselectivity.