Enantioselective and Step-Economic Synthesis of the Chiral Amine Fragment in the Tyrosine Kinase Inhibitor Repotrectinib by Direct Asymmetric Reductive Amination under Batch and Flow

Abstract

A one-step and highly enantioselective synthesis of (R)-2-(1-aminoethyl)-4-fluorophenol ((R)-I), a key chiral intermediate toward preparation of the tyrosine kinase inhibitor repotrectinib, has been developed. Starting from the easily available substrate 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (2a), the target product (R)-I was prepared in an optically pure form through a Ru-catalyzed asymmetric reductive amination with NH4OAc as the nitrogen source and H2 as the reducing agent. The reaction can be carried out on a 20 g scale using a continuous-flow reactor instead of a traditional batch reactor. The flow technology enables higher reaction efficiency and does not require column chromatography for product purification. Compared to the known procedures, this method avoids the use of expensive chiral auxiliaries and protecting group operations, making it a step-economical and cost-effective alternative strategy for production of repotrectinib.

Development of Asymmetric Reductive Amination of Unfunctionalized Ketone with Primary Amine

“…As a subfield of asymmetric hydrogenation, DARA combines the condensation of ketones with amines and the sequential stereoselective hydrogenation of in situ-formed enamine or imine moieties , in one-pot operation. The last 30 years have witnessed the fast development of DARA in the preparation of enantioenriched chiral amines. , Since the great success of the production of ( S )-metolachlor, DARA has been increasingly applied in chemical production of chiral amines. − …”