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

A one-stepand highly enantioselective synthesis of (R)-2-(1-aminoethyl)-4-fluorophenol((R)-I), a key chiral intermediate towardpreparation of the tyrosine kinaseinhibitor repotrectinib, has been developed. Starting from the easilyavailable 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 asymmetricreductive amination with NH4OAc as the nitrogen sourceand H-2 as the reducing agent. The reaction can be carriedout on a 20 g scale using a continuous-flow reactor instead of a traditionalbatch reactor. The flow technology enables higher reaction efficiencyand does not require column chromatography for product purification.Compared to the known procedures, this method avoids the use of expensivechiral auxiliaries and protecting group operations, making it a step-economicaland cost-effective alternative strategy for production of repotrectinib.

Automated summary

A one-step and highly enantioselective synthesis of (R)-2-(1-aminoethyl)-4-fluorophenol((R)-I) was developed as a key chiral intermediate for the preparation of the tyrosine kinase inhibitor repotrectinib. The reaction was carried out using a Ru-catalyzed asymmetric reductive amination with NH4OAc as the nitrogen source and H-2 as the reducing agent. The use of a continuous-flow reactor enabled higher reaction efficiency and eliminated the need for column chromatography for product purification, making it a cost-effective alternative strategy for production of repotrectinib.