Development of Asymmetric Reductive Amination of Unfunctionalized Ketone with Primary Amine

Direct asymmetric reductive amination provides a straightforward approach to preparing α-chiral amine synthons. We herein disclose a chemical process to produce α-chiral secondary amine from alkyl (hetero)aryl ketone, primary amine, and molecular hydrogen. By using high-throughput screening technology, an iridium/bisphosphine catalyst was selected that gives a turnover number of ∼1000 and a ee value of 91–92% in the production of (R)-2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethan-1-ol (1). The formation of diastereomeric salt from the crude chiral amine with L-tartaric acid and crystallization upgrade the ee value to >99% and the purity to >99%. The multikilogram production of an enantiopure chiral secondary amine was realized with good reproducibility with this process.