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 technol...

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Veröffentlicht in:Organic process research & development 2024-07, Vol.28 (7), p.2724-2731
Hauptverfasser: Liu, Xiangyu, Zhan, Ensheng, Wang, Zhi, Dong, Guoliang, Dong, Gaochao, Wu, Shuai, Zhang, Yunlin, Chen, Jingrui, Wen, Jialin, Zhang, Lei
Format: Artikel
Sprache:eng
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Zusammenfassung: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.4c00095