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Enantioselective Synthesis of a 2,3-Benzodiazepine Intermediate of BET Inhibitor BAY 1238097 via Catalytic Asymmetric Hydrogenation

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journal contribution
posted on 06.02.2020, 16:05 by Gerard K. M. Verzijl, Jorma Hassfeld, André H. M. de Vries, Laurent Lefort
Herein, we report the first example of the asymmetric hydrogenation of a prochiral benzodiazepine substrate as key transformation in a pilot-scale synthesis of BET inhibitor BAY 1238097. High-throughput screening in a parallel reactor enabled us to identify an efficient catalyst based on Ir and a chiral bisphosphine. An additive screening allowed significant reduction of catalyst loading. Ultimately, the hydrogenation was performed on a kilogram scale leading to the production of 27 kg of the desired product with an enantiomeric excess of 99% after crystallization.

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