Enantioselective synthesis of a 2,3-benzodiazepine intermediate of BET inhibitor BAY 1238097 via catalytic asymmetric hydrogenation

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 to significantly reduce catalyst loading. Ultimately, the hydrogenation was performed on kg scale leading to the production of 27 kg of the desired product with an enantiomeric excess of 99% after crystallization.