High-pressure asymmetric hydrogenation in a customized flow reactor and its application in multi-step flow synthesis of chiral drugs

Abstract

Asymmetric homogeneous hydrogenation under high pressure in continuous flow was achieved with a slug flow reactor. High hydrogen pressure enabled iridium-catalyzed asymmetric hydrogenation of acetophenone with a turn-over-frequency (TOF) of up to 274,000 h−1. An operando infrared tool was used to provide in-situ monitoring of the reaction. The effect of gas-liquid ratio and speed of slug flow in the microchannel were studied. The multi-step flow synthesis of active pharmaceutical ingredients, in which asymmetric hydrogenation is a key step, was successfully demonstrated, with subsequent reactions carried out under longer residence times within a cascade of CSTRs.