Continuous Flow Asymmetric Hydrogenation with Supported Ionic Liquid Phase Catalysts Using Modified CO₂ as the Mobile Phase: from Model Substrate to an Active Pharmaceutical Ingredient

摘要

The continuous flow asymmetric hydrogenation of (hetero)aromatic enamides has been realized using a Rh-Quinaphos catalyst immobilized in a supported ionic liquid phase (SILP) and employing supercritical CO_(2) modified with toluene (mod CO_(2)) as the mobile phase. This approach allows expansion of the scope of the original SILP/sc CO_(2) system to nonvolatile substrates with poor solubility in pure CO_(2). The potential of a SILP catalyst in combination with mod CO_(2) was demonstrated for an industrial case study using the continuous flow hydrogenation for the synthesis of a key intermediate of an active pharmaceutical ingredient (API) from AstraZeneca’s portfolio. Toluene was selected as the most promising modifier, and the influence of the ratio of modifier to CO_(2) was evaluated in detail. The catalyst support was found to play a major role for maintaining constant performance and the use of hydrophobic fluorous reverse-phase silica (FRP-SiO_(2)) instead of dehydroxylated silica strongly enhanced the long-term stability under continuous flow operation. Virtually a single enantiopure product was obtained over a prolonged time-on-stream of 90 h (quantitative single-pass conversion, ee > 99%) reaching a total turnover number of 10?300 at a space–time yield (STY) of 24 g L~(–1) h~(–1). No metal contamination was detected in the product solutions, indicating effective catalyst retention.