Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis

The development of a continuous flow process for asymmetric hydrogenation with a heterogenized molecular catalyst in a real industrial context is reported. The key asymmetric step in the synthesis of an API (active pharmaceutical ingredient) has been developed on a kilogram scale with constant high single-pass conversion (>95.0%) and enantioselectivity (>98.6% ee) through the asymmetric hydrogenation of the corresponding enamide. This performance was achieved using a commercially available chiral catalyst (Rh/(S,S)-EthylDuphos) immobilized on a solid support via strong interaction resulting from the requirement of electroneutrality. The factors affecting the long-term catalyst stability and enantioselectivity were identified using small-scale continuous flow setups. A dedicated automated software-controlled high-pressure pilot system with a small footprint was then built and the asymmetric hydrogenation on kilogram-scale was realized with a space time yield (STY) of up to 400 g L–1 h–1 at predefined conversion and enantiopurity levels. No catalyst leaching was detected in the virtually metal-free product stream, thereby eliminating costly and time-consuming downstream purification procedures. This straightforward approach permitted an easy and robust scale-up from gram to kilogram scale fully matching the pharmaceutical quality criteria for enantiopurity and low metal content, thus demonstrating the high versatility of fully integrated continuous flow molecular catalysis.