(701a) Development of a Chiral Catalyst Immobilized Continuous Flow Process for a Key Asymmetric Hydrogenation Step of an API Synthesis

The demand for enantiomerically pure compounds as well as for asymmetric catalysis have been steadily growing in the pharmaceutical industry. However, homogenous asymmetric hydrogenation has chiral catalyst recovery and reusability issues as well as product contamination possibility due to catalyst leaching. These challenges of homogeneous asymmetric hydrogenation process can be addressed by developing a heterogenous continuous flow process. The most promising approach for development of a heterogenous continuous flow process is immobilization of a chiral catalyst on a solid support. This process not only solves the catalyst separation and recycling issues but also minimizes the overall cost and provides better process control and handling.

In this work, the viability of converting batch asymmetric hydrogenation to continuous flow solid-supported catalytic process will be demonstrated in an example of a key asymmetric hydrogenation step of an existing API synthesis. The most promising catalyst was identified as Rh chiral catalyst with Josiphos ligand. Homogeneous conversion and enantioselectivity results were 100% and 90% in batch screening, respectively. Several chiral catalyst immobilization methods were explored to prepare the solid Rh catalyst. Initial screening of the Rh immobilized solid chiral catalyst for asymmetric hydrogenation in batch demonstrated high enantioselectivity and low conversion compared with homogenous asymmetric hydrogenation. The catalyst immobilization on solid support procedure and heterogeneous reaction conditions were further optimized under batch conditions to achieve high conversion and enantioselectivity results that were observed in a batch homogenous asymmetric hydrogenation process. Finally, the solid supported Rh-based catalyst was tested in a packed bed reactor under continuous flow conditions. Under steady state conditions 99% conversion of the substrate and 87% enantioselectivity towards the desired enantiomer was achieved in a continuous reactor. No catalyst deactivation was observed during the duration of the continuous run. The catalyst was active for multiple continuous hydrogenation reactions.