(613a) Recent Progress in Heterogeneous Hydrogenations Using an Automated Flow Platform Equipped with PAT

Heterogeneous hydrogenation reactions are widely used in synthesis, and performing them using continuous flow technologies addresses many of the safety, scalability and sustainability issues. Despite their widespread use, they remain highly challenging to handle due to their inherent multiphasic and highly exothermic nature, and also because of the propensity of catalyst inhibition or leaching to occur. Optimization can also be scale-dependent due to the catalyst particle sizing, to balance reactivity against pressure drop, and also reproducible catalyst packing can be difficult to achieve. The recent progress made in 3D printing and coating technologies has resulted in the development of catalytically-coated static mixers (CSMs) to overcome many of the limitations of using packed-bed reactors. There is almost no pressure drop through the use of these supports and they are relatively easy to scale by increasing the number of CSMs in parallel or series.

Efforts made in our laboratory to investigate heterogeneous hydrogenations will be highlighted on the preparation of pharmaceutically-relevant molecules.¹ The hydrogenation reactions were performed using a tube-in-shell reactor with rectangular channels (Ehrfeld, Miprowa), with bespoke CSMs (Fig. 1). The flow setup integrates inline FT-IR and online UHPLC as orthogonal analytical methods for rapid data acquisition and for quantification of the main chemical species in real-time. One of the main potential drawbacks is catalyst deactivation by substrate inhibition. We highlight the utilization of the platform for the efficient and rapid evaluation of functional group/heterocycle tolerance of a heterogeneous hydrogenation reaction.² We will also summarize our efforts in the generation of kinetic models. These models were underpinned with a residence time distribution (RTD) study and computational fluid dynamics (CFD) simulations, which are important for scalability.

(1) R. Lebl, M.-S. Bachmann, P. Tosatti, J. Sedelmeier, K. Püntener, J. D. Williams, C. O. Kappe. Catalytic Static Mixer-Enabled Hydrogenation of a Key Fenebrutinib Intermediate: Real-Time Analysis for a Stable and Scalable Process. Org. Process Res. Dev. 2021, 25 (8), 1988–1995.

(2) K. Simon, P. Sagmeister, R. Munday, K. Leslie, C. A. Hone Hone, C. O. Kappe, C. O. Automated flow and real-time analytics approach for screening functional group tolerance in heterogeneous catalytic reactions. Catal. Sci. Technol. 2022, 12 (6), 1799– 1811.