Catalytic Static Mixer-Enabled Hydrogenation of a Key Fenebrutinib Intermediate: Real-Time Analysis for a Stable and Scalable Process

Catalytic static mixer (CSM) technology is presented as an industrially viable solution for aromatic nitro group reduction in the synthesis of fenebrutinib. Factors affecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR and UHPLC). This facilitated the development of stable and optimal conditions in a system with four CSMs positioned inside a thermostated shell-and-tube reactor. Additional care was taken to ensure the control of three key impurities to low levels (<0.10 area% by offline UHPLC analysis). The optimal conditions (0.4M concentration, 20 bar, 120 °C, 3.3 equiv H2) were then scaled up to a reactor with eight CSMs, whereby an improvement in the space–time yield was achieved. Over 16 h of processing, a stable impurity profile was observed, without metal leaching. Finally, the reaction was performed in a system with 16 CSMs, which also provided an increase in the space–time yield (to 26.2 mol L–1 h–1 or 6.5 kg L–1 h–1), resulting in 174 g h–1 throughput, while maintaining an excellent impurity profile.