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Catalytic static mixer (CSM) technology is presented as an industrially-viable solution for an aromatic nitro group reduction in the synthesis of fenebrutinib. Factors effecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR, UHPLC). This facilitated the development of stable and optimal conditions in a system with 4 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 (0.4 M concentration, 20 bar, 120 °C, 3.3 equiv H2) were then scaled up to a reactor with 8 CSMs, whereby an improvement in space-time yield was observed. 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 space-time yield (to 26.2 mol/L/h or 6.5 kg/L/h), resulting in 174 g/h throughput, whilst maintaining an excellent impurity profile. |
