(336a) Continuous Flow Process Development for a Radical Chlorodifluoromethylation Reaction

A single step continuous manufacturing process has been developed to produce a drug substance intermediate via a radical fluoroalkylation¹. The flow process has considerable advantages over the batch process, notably improved process safety concerns for a highly exothermic reaction with thermally unstable reactants. The flow process offers exquisite control of residence time at any scale, which limited the loss of product to hydrolysis during the reaction and work-up. Utilization of plate reactor technology and continuous liquid-liquid extractors resulted in a safe and highly efficient alternative to a batch synthesis. Further process optimization was completed, and a second-generation process was developed to avoid fouling issues, improve reactant efficiency and avoid dimethyl sulfoxide. The first- and second-generation processes were successfully scaled-up in a GMP facility at the multi-kilogram scale.

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Meng, D.; Li, L.; Brown, A.; Desrosiers, J.-N.; Duan, S.; Hayward, C. M.; He, Z.; Hu, J.; Makowski, T.; Maloney, M.; Monfette, S.; Perfect, H.; Piper, J. L.; Zhou, M.; Widlicka, D. W. A Radical Chlorodifluoromethylation Protocol for Late-Stage Difluoromethylation and Its Application to an Oncology Candidate. Cell Reports Physical Science 2021, 2 (4), 100394. https://doi.org/10.1016/j.xcrp.2021.100394.