Pilot-Scale Operation and Characterization of an Organolithium-Mediated Coupling Reaction in Flow to Form a Ketone Intermediate on the Route to Nemtabrutinib

In one of the two penultimate steps in the commercial route to nemtabrutinib, a ketone intermediate is formed from 7-bromo-6-chloro-7-deazapurine and methyl 2-chloro-4-phenoxybenzoate in a series of reactions mediated by methyllithium and n-butyllithium. Flow chemistry was identified in development as a useful tool for safe and efficient scale-up for two of these reactions while minimizing the formation of unwanted impurities. Here, we present the first pilot-scale implementation of the process where a tubular flow reactor was employed to produce multiple kilograms of the ketone intermediate. Practical considerations for large-scale operations are discussed, including operation at low temperatures around −30 °C, stable and consistent control of flow rates, and planning for the prevention of and recovery from upset scenarios. Careful design and construction of equipment and procedures allowed for the successful execution of five pilot-scale batches with consistent yield and product quality to produce material needed for clinical development. Across the campaign, average isolated yield for the process was approximately 65%, with an average purity of 99.9% by weight. Also presented are the findings from a series of large-scale flow experiments, where temperature, residence time, and reaction stoichiometry were simultaneously varied to assess process robustness. In these experiments, n-butyllithium stoichiometry was found to have the greatest impact on reaction yield, as measured by product LC area percent. Additionally, the process impurities studied were each sensitive to a different combination of the varied parameters. Learnings from this pilot campaign were critical to guide future development efforts en route to a potential commercial supply of nemtabrutinib.