Development of an Organometallic Flow Chemistry Reaction at Pilot-Plant Scale for the Manufacture of Verubecestat

We report the development of an organolithium addition to a chiral ketimine at pilot-plant scale using flow chemistry. Given the mixing sensitivity of this process, established previously at both lab and kilogram scale, we conducted critical experiments to understand the impact of flow rate, temperature, and mixing on the performance of the reaction in a factory-sized static mixer. Online process analytical technology was used to collect real-time data on batches to demonstrate steady-state operation over multiple hours and also to confirm the robustness of the continuous process against fouling. These experiments at pilot-plant scale provided improved operating parameters that enabled the implementation of this chemistry for the commercial manufacture of verubecestat, currently being evaluated in Phase III trials for the treatment of Alzheimer's disease.