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.

中文翻译：

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开发用于Verubecestat的中试规模的有机金属流动化学反应

我们报道了使用流化学技术在中试规模向手性酮亚胺中添加有机锂的进展。鉴于此过程的混合敏感性（以前在实验室和千克规模上都已确定），我们进行了关键实验以了解流速，温度和混合对工厂规模的静态混合器中反应性能的影响。在线过程分析技术用于批量收集实时数据，以演示多个小时内的稳态运行，并确认连续过程对结垢的鲁棒性。这些中试规模的实验提供了改进的操作参数，使该化学方法得以用于Verubecestat的商业生产，