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.

中文翻译：

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有机锂介导的流动偶联反应的中试规模操作和表征，以形成 Nemtabrutinib 的酮中间体

在 nemtabrutinib 商业路线的倒数第二个步骤之一中，在甲基锂和n介导的一系列反应中，由 7-溴-6-氯-7-脱氮嘌呤和 2-氯-4-苯氧基苯甲酸甲酯形成酮中间体。-丁基锂。流动化学在开发过程中被认为是一种有用的工具，可以安全有效地放大其中两个反应，同时最大限度地减少不需要的杂质的形成。在这里，我们展示了该工艺的首次中试规模实施，其中使用管式流动反应器来生产数公斤的酮中间体。讨论了大规模操作的实际考虑因素，包括在-30°C左右的低温下操作、稳定一致的流量控制以及规划预防和从异常情况中恢复。设备和程序的精心设计和建造使得能够成功执行五个中试批次，并具有一致的产量和产品质量，以生产临床开发所需的材料。在整个生产过程中，该工艺的平均分离收率约为 65%，平均纯度为 99.9%（按重量计）。还介绍了一系列大规模流动实验的结果，其中温度、停留时间和反应化学计量同时变化以评估过程的稳健性。在这些实验中，发现正丁基锂化学计量对反应产率具有最大影响，如通过产物LC面积百分比测量的。此外，所研究的工艺杂质均对不同参数的不同组合敏感。从这次试点活动中获得的经验教训对于指导未来的开发工作以及 nemtabrutinib 的潜在商业供应至关重要。