Nemtabrutinib (MK-1026) is a novel oral Bruton’s tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C) were also required to achieve a modest 61% yield, with one major impurity, resulting from dehalogenation, accounting for the majority of the mass balance. An alternative process was developed to increase the yield and decrease the dependence on cryogenic temperatures, and this advancement was critical to the long-term robustness of the commercial process. Key advancements included performing the requisite deprotonation and metalation steps sequentially and performing the metalation and quench steps in flow. The final flow process was rapidly scaled from grams to tens of kilograms and has been successfully executed in a production facility.

中文翻译：

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Nemtabrutinib (MK-1026) 关键中间体的绿色和可持续制造工艺的开发：连续去质子化-锂化作为间歇-流动工艺

Nemtabrutinib (MK-1026) 是一种新型口服布鲁顿酪氨酸激酶 (BTK) 抑制剂，用于治疗 B 细胞癌。生成酮3 的初始合成供应路线依赖于高反应性瞬态中间体的生成和正丁基锂的使用。还需要低温（-60°C）才能实现适度的 61% 收率，其中一种主要杂质是脱卤产生的，占质量平衡的大部分。人们开发了一种替代工艺来提高产量并减少对低温的依赖，这一进步对于商业工艺的长期稳健性至关重要。关键的进步包括顺序执行必要的去质子化和金属化步骤，以及在流程中执行金属化和淬火步骤。最终的流程迅速从克级扩大到数十公斤，并已在生产设施中成功执行。