Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2H)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control,Organic Process Research & Development

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Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2H)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-04-20 , DOI: 10.1021/acs.oprd.2c00057
David N. Primer ₁ , Kelvin Yong ₁ , Antonio Ramirez ₂ , Matthew Kreilein ₁ , Antonio C. Ferretti ₁ , Antonio M. Ruda ₃ , Nadia Fleary-Roberts ₃ , Jonathan D. Moseley _{3,

4} , Siân M. Forsyth ₃ , Graham R. Evans ₃ , John F. Traverse _{1,

5}

Affiliation

We here present an optimized, scalable synthesis of bromodomain and extra-terminal (BET) inhibitor BMS-986378 (CC-90010). The original route and process 1A was 7 steps with 33.8% yield and featured numerous problematic solvents, process safety concerns, difficult to scale unit operations, and challenging to control impurities. Reaction optimization to remove or mitigate these challenges resulted in our first scale-up route and process, 2A. Subsequent challenges encountered on scale-up of route and process 2A warranted the creation and implementation of an enhanced process, which eliminated dichloromethane from a phenol bromination, improved catalyst performance in the penultimate cross-coupling, and finally developed a concomitant solvent charging process for form control in the final API crystallization. The resulting scale-up route and process, 2B, was demonstrated on a >50 kg scale and afforded the final product in 49% yield over 7 steps in >99.9% assay and area purity, meeting all ICH requirements for quality.

中文翻译：

用于治疗实体瘤的 4-芳基化 2-甲基异喹啉-1(2H)-one 工艺的开发：邻溴化、选择性溶解度、钯失活和形态控制方面的经验

我们在这里提出了溴结构域和末端外 (BET) 抑制剂 BMS-986378 (CC-90010) 的优化、可扩展合成。最初的路线和工艺 1A 是 7 个步骤，产率为 33.8%，并且具有许多有问题的溶剂、工艺安全问题、难以规模化的单元操作以及难以控制的杂质。消除或减轻这些挑战的反应优化导致了我们的第一个放大路线和工艺 2A。在扩大路线和工艺 2A 时遇到的后续挑战需要创建和实施增强工艺，该工艺从苯酚溴化中消除二氯甲烷，提高倒数第二个交叉偶联中的催化剂性能，并最终开发出一种伴随溶剂进料的成型工艺控制最终的 API 结晶。由此产生的放大路线和工艺，

更新日期：2022-04-20

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