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Adagrasib’s Second-Generation Synthesis: Transitioning from Route Scouting to Optimization
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-04-10 , DOI: 10.1021/acs.oprd.4c00024 Zhichao Lu 1 , Chengsheng Chen 1 , Dinesh J. Paymode 1 , Yonghong Gan 1 , Thomas Scattolin 1 , Sahar Roshandel 1 , Weitong Dong 1 , Stanley Yu 1 , Stéphane Lemeune 2 , David R. Snead 1 , Cheng-yi Chen 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-04-10 , DOI: 10.1021/acs.oprd.4c00024 Zhichao Lu 1 , Chengsheng Chen 1 , Dinesh J. Paymode 1 , Yonghong Gan 1 , Thomas Scattolin 1 , Sahar Roshandel 1 , Weitong Dong 1 , Stanley Yu 1 , Stéphane Lemeune 2 , David R. Snead 1 , Cheng-yi Chen 1
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Process optimization details are disclosed following the completion of process design for a second-generation manufacturing route of adagrasib. Key objectives for development included control of difficult-to-purge impurities in the key starting materials (KSMs), enhanced scalability of the KSM, improved pyrimidone formation of the core, increased robustness of oxidation, enhanced stability of the step 3 intermediate, removal of the halogenated solvent in the fourth step, and implementation of single crystallization of the final API. These improvements led to more efficient production of adagrasib and a further reduction in the cost of goods by approximately 50%.
中文翻译：
Adagrasib 的第二代综合：从路线搜索过渡到优化
在完成第二代阿达格拉西生产路线的工艺设计后，公开了工艺优化细节。开发的主要目标包括控制关键起始材料 (KSM) 中难以净化的杂质、增强 KSM 的可扩展性、改善核心的嘧啶酮形成、增强氧化稳定性、增强第 3 步中间体的稳定性、去除第四步卤化溶剂，实现最终API的单结晶。这些改进提高了阿达格拉西的生产效率，并将商品成本进一步降低了约 50%。
更新日期：2024-04-10
中文翻译：
Adagrasib 的第二代综合：从路线搜索过渡到优化
在完成第二代阿达格拉西生产路线的工艺设计后，公开了工艺优化细节。开发的主要目标包括控制关键起始材料 (KSM) 中难以净化的杂质、增强 KSM 的可扩展性、改善核心的嘧啶酮形成、增强氧化稳定性、增强第 3 步中间体的稳定性、去除第四步卤化溶剂，实现最终API的单结晶。这些改进提高了阿达格拉西的生产效率，并将商品成本进一步降低了约 50%。
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