Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach,Organic Process Research & Development

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Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-11-25 , DOI: 10.1021/acs.oprd.0c00416
Gabrielle St-Pierre ₁ , Alan H. Cherney ₁ , Wencan Chen ₁ , Xiaofei Dong ₂ , Peter K. Dornan ₃ , Daniel J. Griffin ₃ , K. N. Houk ₂ , Janice B. Lin ₂ , Stephen Osgood ₁ , Maria V. Silva Elipe ₁ , Heath C. Timmons ₁ , Yong Xie ₁ , Jason S. Tedrow ₁ , Oliver R. Thiel ₃ , Austin G. Smith ₁

Affiliation

AMG 176 is a drug candidate in our oncology pipeline. Ring-closing metathesis (RCM) is a key reaction in the AMG 176 synthesis that is used to construct the 16-membered macrocycle. Process intensification was executed on a compressed timeline by combining high-throughput experimentation and computational analysis using density functional theory, which led to the identification of an optimal 4-bromobenzoate protecting group on the allylic alcohol moiety. Comprehensive process improvements led to a reduction in reaction volume from 800 to 50 L/kg with a >20% yield improvement compared with the discovery route. The RCM process developed from these studies was instrumental in the clinical advancement of the AMG 176 program.

中文翻译：

结合高通量实验和计算建模方法，加速开发可伸缩的封闭环复分解以制造AMG 176

AMG 176是我们肿瘤科药物中的候选药物。闭环复分解（RCM）是AMG 176合成中的关键反应，用于构建16元大环。通过结合高通量实验和使用密度泛函理论的计算分析，在压缩的时间轴上进行了工艺强化，从而确定了烯丙基醇部分上的最佳4-溴苯甲酸酯保护基。全面的工艺改进使反应体积从800 L / kg减少到50 L / kg，与发现路线相比，收率提高了20％以上。这些研究开发的RCM流程对AMG 176计划的临床发展至关重要。

更新日期：2020-11-25

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