Development of a Stereoselective Route for Kilogram-Scale Synthesis of STING Agonist BMS-986301

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-10-05 DOI:10.1021/acs.oprd.6c00219

Miao Yu, Bin Zheng, Chao Hang, Geoffrey E. Purdum, Daniel S. Treitler, Melda Sezen-Edmonds, Changxia Yuan, Adam J. Freitag, Siwei Guo, Guanghui Zhu, Jason Zhu, Carlos Alberto Pons Sierpermann, Benjamin Hritzko, Jonathan G. Shackman, Sloan Ayers, Hua Chia Tai, Weiqing Fu, Brian L. He, Jim Paulson, Qinggang Wang, Amanda J. Rogers, Michael A. Schmidt, Benjamin Cohen

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引用次数: 0

Abstract

Following the discovery of a chiral P(V) reagent to enable diastereoselective synthesis of stereogenic thiophosphoramidates, we have developed a scalable synthesis to deliver kilogram quantities of the STING agonist BMS-986301. The route not only reduced the number of steps compared to the enabling route but also avoided the use of hazardous reagents. Further development enabled the use of crystallizations to isolate intermediates, effectively eliminating six chromatographic purifications. This resulted in an eightfold improvement in yield and 90% reduction in process mass intensity (PMI). The route was successfully implemented in a pilot-plant campaign to deliver 1.65 kg of BMS-986301 (1) and was therefore deemed suitable as a long-term option for commercial synthesis.

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千克级立体选择性合成STING激动剂BMS-986301的研究

继手性P(V)试剂的发现，使立体硫磷酰胺的非对对选择性合成，我们已经开发了一种可扩展的合成，以提供公斤量的STING激动剂BMS-986301。该路线不仅比启用路线减少了步骤数，而且避免了危险试剂的使用。进一步的发展使使用结晶分离中间体，有效地消除了六层色谱纯化。这导致产量提高了8倍，工艺质量强度（PMI）降低了90%。该路线在一个中试工厂成功实施，生产了1.65千克BMS-986301(1)，因此被认为是适合商业合成的长期选择。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.