Adagrasib’s Second-Generation Synthesis: Transitioning from Route Scouting to Optimization

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-04-10 DOI:10.1021/acs.oprd.4c00024

Zhichao Lu, Chengsheng Chen, Dinesh J. Paymode, Yonghong Gan, Thomas Scattolin, Sahar Roshandel, Weitong Dong, Stanley Yu, Stéphane Lemeune, David R. Snead, Cheng-yi Chen

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Abstract

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%.

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Adagrasib 的第二代合成技术：从路线侦察到优化过渡

在完成阿达拉西布第二代生产路线的工艺设计后，披露了工艺优化细节。开发的主要目标包括控制关键起始原料（KSM）中难以清除的杂质、提高 KSM 的可扩展性、改善核心嘧啶酮的形成、提高氧化的稳健性、提高第 3 步中间体的稳定性、去除第 4 步中的卤化溶剂以及实现最终原料药的单结晶。这些改进提高了阿达拉昔布的生产效率，并将商品成本进一步降低了约 50%。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.