Enantioselective Synthesis of Savolitinib: Application of Mosher’s Method in the Development of Ellman’s Auxiliary-Directed Construction of the Key Chiral Amine Fragment

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-04-21 DOI:10.1021/acs.oprd.4c0044610.1021/acs.oprd.4c00446

Saikat Sen*, Vishnuvardhan Reddy Eda, Magesh Sampath, Karthik Pulluri, Shirshendu Das Gupta, Rajeev Rehani Budhdev, Rakeshwar Bandichhor and Srinivas Oruganti*,

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引用次数: 0

Abstract

An efficient rational synthesis of (S)-1-(imidazo[1,2-a]pyridin-6-yl)ethan-1-amine via Ellman’s auxiliary approach and elaboration of this key chiral intermediate into the anticancer drug Savolitinib has been described. An apt combination of Ellman’s sulfinamide and reducing agent afforded high levels of diastereofacial control during hydride addition and secured the desired S configuration in the intermediate, which was unambiguously verified by application of Mosher’s amide method. Our nine-step synthetic sequence to Savolitinib commences with commercially available 6-amino-nicotinic acid and was first demonstrated as a proof-of-concept study on a lab scale. It was then refined during scale-up to allow telescoping of six stages and afford the final API Savolitinib with >99% chiral purity.

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萨伏替尼的对映选择性合成：Mosher法在Ellman辅助定向构建关键手性胺片段中的应用

本文描述了通过Ellman辅助法高效合理地合成(S)-1-（咪唑[1,2-a]吡啶-6-基）乙二胺，并将这一关键手性中间体加工成抗癌药物Savolitinib。Ellman的亚胺和还原剂的适当组合在氢化物加成过程中提供了高水平的非对构面控制，并在中间体中获得了所需的S结构，这一点通过Mosher的酰胺方法得到了明确的验证。我们对Savolitinib的9步合成序列从市售的6-氨基烟酸开始，并首次在实验室规模上作为概念验证研究进行了演示。然后，在放大过程中对其进行细化，使其可以伸缩6级，最终获得手性纯度为99%的原料药Savolitinib。

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.