First-Generation Process Development for the Synthesis of Baloxavir Marboxil: Early-Stage Development of Synthetic Methods to Prepare Baloxavir Marboxil Intermediates

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-04-03 DOI:10.1021/acs.oprd.3c00514

Kosuke Anan*, Masayoshi Miyagawa, Azusa Okano, Hideki Sugimoto, Naoki Miyake, Nobuaki Fukui, Akihito Kijima, Emi Tanimoto and Makoto Kawai,

引用次数: 0

Abstract

Described herein is the discovery and development of a process to prepare chiral triazinanone R-3 and diastereomeric intermediate 5, the key intermediates in the synthesis of the cap-dependent endonuclease inhibitor baloxavir marboxil (1), which can suppress the replication of influenza virus. Chiral triazinanone R-3 was obtained via optical resolution of its racemic form rac-3. Diastereomeric intermediate 5 was obtained by the condensation reaction of triazinanone R-3 and thiepin alcohol 4 using a combination of T3P and MsOH. These reactions were performed successfully on kilogram scale and were critical to the establishment of the baloxavir marboxil manufacturing process.

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合成巴洛沙韦 Marboxil 的第一代工艺开发：制备巴洛沙韦 Marboxil 中间体的合成方法的早期开发

本文描述的是发现和开发制备手性三嗪酮 R-3 和非对映异构中间体 5 的工艺，它们是合成依赖于帽子的内切酶抑制剂巴洛沙韦 marboxil (1) 的关键中间体，可抑制流感病毒的复制。手性三嗪酮 R-3 是通过光学分解其外消旋体 rac-3 而得到的。三嗪酮 R-3 和噻吩醇 4 通过使用 T3P 和 MsOH 的组合进行缩合反应得到非对映中间体 5。这些反应在公斤级规模上成功进行，对建立巴洛沙韦马来霉素生产工艺至关重要。

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.

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