Identification, Synthesis, Characterization, and Control Strategy Establishment for Process Impurities of Baloxavir Marboxil

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-03-22 DOI:10.1021/acs.oprd.4c00011

Huixiong Lu, Guobin Xu, Jingping Kou, Shuming Wu, Jiebin Zeng, Yuting Liu, Jidi Lin, Yongbo Xu, Wei Shang, Yaoyao Li and Zhongqing Wang*,

引用次数: 0

Abstract

This manuscript provides a comprehensive summary of 12 process impurities in baloxavir marboxil, including four previously unreported impurities. Through identification, synthesis, and characterization using MS and NMR techniques, the formation pathways of each impurity were proposed to enhance the understanding of the process. Corresponding control strategies were established. Three batches of kilogram-scale demonstrations were conducted, resulting in baloxavir marboxil with a yield of 51%, purity exceeding 99.8%, and a single impurity detected at <0.10%, all achieved from chiral starting material A-1. Notably, the two genotoxic impurities were effectively purged to levels below detection limits, meeting the criteria specified by the Threshold of Toxicological Concern (TTC).

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巴洛沙韦 Marboxil 工艺杂质的鉴定、合成、表征和控制策略的制定

本手稿全面总结了巴洛沙韦 marboxil 中的 12 种工艺杂质，包括 4 种以前未报道过的杂质。通过使用 MS 和 NMR 技术进行鉴定、合成和表征，提出了每种杂质的形成途径，以加深对工艺的理解。并制定了相应的控制策略。在进行了三批公斤级示范后，巴洛沙韦 marboxil 的收率达到 51%，纯度超过 99.8%，只检测到 0.10% 的杂质，所有杂质均来自手性起始原料 A-1。值得注意的是，两种基因毒性杂质被有效清除至检测限以下，达到了毒理学关注阈值（TTC）规定的标准。

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.