Efficient Synthesis of a Key Intermediate for Baloxavir Marboxil from a Greener Starting Material: Ethylene Glycol

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2021-09-08 DOI:10.1021/acs.oprd.1c00141

Zhongqing Wang*, Zihong Zhou, Jingping Kou, Shuming Wu, Yongbo Xu, Jiebin Zeng

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引用次数: 0

Abstract

In this article, a robust and scalable process to prepare the key intermediate 7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1) for the synthesis of the influenza antiviral drug baloxavir marboxil is described. The process is based on a novel preparation of 2-(2,2-dimethoxyethoxy)ethanamine 5 employing inexpensive and readily available ethylene glycol as the starting material with more convenient manipulation and fewer environmental hazards compared with the original routes starting with ethanolamine or its derivatives. Large-scale applicability of this new route has been successfully demonstrated on kilogram-scale production to afford 700 grams of 1 with 99.3% purity in 31% yield over six steps. With such satisfactory quality, baloxavir marboxil is eventually furnished with excellent purity (>99.5%, single impurity < 0.1%). Meanwhile, the corresponding impurity profile is studied in detail.

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以乙二醇为原料高效合成巴洛昔韦马博西酯的关键中间体

本文介绍了合成流感抗病毒药物巴洛昔韦马博西的关键中间体7-(苯氧基)-3,4,12,12a-四氢- 1h -[1,4]恶嗪[3,4-c]吡哆[2,1-f][1,2,4]三嗪-6,8-二酮(1)的稳健和可扩展工艺。该工艺是基于一种新的制备2-(2,2-二甲氧基乙氧基)乙胺5的方法，采用廉价且易得的乙二醇作为起始原料，与以乙醇胺或其衍生物为起始原料的原始路线相比，操作更方便，对环境的危害更小。这条新路线的大规模适用性已经成功地在公斤级生产中得到验证，通过六个步骤，以31%的收率生产出纯度为99.3%的700克1。在这样令人满意的质量下，巴洛韦马博西最终具有优异的纯度(99.5%，杂质单一)。0.1%)。同时对相应的杂质谱进行了详细的研究。

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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.