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Efficient Synthesis of a Key Intermediate for Baloxavir Marboxil from a Greener Starting Material: Ethylene Glycol
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-09-08 , DOI: 10.1021/acs.oprd.1c00141 Zhongqing Wang 1, 2, 3 , Zihong Zhou 1, 2 , Jingping Kou 2 , Shuming Wu 2 , Yongbo Xu 2 , Jiebin Zeng 2
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-09-08 , DOI: 10.1021/acs.oprd.1c00141 Zhongqing Wang 1, 2, 3 , Zihong Zhou 1, 2 , Jingping Kou 2 , Shuming Wu 2 , Yongbo Xu 2 , Jiebin Zeng 2
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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.
中文翻译：
从更绿色的起始材料：乙二醇有效合成 Baloxavir Marboxil 的关键中间体
在本文中，一种稳健且可扩展的制备关键中间体 7-(benzyloxy)-3,4,12,12a-tetrahydro-1 H- [1,4]oxazino[3,4- c ]pyrido[2, 1- ˚F ] [1,2,4]三嗪-6,8-二酮（1），用于流感的抗病毒药物baloxavir marboxil的合成进行说明。该方法基于 2-(2,2-二甲氧基乙氧基) 乙胺5的新制备方法，采用廉价且易得的乙二醇作为起始材料，与从乙醇胺或其衍生物开始的原始路线相比，具有更方便的操作和更少的环境危害. 这条新路线的大规模适用性已在公斤级生产中得到成功证明，可提供 700 克1具有 99.3% 的纯度和 31% 的产率，经过六个步骤。凭借如此令人满意的质量，baloxavir marboxil 最终具有优异的纯度（>99.5%，单一杂质<0.1%）。同时，详细研究了相应的杂质分布。
更新日期：2021-09-17
中文翻译：
从更绿色的起始材料：乙二醇有效合成 Baloxavir Marboxil 的关键中间体
在本文中，一种稳健且可扩展的制备关键中间体 7-(benzyloxy)-3,4,12,12a-tetrahydro-1 H- [1,4]oxazino[3,4- c ]pyrido[2, 1- ˚F ] [1,2,4]三嗪-6,8-二酮（1），用于流感的抗病毒药物baloxavir marboxil的合成进行说明。该方法基于 2-(2,2-二甲氧基乙氧基) 乙胺5的新制备方法，采用廉价且易得的乙二醇作为起始材料，与从乙醇胺或其衍生物开始的原始路线相比，具有更方便的操作和更少的环境危害. 这条新路线的大规模适用性已在公斤级生产中得到成功证明，可提供 700 克1具有 99.3% 的纯度和 31% 的产率，经过六个步骤。凭借如此令人满意的质量，baloxavir marboxil 最终具有优异的纯度（>99.5%，单一杂质<0.1%）。同时，详细研究了相应的杂质分布。
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