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

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First-Generation Process Development for the Synthesis of Baloxavir Marboxil: Early-Stage Development of Synthetic Methods to Prepare Baloxavir Marboxil Intermediates
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-04-03 , DOI: 10.1021/acs.oprd.3c00514
Kosuke Anan ₁ , Masayoshi Miyagawa ₁ , Azusa Okano ₁ , Hideki Sugimoto ₁ , Naoki Miyake ₁ , Nobuaki Fukui ₂ , Akihito Kijima ₂ , Emi Tanimoto ₂ , Makoto Kawai ₁

Affiliation

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.

中文翻译：

Baloxavir Marboxil 合成的第一代工艺开发：制备 Baloxavir Marboxil 中间体的合成方法的早期开发

本文描述的是制备手性三嗪酮 R-3 和非对映异构体中间体 5 的方法的发现和开发，这是合成帽依赖性核酸内切酶抑制剂 baloxavir 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 通过光学拆分其外消旋形式 rac-3 获得。使用T3P和MsOH的组合，通过三嗪酮R-3和硫杂苯醇4的缩合反应得到非对映体中间体5。这些反应在公斤级上成功进行，对于巴洛沙韦马波西生产工艺的建立至关重要。

更新日期：2024-04-03

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