Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is an antiviral drug for influenza. This paper presents the development of two alternative routes for the industry-oriented preparation of a key tricyclic triazinanone 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, in order to overcome the drawbacks of the initial scaled-up synthetic route used in the kilo lab. The first candidate route is based on a late-stage reductive approach to the target starting with raw materials used in the previous route, namely, morpholin-3-one and a pyridone carboxylic acid derivative. The highlight of this approach is the tandem condensation of the morpholine and pyridone units to construct the tricyclic core of the substrate for the final reduction step. The other candidate route engages less expensive raw materials, combination of a protected 2-aminoethanol and 2-bromo-1,1-dimethoxyethane instead of morpholin-3-one, and six chemical steps in total. The efficient transformation was accomplished by a single-step conversion consisting of four elementary steps, including tandem cyclizations accompanied by deprotections. The latter process proved to be robust for production of more than tens of kilograms for practical large-scale manufacturing, providing >27 kg of the targeted triazinanone intermediate per batch in 56% overall yield with satisfactory purity.

中文翻译：

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Baloxavir Marboxil 的实用制造工艺：三环三嗪酮支架的有效途径

Baloxavir marboxil 是一种帽子依赖性核酸内切酶抑制剂，是一种治疗流感的抗病毒药物。本文提出了两种替代路线的开发，用于工业化制备关键的三环三嗪酮中间体 7-(苄氧基)-3,4,12,12a-四氢-1 H -[1,4]恶嗪[3, 4- c ]吡啶并[2,1- f ][1,2,4]三嗪-6,8-二酮，以克服公斤级实验室最初放大合成路线的缺点。第一条候选路线基于对目标的后期还原方法，从前一路线中使用的原材料（即吗啉-3-酮和吡啶酮羧酸衍生物）开始。该方法的亮点是吗啉和吡啶酮单元的串联缩合，以构建最终还原步骤底物的三环核心。另一条候选路线采用较便宜的原材料，将受保护的 2-氨基乙醇和 2-溴-1,1-二甲氧基乙烷组合，而不是吗啉-3-酮，总共有六个化学步骤。有效的转化是通过由四个基本步骤组成的单步转化完成的，包括串联环化和脱保护。事实证明，后一种工艺对于实际大规模生产来说是稳健的，可以生产超过数十公斤的产品，每批可提供 >27 公斤的目标三嗪酮中间体，总收率为 56%，纯度令人满意。