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).

中文翻译：

---

Baloxavir Marboxil 工艺杂质的鉴定、合成、表征及控制策略建立

本手稿全面总结了 baloxavir marboxil 中的 12 种工艺杂质，其中包括 4 种之前未报告的杂质。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，以增强对该过程的理解。制定了相应的控制策略。进行了三批公斤级示范，巴洛沙韦马波西尔收率51%，纯度超过99.8%，单一杂质检出率<0.10%，均由手性原料A-1获得。值得注意的是，这两种基因毒性杂质被有效清除至低于检测限的水平，符合毒理学关注阈值 (TTC) 规定的标准。