Baloxavir marboxil (BXM) is an influenza antiviral drug that exploits a cap-dependent endonuclease (CEN) inhibitor. The synthesis route used in the initial CMC development study had several problems hampering scale-up, such as poor stereochemical outcome which decreased the yield, usage of a corrosive reagent, and a cumbersome protocol for the key step. We addressed these problems to enable practical and operation-friendly manufacture of BXM at a larger production scale for early and successive CMC development. The new route includes the following steps: (1) a magnesium-mediated alkoxy displacement reaction to prepare an intermediate without loss of optical purity and (2) diastereoselective preparation of an intermediate via a dehydration condensation reaction with a crystallization-induced diastereomer transformation (CIDT) process. This facile route enabled scalable manufacturing to supply BXM.

中文翻译：

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Baloxavir Marboxil 的实用制造工艺：保护基团的有效选择和替换以增强结晶诱导的非对映异构体转化

Baloxavir marboxil (BXM) 是一种流感抗病毒药物，利用帽依赖性核酸内切酶 (CEN) 抑制剂。最初的 CMC 开发研究中使用的合成路线存在一些阻碍放大的问题，例如立体化学结果差导致产率下降、腐蚀性试剂的使用以及关键步骤的繁琐方案。我们解决了这些问题，以便能够以更大的生产规模实际且易于操作地制造 BXM，以用于早期和后续的 CMC 开发。新路线包括以下步骤：（1）镁介导的烷氧基置换反应制备中间体而不损失光学纯度；（2）通过脱水缩合反应和结晶诱导的非对映体转化（CIDT）非对映选择性制备中间体） 过程。这种便捷的路线使可扩展的制造能够供应 BXM。