巴洛昔韦马博西连续生产工艺的开发

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-03-10 DOI:10.1021/acs.oprd.4c00517

Keith S. Barbato, Qinglin Su, Youhua Li, Anjana Ramnath, Wei Wu, Chuntian Hu, Stephen C. Born, Paul Hermant, Paul Stonestreet, Michael Berg, Bayan Takizawa, Salvatore Mascia

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引用次数: 0

摘要

我们报告了罗氏商业产品Xofluza的活性药物成分（API） Baloxavir Marboxil连续加工的初步研究。这一努力背后的动机是过渡到集成连续制造（ICM）作为一个平台，为具有高度可变市场需求的药物创建敏捷和按需供应链能力。本文所述的工作包括改进巴洛昔韦马博西的后期合成路线，该路线(1)将四步合成减少到两步，(2)确定了达到所需材料规格的关键非对异构体结晶条件，以及(3)不再使用N，N-二甲基乙酰胺，取而代之的是更环保的乙腈和水的溶剂混合物。在批量模式下对两步合成路线进行全面修正后，将关键单元操作转换为连续模式以评估其性能。总的来说，这项工作减少了16个单元作业，大大简化了流程，并且预计使用ICM将把交货时间从12个月缩短到几天。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Process Development toward the Continuous Manufacturing of Baloxavir Marboxil

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Process Development toward the Continuous Manufacturing of Baloxavir Marboxil

We report the initial studies toward the continuous processing of Baloxavir Marboxil, the active pharmaceutical ingredient (API) of Roche’s commercial product Xofluza. The motivation behind this effort is to transition to integrated continuous manufacturing (ICM) as a platform to create an agile and on-demand supply chain capability for a drug that has highly variable market demand. The work described herein includes an improved late-stage synthetic route to Baloxavir Marboxil that (1) reduced a four-step synthesis down to two steps, (2) identified key diastereomeric crystallization conditions to reach required material specifications, and (3) removed the use of N,N-dimethylacetamide in exchange for a more environmentally benign solvent mixture of acetonitrile and water. After a full revision of the two-step synthetic route in batch mode, key unit operations were translated to continuous mode to evaluate their performance. Collectively, this work eliminated 16 unit operations, significantly simplified the process, and is projected to reduce the lead time from 12 months to several days using ICM.

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.