Improved Synthesis for the 4-Pyridone Intermediate of Baloxavir Marboxil: Elimination of Polar Aprotic Solvents and Optimization Through Design of Experiments (DoE)

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-03-07 DOI:10.1021/acs.oprd.4c00473

Jianwu Lu, Yinfei Shi, Kongcheng Huang, Yuebin Liu, Shun Yuan, Xiaolong Yang, Yansheng Xu, Xun Sun, Taizhi Wu

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Abstract

This article presents the development of an improved synthetic process for a crucial intermediate in the production of the antiviral drug baloxavir marboxil. The focus is on optimizing the telescoped synthesis of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)-amino)-4-oxo-1,4-dihydropyridine-2-carboxylate (compound 7) built on the original method, which used polar aprotic solvents to improve selectivity in the acid-catalyzed dehydration-condensation reaction between intermediate ester 6 and tert-butyl carbazate. This process encountered difficulties related to high-boiling solvent recovery and the generation of nitrogen-rich wastewater. To overcome these challenges, we evaluated three optimization strategies. Notably, the use of a PPTS-organic base buffering system (Strategy III) enabled the replacement of the polar aprotic solvent DMAc with readily recoverable THF under the acidity adjustment and Lewis base catalysis effect of triethylamine (TEA). Design of experiments (DoE) further optimized the reaction parameters, significantly reducing the level of impurities, including the identification of three previously unreported process impurities. The optimized process was successfully scaled up to 135 g in the laboratory, yielding the monohydrate form of compound 7 with a purity of 98.3% and an overall yield improved from 78.6% to 85.1%.

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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.