Evolution of the Manufacturing Route towards a Key Benzothiophen-2-yl-Boronic Acid Building Block of Rogaratinib

IF 1.5 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Jörg Gries, Johannes Platzek, Holger Paulsen
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引用次数: 0

Abstract

The evolution of the synthesis of a benzothiophene-2-yl-boronic acid - a key building block for the anti-cancer agent Rogaratinib - is reported from multi-gram scale to industrialization. The pitfalls and learnings during process development are outlined, describing the optimization of the initial research synthesis route, investigation of an alternative approach based on a palladium-catalyzed Newman-Kwart rearrangement and finally changing the synthetic strategy from thiophene-construction to benzene-ring formation. Although the initial route was utilized to deliver material on kg-scale, the requirements for market-supply triggered the decision to pursue a new synthetic route. Catalyst costs, high purity-requirements, and not the least technical practicality caused the change to a synthesis with indeed higher step-count. However, this could be mitigated by repeated application of a telescoping approach. The free boronic acid was finally selected and manufactured as a stable isolated intermediate after challenges like proto-deboronation and trimerization to boroxine upon drying could be solved by an optimized crystallization procedure.

Abstract Image

罗加替尼的关键苯并噻吩-2-基硼酸结构单元生产工艺的演变
报告了苯并噻吩-2-基硼酸--抗癌药罗加替尼的关键构件--的合成从多克规模到工业化的演变过程。报告概述了工艺开发过程中的陷阱和经验教训,介绍了初始研究合成路线的优化、基于钯催化纽曼-克瓦特重排的替代方法的研究,以及最终将合成策略从噻吩构建改为苯环形成。虽然最初的合成路线可以按公斤级提供材料,但市场供应的要求促使我们决定采用新的合成路线。催化剂成本、高纯度要求以及最起码的技术实用性,都促使我们改用步骤数更多的合成方法。不过,通过反复应用伸缩方法,这一问题得以缓解。通过优化结晶程序,解决了原硼化和干燥后三聚化为硼氧的难题,游离硼酸最终被选中并制成稳定的分离中间体。
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来源期刊
Helvetica Chimica Acta
Helvetica Chimica Acta 化学-化学综合
CiteScore
3.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Helvetica Chimica Acta, founded by the Swiss Chemical Society in 1917, is a monthly multidisciplinary journal dedicated to the dissemination of knowledge in all disciplines of chemistry (organic, inorganic, physical, technical, theoretical and analytical chemistry) as well as research at the interface with other sciences, where molecular aspects are key to the findings. Helvetica Chimica Acta is committed to the publication of original, high quality papers at the frontier of scientific research. All contributions will be peer reviewed with the highest possible standards and published within 3 months of receipt, with no restriction on the length of the papers and in full color.
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