{"title":"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","authors":"Jörg Gries, Johannes Platzek, Holger Paulsen","doi":"10.1002/hlca.202400008","DOIUrl":null,"url":null,"abstract":"<p>The evolution of the synthesis of a benzothiophene-2-yl-boronic acid - a key building block for the <i>anti</i>-cancer agent <i>Rogaratinib</i> - 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 <i>Newman-Kwart</i> 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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":null,"pages":null},"PeriodicalIF":16.4000,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hlca.202400008","citationCount":"0","resultStr":"{\"title\":\"Evolution of the Manufacturing Route towards a Key Benzothiophen-2-yl-Boronic Acid Building Block of Rogaratinib\",\"authors\":\"Jörg Gries, Johannes Platzek, Holger Paulsen\",\"doi\":\"10.1002/hlca.202400008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The evolution of the synthesis of a benzothiophene-2-yl-boronic acid - a key building block for the <i>anti</i>-cancer agent <i>Rogaratinib</i> - 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 <i>Newman-Kwart</i> 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.</p>\",\"PeriodicalId\":1,\"journal\":{\"name\":\"Accounts of Chemical Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.4000,\"publicationDate\":\"2024-03-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hlca.202400008\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Accounts of Chemical Research\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/hlca.202400008\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/hlca.202400008","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Evolution of the Manufacturing Route towards a Key Benzothiophen-2-yl-Boronic Acid Building Block of Rogaratinib
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.
期刊介绍:
Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance.
Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.