KRAS G12C抑制剂中间体(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)硼酸的合成新方法  

A Novel Synthetic Process of KRAS G12C Inhibitors Intermediate(2-((Tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)boronic Acid

作　　者：朱益忠 王路路 梁潮根 ZHU Yizhong;WANG Lulu;LIANG Chaogen(Chia Tai Tianqing Pharmaceutical Group Co.,Ltd.,Nanjing 210009,China)

机构地区：[1]正大天晴药业集团股份有限公司,江苏南京210009

出　　处：《合成化学》2024年第5期457-462,共6页Chinese Journal of Synthetic Chemistry

摘　　要：RAS基因突变是癌症中常见的基因突变类型,而KARS基因突变是RAS突变中影响最大的突变。KRAS G12C突变是KRAS基因中发生率较高的一种突变形式,是当前药物开发的重要靶点。构效关系表明:苯并[d]噻唑片段的引入有助于提高化合物对KRAS G12C的抑制活性,因此对该关键中间体的合成方法做了进一步的研究。本研究改进了KRAS G12C抑制剂中间体(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)硼酸(A)的合成方法,以2-溴-3,5-二氟苯胺为起始物料,经4步反应制备得到(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)硼酸。该方法合成步骤较文献方法节约2步,且无需使用昂贵的钯催化剂。同时也对合成方法中关键工艺步骤进行了优化,选用NBS/MeSO_(3)H关环,80℃下反应4 h,中间体2收率提高至90%以上;此外还对最后一步硼化反应进行了优化,放弃使用昂贵的钯催化剂,采用硼酸三异丙酯和正丁基锂的条件来制备产物硼酸,经柱层析纯化后收率可以达到30%以上,节约了生产成本。并利用MS和~1H NMR确证了其结构。RAS gene mutation is a common type of gene mutation in cancers, and KARS gene mutation is the most influential mutation among RAS mutations. The KRAS G12C mutation is a mutation with a high incidence in the KRAS gene, and is an important target for current drug development. The structure-activity relationship shows that the introduction of benzo[ d ]thiazole fragment helps to improve the inhibitory activity of the compound on KRAS G12C. Therefore, the synthetic process of this key intermediate is further studied. In this study, the synthetic process of KRAS G12C inhibitors intermediate (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[ d ]thiazol-4-yl)( A )boronic acid was improved, and (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[ d ]thiazol-4-yl)boronic acid was prepared by four steps from 2-bromo-3,5-difluoroaniline as the starting material. This method saved two steps compared with the literature method, and did not need to use expensive palladium catalyst. Moreover, the key process steps were optimized. NBS/MeSO_(3) H was selected for ring closure and the yield of intermediate 2 could reach more than 90% at 80 ℃ for 4 h. Furthermore, the last step of borylation reaction was optimized. It was found that triisopropyl borate and n-butyllithium could be used to prepare the boric acid instead of palladium catalyst, and the yield could reach more than 30% after purification by column chromatography, and the structure was confirmed by MS and 1 H NMR.

关 键 词：KRAS G12C 苯并[d]噻唑 硼酸 合成 新方法 

分 类 号：TQ128[化学工程—无机化工]