A Novel Synthetic Process of KRAS G12C Inhibitors Intermediate(2-((Tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)boronic Acid
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 struc-ture-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 inter-mediate 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/MeSO3H was selected for ring closure and the yield of in-termediate 2 could reach more than 90％at 80 ℃ for 4 h.Furthermore,the last step of borylation re-action 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 1H NMR.
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