A Novel Synthetic Route Research Of A B-Raf Kinase Inhibitor Drug Intermediates

In recent years,the high incidence of cancer,targeted drug therapy is one of the treatment options.In about 7% of human tumors,the B-Raf gene is mutated,and the study of B-Raf kinase inhibitors is a hot field in the study of targeted anti-cancer drugs.This thesis is about the research of a novel synthetic route of a B-Raf kinase inhibitor drug intermediates(2,6-difluoro-3-(propylsulfonamido)benzoic acid),which is a class of targeted anti-cancer drugs intermediates.2,6-Difluoro-3-(propylsulfonamido)benzoic acid is a common key intermediate of three types of general formula for B-Raf kinase inhibitor drugs,its synthesis has been reported in a large number of literatures.This thesis summarizes the reported several synthetic schemes,discussed the advantages and disadvantages of their schemes,then proposed a novel synthetic route.The starting material is 2,6-difluorobenzoic acid,through nitration,reduction,esterification,sulfonamidation,hydrolysis steps,and obtain the target product with high yield,total yield of five steps was 58.3%.The structure of target product was confirmed by by IR,UV,MS and NMR(1H NMR、13C NMR、19F NMR)analysis.In order to make the novel synthetic route can be successfully transferred to the industrial production,we optimized the process through experiments,and finally got a higher yield.The optimized conditions of nitrification step were 2,6-difluorobenzoic acid: sulfuric acid: fuming nitric acid =1:3:1.4(molar ratio),reaction temperature-10~-5℃,yield was 91%,purity≥98%;The optimized conditions of reduction step were BRAF-1: methanol: 5% Pd/C =1:10:0.03,reaction pressure 0.01 Mpa,temperature 20~30,yield was 100%(product was not separated),purity≥98%;The optimized conditions of esterification step were BRAF-2: thionyl chloride =1:1.15(molar ratio),yield was 71%,purity ≥ 99%;The optimized conditions of sulfonamidation step were BRAF-3: pyridine: propyl sulfonyl chloride =1:4: 1.15(molar ratio),adding time of propyl sulfonyl chloride was at least 8 hours,and by adding 0.05(molar ratio)4-Dimethylaminopyridine,the reaction conditions were mild,and the purity of product can be significantly increased,yield was 95%,purity≥98%;The hydrolysis step was optimized by orthogonal experiment with three factors and three levels,The optimized conditions were BRAF-4: methanol: water =1:4:2,crystallization temperature was-10~-5℃,yield was 95%,purity≥99%.