Research On Synthesis Of The Key Intermediate Of The Tyrosine Kinase Inhibitor Pazopabib

At present,6-[N-(2-chloro-4-pyrimidinyl)methylamino]-2,3-dimethyl-2H-indazole,what is the key intermediates of pazopanib,and pazopanib are the research hotspot of anticancer drugs.In this thesis,the synthesis routes of pazopanib and 6-[N-(2-chlor-4-pyridinyl)methylamino]-2,3-dimethyl-2H-indazole were summarized,and the synthesis route of 6-[N-(2-chlor-4-pyridinyl)methylamino]-2,3-dimethyl-2H-indazole was optimized.The target product was synthesized from 2-ethylaniline via nitrification,cyclization,N-methylation,reduction,nucleophilic substitution and N-methylation.The two steps of N-methylation reaction were carried out using DMC/TBAB system,and this method has not been reported.The reduction reaction and nucleophilic substitution reaction were combined into“one-pot Method",and the reaction conditions of each step were optimized.Finally,the overall yield of pazopanib was 60.07%(literature yield 42.6%),and its purity was more than 99.8%.The structure of pazopanib was confirmed by IR,UV,1HNMR,13CNMR and DEPT-135°spectra.The optimized process conditions for each step reation were shown below.Nitration reaction,the mole ratio of 2-ethylaniline to concentrated sulfuricacid to potassium nitrate was 1.0:4.9:1.3,the reaction temperature for-5?5?,yield of 85.0%,and its purity was greater than 98.0%.Cyclizationreaction,the mole ratio of 2-ethyl-5-nitrobenzenamine to acetic acid to sodium nitrite was 1.0:27.7:1.1,yield of 98.0%,and its purity was greater than 98.0%.Nitrogen methylation reaction,the mole ratio of 3-methyl-6-nitro-2H-indazole to TBAB to DMC to potassium carbonate was 1.0:2.7%:2.0:3.0,yield of 92.0%,and its purity was greater than 98.0%.Reduction reaction,the mole ratio of 2,3-dimethyl-2H-indazol-6-amine to ethanol to 5%Pd/C was 1.0:26.6:0.5%,the reaction pressure 2.0MPa,and the reaction temperature 50-55 ?.Nucleophilic substitution reaction,the mole ratio of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine to 1,2-dichloropyrimidine was 1.0:1.2.When the reduction reaction and nucleophilic substitution reaction were carried out in one-pot method,the process is simple and the yield of products improved remarkably,yield of 87.0%,and its purity was greater than 98.0%.Again after the nitrogen methylation reaction to obtain the target product,the refined and satisfactory condition was the weight ratio of 6-[N-(2-chloro-4-pyrimidinyl)methylamino]-2,3-dimethyl-2H-indazole to ethanol to water was 1.0:2.8:2.8,yield of 90.0%,and its purity was greater than 99.8%.