Research On Synthesis Of The Tyrosine Kinase Inhibitor Pazopanib

Pazopanib hydrochloride,chemically knownas 5-[[4-[?2,3-dimethyl-2H-indazole-6-yl??methyl?amino]pyrimidine-2-yl]amino]-2-methyl benzenesulfonamide hydrochloride,is a research hotspot of anticancer drugs.In this assay,the synthesis routes of pazopani have been summarized and optimized.The new process is based on 3-methyl-6-nitro-1H-indazole and the target product pazopanib have been obtained by five-step reaction through N-methylation,reduction,nucleophilic substitution,secondary N-methylation and secondary nucleophilic substitution.The two steps of N-methylation reaction have been carried out using DMC/TBAB system,which has not been reported yet.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 the new process is 69.0%?literature yield 32.3%?,and its purity?99.9%.The structure of target compound has been confirmed by MS,¹H NMR,HSQC,IR,UV,¹³C NMR and DEPT-135°spectra.The optimized process conditions for each step reation showed as below.For the nitrogen methylation reaction,the molar ratio of3-methyl-6-nitro-2H-indazole,TBAB,DMC,and potassium carbonate is1.0:2.7%:2.0:3.0,yield is 92.0%,and the purity was?98.0%.For the reduction reaction,the molar ratio of compound 4,ethanol,and 5%Pd/C is1.0:26.6:0.5%,the reaction pressure is 0.4 MPa,and the reaction temperature range is 50⁵5?.For the nucleophilic substitution reaction,the mole ratio of compound 5,and 1,2-dichloropyrimidine was 1.0:1.2.The reaction operation is more basic after using the"one-pot"method of the reduction reaction and the nucleophilic substitution reaction.The product yield has been obviously improved,the yield of the two steps is around 87.0%,and the purity is?98.0%.For the secondary nitrogen methylation reaction,the molar ratio of the compound 6,TBAB,DMC,and potassium carbonate is 1.0:2.7%:2.0:3.0.The purification condition of the weight ratio for the compound 7,the ethanol to the water is 1.0:2.8:2.8.The condition has shown the good performances,obtained the yield of 90.0%and the purity more than 99.8%.For the secondary nucleophilic substitution reaction,the molar ratio of the compound 7,5-amino-2-methylbenzenesulfonamide,andisopropanolwas1.0:105.0%:38.3,the reaction temperature is 80-85?,yield is 95.8%,and the purity has been reached 99.9%.