Synthesis Of Anti-cancer Targeted Therapies Drug Tivozanib

Tivozanib was synthesized through the Friedel-Crafts acylation, nitration,reduction,cyclization,chlorinated,condensation reaction with1,2-dimethoxybenzene as the startingmaterial. All synthetic compounds were analyzed by1H-NMR and MS. The total yieldof tivozanib was35.1%.Synthetic routs and methods of tivozanib were feasible to Industial production owing to the cheap raw materials, mild reaction conditions, stable technology and high yield.Through a very large number of experimental researches, some conclusions areconcluded:(1) In the Friedel-Crafts acylation, the best ratio of trichloromethane:auminiumtrichloride:ethanoyl chloride was1:1.6:1.3,the reaction time was6hours,and the bestreaction temperature was0~10℃. The reaction yield was83%.(2) In the nitrification, the best reaction ratio of1-(3,4-dimethox-yphenyl) ethanone:nitric acid was1:6.67, the optimum reaction temperature was20~25℃, and the reactiontime was0.5h. The reaction yield was82%.(3) In the reduction,the best molar ratio of1-(4,5-dimethoxy-2-nitrophenyl)ethanone: iron powder: water was1:3.0~3.5:60~80, PH value was adjusted to3.5~4by acetic acid,refluxing time was6h,the optimal PH value for sodium carbonate was9~10andthe reaction yield was96%.(4) During the cyclization, the best reaction ratio of1-(2-amino-4,5-dimethoxyphenyl)ethanone: ethyl formate: dicyclohexylcarbodiimide was1:4.05:3.02. The reactionyield was81.5%(5) In the process of chlorination, the best molar ratio of6,7-dimethoxyquinolin-4(1H)–one: phosphorus chloride was1:1.65, and refluxing time was1h. The reactionyield was97%.(6) In the addition condensation, the best molar ratio of4-amino-3–chlorophenolhydrochloricde:potassium carbonate:4-chloro-6,7-dimethoxy-quinoline was1:2.35:0.67,the optimum reaction time was5h at115℃. The reaction yield was64.3%.(7) During the condensation, the best molar ratio of Phenylchloroformate:3-amino-5-methylisoxazole:2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)benzenamine was1:1:0.66, and the best reaction time was5h at80℃. The reaction yield was86.1%.(8) Tivozanib was synthesized through the Friedel-Crafts acylation,nitration,reduction, cyclization,chlorinated,condensation reaction with1,2-dimethoxybenzene asthe starting material. The total yield of tivozanib was35.1%.