High-yield synthesis method of radotinib
A synthesis method and technology of ladotinib, applied in the field of drug organic synthesis, can solve the problems of high synthesis cost and low total yield, and achieve the effects of reducing cost input, simplifying reaction operation, and reducing the amount of three wastes generated.
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Embodiment 1
[0024] (1) 3-acetamido-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl]benzamide (intermediate I )Synthesis:
[0025] 100 g of 3-acetamido-4-methylbenzoic acid and 100 mL of dichloromethane were put into a dry reaction flask, and 200 mL of thionyl chloride was added under stirring, and the temperature was raised to reflux for 4 h. After dichloromethane solvent and excess sulfone chloride were evaporated under reduced pressure, 300 mL of dichloromethane, 3-(4-methyl-1H-imidazolyl)-5-trifluoromethyl 125g of aniline and 108g of triethylamine were heated and refluxed for 8h. After the reaction, the solvent methylene chloride was evaporated, and the residue was poured into 300 mL of water to precipitate a yellow solid, which was filtered by suction and dried to obtain 204 g of the product, with a yield of 94.7%.
[0026] (2) Synthesis of 4-methyl-N-[3-(4-methyl-1H imidazolyl)-5-trifluoromethylphenyl]-3-guanidinobenzamide salt (intermediate II):
[0027] Put 45g...
Embodiment 2
[0031] (1) 3-acetamido-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl]benzamide (intermediate I )Synthesis:
[0032] 100 g of 3-acetamido-4-methylbenzoic acid and 100 mL of dichloromethane were put into a dry reaction flask, and 200 mL of thionyl chloride was added under stirring, and the temperature was raised to reflux for 4 h. After dichloromethane solvent and excess sulfone chloride were evaporated under reduced pressure, 300 mL of dichloromethane, 3-(4-methyl-1H-imidazolyl)-5-trifluoromethyl 125g of aniline and 108g of triethylamine were heated and refluxed for 8h. After the reaction, the solvent methylene chloride was evaporated, and the residue was poured into 300 mL of water, and a yellow solid was precipitated, which was filtered by suction and dried to obtain 202 g of the product, with a yield of 93.7%.
[0033] (2) Synthesis of 4-methyl-N-[3-(4-methyl-1H imidazolyl)-5-trifluoromethylphenyl]-3-guanidinobenzamide salt (intermediate II):
[0034] ...
Embodiment 3
[0039] (1) 3-acetamido-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl]benzamide (intermediate I )Synthesis:
[0040] 100 g of 3-acetamido-4-methylbenzoic acid and 100 mL of dichloromethane were put into a dry reaction flask, and 200 mL of thionyl chloride was added under stirring, and the temperature was raised to reflux for 4 hours. After dichloromethane solvent and excess sulfone chloride were evaporated under reduced pressure, 300 mL of dichloromethane, 3-(4-methyl-1H-imidazolyl)-5-trifluoromethyl 125g of aniline and 108g of triethylamine were heated and refluxed for 8h. After the reaction, the solvent methylene chloride was evaporated, and the residue was poured into 300 mL of water to precipitate a yellow solid, which was filtered by suction and dried to obtain 205 g of the product, with a yield of 95.1%.
[0041] (2) Synthesis of 4-methyl-N-[3-(4-methyl-1H imidazolyl)-5-trifluoromethylphenyl]-3-guanidinobenzamide salt (intermediate II):
[0042] Put...
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