Aminopyridine derivatives and use thereof
An amino and alkyl technology, which is applied in the field of preparing drugs for inhibiting excessive cell proliferation, can solve problems such as difficulty in large-scale production, complex molecular structure, and limited resources.
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Embodiment 1
[0094] Example 1 3,4,5-trifluoro-2[(3-methyl-5-iodo-2-pyridyl)amino]benzoic acid
[0095] Step 1. Methyl 2,3,4,5-tetrafluorobenzoate
[0096] 2,3,4,5-Tetrafluorobenzoic acid (48.5 g, 0.25 mol) was dissolved in 130 mL of anhydrous methanol, and trimethylchlorosilane (63 mL, 0.50 mol) was slowly added dropwise. After the dropwise addition, reflux for 12h. Evaporate the solvent and excess trimethylchlorosilane under reduced pressure with a water pump to obtain a light yellow liquid, add 200mL of dichloromethane, and wash with 10% aqueous sodium hydroxide solution, extract the water layer with dichloromethane, combine the organic layers, and Dry overnight with anhydrous sodium sulfate. Filtration the next day, the solvent was evaporated under reduced pressure to obtain a colorless liquid methyl 2,3,4,5-tetrafluorobenzoate (30.52g, 97.8%), 1 H-NMR (400MHz, CDCl 3 ) δppm: 7.65-7.60 (m, 1H), 3.97 (s, 1H).
[0097] Step 2, 2,3,4,5-tetrafluorobenzamide
[0098] Add methyl 2,3,4,5...
Embodiment 2
[0107] Example 2 N-{3-[(tert-butyl-dimethyl)silyloxy]propoxy}-3,4,5-trifluoro-2-[(3-methyl-5-iodo-2 -pyridyl)amino]benzamide
[0108] 3,4,5-trifluoro-2[(3-methyl-5-iodo-2-pyridyl)amino]benzoic acid (0.29g, 0.71mol) prepared in Example 1, O-{3 [(tert-butyl-dimethylsilyl)oxy]propyl}hydroxylamine (0.27g, 1.303mmol), N,N-diisopropylethylamine (DIEA) (0.15mL, 0.855mmol) were dissolved in 20mL di In methyl chloride, benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (0.43 g, 0.82 mmol) was added, and the reaction was stirred at room temperature for 1.5 h. Add 40 mL of anhydrous diethyl ether to the reaction system, wash the organic phase with water and saturated aqueous sodium chloride solution, and dry the organic layer with anhydrous sodium sulfate overnight. The next day, it was filtered, the solvent was evaporated under reduced pressure, and column chromatography gave white solid N-{3-[(tert-butyl-dimethyl)silyloxy]propoxy}-3,4,5-trifluoro-2 - [(3-Met...
Embodiment 3
[0109] Example 3 N-[(2,2-methyl-1,3-dioxolan-4-yl)methoxy]-3,4,5-trifluoro-2-[(3-methyl-5- Iodo-2-pyridyl)amino]benzamide
[0110] 3,4,5-trifluoro-2[(3-methyl-5-iodo-2-pyridyl)amino]benzoic acid (0.43g, 1.06mmol) prepared in Example 1 was dissolved in anhydrous In THF 20mL, the system was cooled to -15°C, diphenylphosphonyl chloride (0.27mL, 1.38mmol) was added, and reacted at -15°C for 30min. Add N-methylmorpholine (0.12 mL, 1.06 mmol) and react at -15°C for 30 min. Add O-[(2,2-dimethyl-1,3-diketon-4-yl)methyl]hydroxylamine (0.19 g, 1.27 mmol) and react at -15°C for 30 min. Add N-methylmorpholine (0.18 mL, 1.59 mmol), return to room temperature, and stir at room temperature overnight. 60 mL of ethyl acetate was added to the reaction solution, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate overnight. The next day, it was filtered, the solven...
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