反应详情

HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 5-methyl-3-isoxazolecarboxylic acid (0.127 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.115 g). 1H NMR Spectrum: (DMSO d6 373K) 1.87 (m, 2H), 2.08 (m, 2H), 2.48 (s, 3H), 3.61 (m, 2H), 3.89 (m, 2H), 3.96 (s, 3H), 4.80 (m, 1H), 6.40 (s, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.90 (s, 1H), 8.39 (s, 1H), 9.26 (br s, 1H); Mass Spectrum: (M+H)+ 512.

1. washthe organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml)
2. customThe crudes were then purified by flash column chromatography
3. washeluting with methanol/methylene chloride (2.5/97.5)
4. additionFractions containing the desired product
5. customwere evaporated to a white foam which
6. customwas triturated with diethyl ether (20 ml)