81% |
With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
54
Example 54. Preparation of 2-(4-(2-(isoxazol-3-ylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one [0317] To a solution of isoxazol-3-amine (2.28 g, 27.1 mmol) in CH2CI2 at 0°C under nitrogen was added Et3N (2.74 g, 27.1 mmol), followed by bromoacetyl chloride (4.26 g, 27.1 mmol). The mixture was warmed to room temperature, stirred for 2 hours, washed sequentially with water (200 ml_) and brine (200 ml_), dried (Na2SO4), filtered, and concentrated, to afford 2-bromo-N-(isoxazol-3-yl)acetamide as a tan solid (4.5 g, 81%).[0318] To a solution of 2-bromo-N-(isoxazol-3-yl)acetamide (1.0 g, 4.9 mmol) in THF (50 mL) under nitrogen was added 1.0 M BH3^THF (14.6 ml_, 14.6 mmol). The mixture was stirred at room temperature for 3.5 hours and then an additional portion of BH3»THF (5.0 mL, 5.0 mmol) was added. After an additional 15 hours at room temperature, the reaction was quenched with 1 M NaOH, extracted with ethyl acetate (2 * 150 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1 :1 ethyl acetate/heptane to 100% ethyl acetate, to afford N-(2-bromoethyl)isoxazol-3-amine (0.133 g, 14%).[0319] To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (0.471 g, 3.14 mmol) in DMF (20 mL) was added K2CO3 (0.650 g, 4.71 mmol). The reaction mixture was stirred at room temperature under nitrogen for 30 minutes. Then, a solution of N-(2-bromoethyl)isoxazol-3-amine (0.600 g, 3.14 mmol) in DMF (10 mL) was added. The mixture was heated at reflux for 3 hours, concentrated, and purified by flash chromatography on silica gel, eluting with 30% ethyl acetate/heptane to 100% ethyl acetate, to afford 4-(2-(isoxazol-3-ylamino)ethoxy)-3,5-dimethylbenzaldehyde as a white solid (0.260 g, 32%).[0320] A mixture of 4-(2-(isoxazol-3-ylamino)ethoxy)-3,5-dimethylbenzaldehyde (0.253 g, 0.97 mmol), 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97 mmol), NaHSO3 (0.111 g, 1.07 mmol), and p-TsOH (0.018 g, 0.097 mmol) in DMA (10 mL) was heated at 1500C under nitrogen for 44 hours. Then, the reaction mixture was concentrated, diluted with ethyl acetate (200 mL), and washed with water (150 mL), then brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% CH2CI2 to 100% 92:7:1 CHCb/MeOH/concentrated NH4OH, to afford the title compound (0.150 g, 35%). 1H NMR (300 MHz, DMSO-c/6: δ 11.82 (s, 1 H), 8.39 (d, J = 1.7 Hz, 1 H), 7.89 (s, 2H), 6.73 (d, J = 2.2 Hz, 1 H), 6.51 (d, J = 2.2 Hz, 1 H), 6.44 (t, J = 6.1 Hz, 1 H), 6.02 (d, J = 1.7 Hz, 1 H), 3.94 (t, J = 5.5 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.46- 3.51 (m, 2H), 2.27 (s, 6H). APCI MS m/z 437 [M+H]+. |
81% |
With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
48
To a solution of isoxazol-3-amine (2.28 g, 27.1 mmol) in CH2Cl2 at 0° C. under nitrogen was added Et3N (2.74 g, 27.1 mmol), followed by bromoacetyl chloride (4.26 g, 27.1 mmol). The mixture was warmed to room temperature, stirred for 2 hours, washed sequentially with water (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated, to afford 2-bromo-N-(isoxazol-3-yl)acetamide as a tan solid (4.5 g, 81%) |