91% |
In tetrahydrofuran; for 3h;Reflux; Inert atmosphere; |
[000220] To <strong>[3177-80-8]2-amino-3-methoxybenzoic acid</strong> (5 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added triphosgene (3.55 g, 12 mmol). This mixture was heated to reflux under a nitrogen atmosphere for 3 hours. It was cooled to ambient temperature, and diethyl ether (50 mL) was added. The mixture was filtered to yield 8-methoxy-lH-benzo[d][l,3]oxazine-2,4- dione (5.25 g, 91%) as a solid. |
89% |
With pyridine; In dichloromethane; acetonitrile; at 50 - 55℃; for 2.33333h; |
Example 17. Preparation of 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-8-methoxyquinazolin-4(3H)-one; [0187] To a solution of <strong>[3177-80-8]2-amino-3-methoxy-benzoic acid</strong> (2.50 g, 14.9 mmol) in anhydrous acetonitrile (25 mL) at 50-550C were simultaneously added pyridine (2.36 g, 29.8 mmol) and a solution of triphosgene (1.46 g , 4.90 mmol) in anhydrous dichloromethane (10 mL) over 20 minutes, the reaction was stirred at 50-550C for 2 hours. The solvent was removed and the residue was mixed with water (100 ml_), the solid was filtered and rinsed with cold water (30 ml_) and dried. The crude was further washed with ether (20 ml_) to give 6-methoxy-1/-/-benzo[dJ[1 ,3]oxazine-2,4- dione. Yield: 2.56 g (89%).[0188] A solution of 8-methoxy-1H-benzo[c/][1 ,3] oxazine-2,4-dione (1.50 g, 7.70 mmol) and 4-bromoaniline (1.40 g, 8.10 mmol) in anhydrous DMF (10 ml_) was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 ml_) and ethyl acetate (150 ml_). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 : 1 ) to give 2-amino-Lambda/-(4-bromo-phenyl)-3-methoxy-benzamide. Yield: 1.49 g (60%).[0189] To a solution of 2-amino-Lambda/-(4-bromo-phenyl)-3-methoxy-benzamide (0.600 g, 1.86 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.360 g, 1.86 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.750 g, 5.58 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). After separation, the organic phase was further backwashed with water (100 mL), then brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 :1) to give the title compound as a white solid. Yield: 250 mg (27%). MP 100-1020C. 1H-NMR (400 Hz, CDCI3): delta 7.90 (d, 1 H), 7.47 (m, 3H), 7.25 (m, 1 H), 7.03 (d, 2H)1 7.00 (s, 2H), 4.02 (s, 3H), 3.91 (m, 2H), 3.80 (t, 2H), 2.15 (s, 6H), 2.06 (t, 1 H). MS (ES+) m/z: 497.41 (M+1). |