Ammonia → 4-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol

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Reaction Steps

6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in WO01/66099; 10.0 g, 39.6 mmole) was suspended in acetonitrile (400 ml) and 3-chloro-2-fluoroaniline (6.05 g, 41.6 mmole) and hydrogen chloride (4.0M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were added. The reaction mixture was refluxed for one hour and then allowed to cool to ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile and diethylether to give a white solid. This solid was added in portions to a stirred 1N methanolic ammonia solution (400 ml). The mixture was stirred for two hours and the precipitate filtered, washed with acetonitrile followed by diethylether and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline as a white solid (12.1 g, 95%); 1H NMR Spectrum: (DMSOd6) 3.95 (s, 3H); 7.18 (s, 1H); 7.20-7.25 (m, 1H); 7.39-7.44 (m, 1H); 7.47-7.52 (m, 1H); 7.65 (s, 1H); 8.31 (s, 1H); 9.45 (br.s, 1H); Mass Spectrum: (M+H)+ 320.

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