N-methyl-2-pyrrolidone → N-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

참여 물질

반응 조건

반응 단계

4-(6-Chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (80 g) was added portionwise to a stirred mixture of sodium tert-pentoxide (90.2 g) and N-methylpyrrolidin-2-one (500 ml) under an atmosphere of nitrogen gas. 4-Hydroxytetrahydropyran (23.5 ml) and N-methylpyrrolidin-2-one (35 ml) were added and the resultant mixture was heated to 60° C. for 3 hours. Water (764 ml) was added to the heated reaction mixture during 3 hours and the mixture was stirred and heated to 60° C. for a further 3 hours. The warm reaction mixture was filtered and the isolated solid was washed with water (2×230 ml) and dried in vacuo to constant weight. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (68.6 g, 95% HPLC purity using Method A, retention time 4.6 minutes); m.p. 209-212° C.; NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.05 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).

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