Phosphorus oxychloride → 4-Chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline

Participants

Reaction Conditions

Reaction Steps

A first portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added to a stirred mixture of phosphoryl chloride (1.76 ml), diisopropylethylamine (3.95 ml) and acetonitrile (10 ml) that had been heated to 80° C. The resultant mixture was heated to 80° C. for 3 hours. A second portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added and the mixture was heated to reflux for a further 90 minutes. There was thus obtained a solution of 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (0.32 g) in acetonitrile (3 ml) was added and the reaction mixture was heated to 80° C. for 2.5 hours. As the required conversion was incomplete, the reaction mixture was evaporated and toluene (15 ml) was added as reaction solvent. A second portion of 6-chloro-2,3-methylenedioxyaniline (0.32 g) was added and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and an aqueous sodium chloride solution. The organic phase was washed with water, dried over magnesium sulphate and evaporated. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline as a foam (0.73 g); NMR Spectrum: (DMSOd6) 1.9-2.05 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 8.6 (s, 1H), 9.3 (s, 1H).

Provenance & Evidence