Phosphorus oxychloride → 4-Chloro-5,7-difluoroquinazoline

Participants

Reaction Conditions

Reaction Steps

Phosphoryl chloride (3.32 ml) was added to a stirred mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (5 g), diisopropylethylamine (7.16 ml) and acetonitrile (120 ml) that was cooled in an ice bath. The resultant reaction mixture was heated to 80° C. for 2 hours. A second portion of phosphoryl chloride (1.52 ml) was added and the reaction mixture was heated to reflux for a further 2.75 hours to provide a solution of 4-chloro-5,7-difluoroquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (International Application WO 01/94341, Example 17, Note [30]; 4.95 g) in acetonitrile (15 ml) was added and the reaction mixture was heated to 80° C. for 4 hours. The resultant reaction mixture was stirred at ambient temperature for 16 hours. A solution of a second portion of 6-chloro-2,3-methylenedioxyaniline (1.18 g) in acetonitrile (5 ml) was added and the reaction mixture was reheated to 80° C. for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was stirred for one hour. The resultant slurry was filtered and the isolated solid was washed with acetonitrile (20 ml) and dried. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline as a mono-hydrochloride salt (7.88 g, 99.3% HPLC purity using Method A, retention time 4.46 minutes); NMR Spectrum: (DMSOd6) 5.5-6.0 (br s, 1H), 6.15 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.7 (s, 1H), 1.9-2.0 (m, 2H).

Provenance & Evidence