反应详情

温度

80 °C

A first portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.19 g) in toluene (3 ml) was added to a stirred mixture of phosphoryl chloride (0.059 ml), diisopropylethylamine (0.13 ml) and toluene (3 ml) that was heated to 80° C. and the resultant mixture was heated to 80° C. for 6 hours. The mixture was allowed to cool to ambient temperature and was stirred overnight. The mixture was re-heated to 80° C. and a solution of 6-chloro-2,3-methylenedioxyaniline (0.088 g) in toluene (2 ml) was added. The resultant mixture was stirred and heated to 80° C. for 1.5 hours. The mixture was cooled to ambient temperature and the solvent was decanted from the oily gum that had been deposited. The oily gum was suspended in DMF (3 ml), a second portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.088 g) was added and the reaction mixture was heated to 100° C. for 9 hours. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and a 2M aqueous hydrochloric acid solution (10 ml). The aqueous solution was basified by the addition of 10M aqueous sodium hydroxide solution (10 ml) and extracted with methylene chloride. The organic solution was dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.008 g); NMR Spectrum: (DMSOd6) 1.85-1.95 (m, 2H), 2.1-2.2 (m, 2H), 2.2 (s, 3H), 2.2-2.4 (m, 4H), 2.4-2.6 (m, 4H), 2.87 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.9 (m, 2H), 4.2 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 6.85 (s, 1H), 6.9 (s, 1H), 6.95 (d, 1H), 7.05 (d, 1H), 8.35 (s, 1H), 9.2 (s, 1H).

1. temperatureto cool to ambient temperature
2. temperatureThe mixture was re-heated to 80° C.
3. temperatureheated to 80° C. for 1.5 hours
4. temperatureThe mixture was cooled to ambient temperature
5. customthe solvent was decanted from the oily gum that
6. additiona second portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.088 g) was added
7. temperaturethe reaction mixture was heated to 100° C. for 9 hours
8. temperatureto cool to ambient temperature
9. custompartitioned between ethyl acetate
10. additionThe aqueous solution was basified by the addition of 10M aqueous sodium hydroxide solution (10 ml)
11. extractionextracted with methylene chloride
12. dry with materialThe organic solution was dried over magnesium sulphate
13. customevaporated
14. customThe resultant oil was purified by column chromatography on silica using
15. temperatureincreasingly polar mixtures of methylene chloride and methanol as eluent