反应详情

温度

70 °C

To a 3-necked flask charged with 1-(4-chloroanilino) 4-[(2-methyl-4-pyridyl)methyl] phthalazine (for preparation see Novartis patent WO98/35958, 11.02.98) (0.828 g, 2.39 mmol) in anhydrous N-methylformamide (4.8 mL) was added concentrated sulfuric acid)0.12 mL. 2.39 mmol) and iron (II) sulfate heptahydrate (0.33 g, 1.19 mmol). Hydrogen peroxide (0.256 mL, 8.35 mmol; 30 wt. % solution in water) was added dropwise to keep the internal temperature below 80° C. The resultant wine color reaction was then stirred at 70° C. for 5 h. The reaction mixture was cooled to RT and quenched with 10% aqueous sodium hydroxide (10 mL) followed by 10% aqueous ammonia (˜100 mL). The resultant brown precipitate was filtered through a pad of celite, and the filtrate was extracted with 10% methanol-dichloromethane (3×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (1×50 mL), dried over MgSO4, filtered, and evaporated in vacuo. The crude oil was purified by flash column chromatography (10% acetone-dichloromethane followed by 1:4:20 v/v methanol-acetone-dichloromethane). Recrystallization from methanol afforded 0.165 g (0.404 mmol, 17% yield) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) 9.28 (s, 1H), 8.70 (d, J=4.9, 1H), 8.58 (d, J=7.4, 1H), 8.49 (d, J=5.4, 1H), 8.12 (d, J=8.4, 1H), 7.89 to 7.99 (m, 5H), 7.51 (dd, J=5.1, 1.7, 1H), 7.38 (dd, J=7.1, 1.9, 2H), 4.67 (s, 2H), 2.75 (d, J=4.9, 3H); MS ES 404 (M+H)+, calc. 403; TLC (1:4:15 v/v methanol-acetone-dichloromethane) Rf=0.74.

1. customthe internal temperature below 80° C
2. customThe resultant wine color reaction
3. temperatureThe reaction mixture was cooled to RT
4. customquenched with 10% aqueous sodium hydroxide (10 mL)
5. filtrationThe resultant brown precipitate was filtered through a pad of celite
6. extractionthe filtrate was extracted with 10% methanol-dichloromethane (3×100 mL)
7. washThe combined organic phases were washed with water (2×50 mL) and brine (1×50 mL)
8. dry with materialdried over MgSO4
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe crude oil was purified by flash column chromatography (10% acetone-dichloromethane followed by 1:4:20 v/v methanol-acetone-dichloromethane)
12. customRecrystallization from methanol