反应详情

温度

140 °C

A stirred mixture of 4-(1-methylpiperidin-4-yl)quinazolin-2(1H)-one (500 mg, 2.29 mmol) and phosphorous oxychloride (5 mL, 56 mmol) was heated to reflux for 3 h. The reaction was then concentrated on a rotary evaporator and treated with ice water. The aqueous mixture was then extracted with ethyl acetate, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was treated with 4-aminobenzoic acid (534 mg, 3.90 mmol), triethylamine (660 μL, 4.58 mmol) and n-butanol (5 mL) and the mixture was heated to 140° C. for 25 min. The mixture was cooled and the solvent removed on a rotary evaporator. This material was then treated with HATU (1.63 g, 4.29 mmol) and Hunig's base (1.1 mL, 6.3 mmol) in dimethylformamide (10 mL) and the mixture stirred until it became homogenous. To this mixture was added 2,6-dimethylaniline (620 mg, 5.12 mmol) and the reaction was heated to 50° C. overnight. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N sodium bicarbonate and a 5% aqueous solution of lithium chloride, then was extracted with 1 N hydrochloric acid. The combined acidic washes were neutralized with 1 N sodium hydroxide and extracted with dichloromethane. These combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. Purification of this material via preparative reverse phase HPLC gave N-(2,6-dimethylphenyl)-4-{[4-(1-methylpiperidin-4-yl)quinazolin-2-yl]amino}benzamide as a white solid (19.7 mg, 2%). 1H NMR (400 MHz, CDCl3): δ 8.02-7.95 (m, 5H), 7.85-7.72 (m, 3H), 7.44-7.32 (m, 2H), 7.18-7.08 (m, 3H), 4.20-3.65 (br s, 3H), 3.55-3.45 (m, 1H), 3.20 (d, 2H), 2.44 (s, 3H), 2.39-2.18 (m, 10H), 2.07 (s, 2H), 1.99 (d, 2H). MS (EI) for C29H31N5O: 466.0 (MH+).

1. temperaturewas heated
2. temperatureto reflux for 3 h
3. concentrationThe reaction was then concentrated on a rotary evaporator
4. additiontreated with ice water
5. extractionThe aqueous mixture was then extracted with ethyl acetate
6. dry with materialthe combined organic extracts were dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated on a rotary evaporator
9. temperatureThe mixture was cooled
10. customthe solvent removed on a rotary evaporator
11. temperaturethe reaction was heated to 50° C. overnight
12. temperatureThe mixture was cooled to rt
13. extractionextracted with ethyl acetate
14. washThe combined organic extracts were washed with 1 N sodium bicarbonate
15. extractiona 5% aqueous solution of lithium chloride, then was extracted with 1 N hydrochloric acid
16. extractionextracted with dichloromethane
17. dry with materialThese combined organic extracts were dried over sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated on a rotary evaporator
20. customPurification of this material via preparative reverse phase HPLC