反应详情

温度

0 °C

To a solution of 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine (333 mg, 0.84 mmol) in THF (5 mL) at 0° C. was added ethyl isothiocyanate (74 uL, 0.84 mmol). After stirring for 2 h at 0° C., the reaction mixture was warmed to rt for 1 h and was then heated to 45° C. for 4 h. The mixture was then cooled back to rt and allowed to stir for 3 d. Addition of water was followed by extraction into ethyl acetate. The organic phase was then dried over magnesium sulfate, filtered, and concentrated. The residue obtained was then dissolved in acetonitrile (5 mL) and ethyl acetate (2 mL). To this solution was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol). The mixture was heated to reflux for 1.5 h and was then cooled to rt. Water and ethyl acetate were then added. The biphasic mixture was filtered to remove solid materials, and the filtrate was then partitioned. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase preparative HPLC to provide N-ethyl-6-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazol-2-amine as a diacetate salt (137 mg, 0.24 mmol, 29% yield). 1H NMR (400 MHz, dmso) δ 8.01 (d, 1H), 7.79-7.72 (m, 1H), 7.72-7.67 (m, 1H), 7.60 (d, 1H), 7.47-7.39 (m, 2H), 7.35 (s, 1H), 7.20-7.11 (m, 2H), 6.99 (d, 1H), 6.72 (br s, 1H), 5.02 (s, 2H), 4.47-4.38 (m, 2H), 4.22-4.13 (m, 2H), 3.37-3.27 (m, 2H), 2.48 (s, 3H), 1.89 (s, 7H), 1.18 (t, 3H); MS (EI) for C27H26N6O: 451 (MH+).

1. temperaturethe reaction mixture was warmed to rt for 1 h
2. temperaturewas then heated to 45° C. for 4 h
3. temperatureThe mixture was then cooled back to rt
4. stirringto stir for 3 d
5. extractionwas followed by extraction into ethyl acetate
6. dry with materialThe organic phase was then dried over magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. customThe residue obtained
10. temperatureThe mixture was heated
11. temperatureto reflux for 1.5 h
12. temperaturewas then cooled to rt
13. filtrationThe biphasic mixture was filtered
14. customto remove solid materials
15. customthe filtrate was then partitioned
16. extractionThe aqueous phase was extracted with ethyl acetate
17. dry with materialThe combined organic extracts were dried over magnesium sulfate
18. filtrationfiltered
19. concentrationconcentrated
20. customThe residue was purified by reverse-phase preparative HPLC