反应详情

To a solution of half of the crude addition product from Example 9 in anhydrous DMF (5 mL) was added under nitrogen at room temperature sodium hydride (25 mg, 0.63 mmol). The mixture was stirred at ambient temperature for 30 minutes and treated with methyl iodide (0.5 mL, excess). After stirring for 3.5 hours, a mixture of saturated aqueous ammonium chloride and IN HCl aqueous solution (10 mL/5 mL) was added to the reaction mixture. Ethyl acetate (30 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layers were washed with brine and dried (MgSO4). The solvent was removed and residue was dissolved in a mixture of methylene chloride and TFA (2 mL/2 mL). After stirring for 3 hours, the solution was poured onto ice-water and neutralized by addition of a saturated aqueous sodium bicarbonate solution. The ethyl acetate (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-3,4-dimethyl-3,4-dihydro-1H-quinazolin-2-one as a white solid (11 mg, 11% for three steps): mp 193-194° C.; 1H-NMR (DMSO-d6) δ 9.51 (s, 1H), 7.68 (s, 1H), 7.59 (d, 1H, J=8.0 Hz), 7.57 (d, 1H, J=1.6 Hz), 7.51 (dd, 1H, J=8.3, 1.7 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.35 (d, 1H, J=8.1 Hz), 6.87 (d, 1H, J=8.3 Hz), 3.02 (s, 3H), 1.51 (s, 3H), 1.25 (m, 1H), 0.32-0.51 (m, 3H), 0.25 (m, 1H); MS (CI) m/z 327 ([M+H]+, 100%). Anal. Calc. For C19H19Cl2O.0.3 H2O: C, 68.69, H, 5.95, N, 8.43. Found: C, 68.69, H, 5.70, N, 8.18.

1. stirringAfter stirring for 3.5 hours
2. customorganic layer was separated
3. extractionThe aqueous layer was extracted with ethyl acetate (3×10 mL)
4. washthe combined organic layers were washed with brine
5. dry with materialdried (MgSO4)
6. customThe solvent was removed
7. dissolutionresidue was dissolved in a mixture of methylene chloride and TFA (2 mL/2 mL)
8. stirringAfter stirring for 3 hours
9. additionthe solution was poured onto ice-water
10. additionneutralized by addition of a saturated aqueous sodium bicarbonate solution
11. additionThe ethyl acetate (30 mL) was added
12. customthe organic layer was separated
13. extractionThe aqueous layer was extracted with ethyl acetate (3×10 mL)
14. washThe combined organic layers were washed with brine
15. dry with materialdried (MgSO4)
16. customThe solvent was removed in vacuo
17. customthe residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1)