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 1N HCl aqueous solution (10 mL/5 mL) was added to the reaction mixture. Ethyl acetate (30 mL) was added and the 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 C19H19ClN2O.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. additionwas added to the reaction mixture
3. customthe organic layer was separated
4. extractionThe aqueous layer was extracted with ethyl acetate (3×10 mL)
5. washthe combined organic layers were washed with brine
6. dry with materialdried (MgSO4)
7. customThe solvent was removed
8. dissolutionresidue was dissolved in a mixture of methylene chloride and TFA (2 mL/2 mL)
9. stirringAfter stirring for 3 hours
10. additionthe solution was poured onto ice-water
11. additionneutralized by addition of a saturated aqueous sodium bicarbonate solution
12. additionThe ethyl acetate (30 mL) was added
13. customthe organic layer was separated
14. extractionThe aqueous layer was extracted with ethyl acetate (3×10 mL)
15. washThe combined organic layers were washed with brine
16. dry with materialdried (MgSO4)
17. customThe solvent was removed in vacuo
18. customthe residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1)