反应详情

To a suspension of 5-cyanooxindole (720 mg, 4.55 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (248 mg, 6.2 mmol, 60% dispersion in oil). After 15 min, was added 4-[(6-chloropyridin-3-yl)methyl]morpholine (323 mg, 1.52 mmol; described in: Maienfisch, P. et al. J. Med. Chem. 2000, 43, 5003) to the solution. The reaction mixture was heated at reflux for 1 h. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. A 2 M aqueous HCl solution was added to the ethyl acetate and water mixture until slightly acidic pH, and then NaHCO3 (s) was added until saturation. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and the solvent was removed in vacuo. The crude product was dissolved in a mixture of methanol and ethyl acetate and was cooled on ice. A solution of HCl in diethyl ether was added until acidic pH. Approximately half of the solvent volume was removed in vacuo. The precipitated hydrochloride salt was filtered, washed with ethyl acetate, and dried in vacuo. The salt was converted back to the base by partitioning between ethyl acetate and an aqueous saturated NaHCO3 solution. The obtained material (142 mg) was purified on a silica gel column using chloroform/ethanol, (9:1), as the eluent affording 34 mg (7% yield) of the title compound as the base as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 14.96 (br s, 1 H), 8.83 (br s, 1 H), 7.79 (dd, J=9, 1 Hz, 1 H), 7.69 (s, 1 H), 7.63 (s, 1 H), 7.50 (d, J=9 Hz, 1 H), 7.29-7.26 (m, 1 H), 7.06 (d, J=8 Hz, 1 H), 3.75-3.72 (m, 4 H), 3.44 (s, 2 H), 2.50-2.49 (m, 4 H).

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 1 h
3. customThe solvent was removed in vacuo
4. customthe residue was partitioned between ethyl acetate and water
5. additionA 2 M aqueous HCl solution was added to the ethyl acetate and water mixture until slightly acidic pH
6. additionNaHCO3 (s) was added until saturation
7. extractionThe mixture was extracted with ethyl acetate
8. washThe organic layer was washed with brine
9. dry with materialdried (Na2SO4)
10. customthe solvent was removed in vacuo
11. dissolutionThe crude product was dissolved in a mixture of methanol and ethyl acetate
12. temperaturewas cooled on ice
13. additionA solution of HCl in diethyl ether was added until acidic pH
14. customApproximately half of the solvent volume was removed in vacuo
15. filtrationThe precipitated hydrochloride salt was filtered
16. washwashed with ethyl acetate
17. customdried in vacuo
18. customby partitioning between ethyl acetate
19. customThe obtained material (142 mg) was purified on a silica gel column