反应详情

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (49 mg, 0.30 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask and heated at reflux for 48 hours under an N2 atmosphere. Analysis after overnight reaction showed only partial conversion, so additional N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (33 mg, 0.21 mmol) and sodium hydride (60% dispersion in mineral oil, 25 mg, 1.03 mmol) were added and the vessel was resealed and heated at reflux for an additional 48 hours. The reaction solution was then cooled to room temperature, diluted with EtOAc, transferred to a separatory funnel, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H24Cl2N4O2, 518.1; m/z found, 519.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.17 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 7.69 (s, 1H), 7.50-7.45 (m, 2H), 7.44-7.40 (m, 1H), 7.39-7.33 (m, 6H), 6.26 (s, 1H), 4.67-4.60 (m, 2H), 3.47 (s, 3H), 3.20 (t, J=5.3 Hz, 2H).

1. temperatureheated
2. temperatureat reflux for 48 hours under an N2 atmosphere
3. customAnalysis after overnight reaction
4. additionwere added
5. temperatureheated
6. temperatureat reflux for an additional 48 hours
7. customtransferred to a separatory funnel
8. extractionextracted with saturated, aqueous NH4Cl
9. customThe organic phase was separated
10. dry with materialthen dried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe crude product was purified via reverse phase chromatography
14. customThe fractions from the purification
15. additioncontaining the desired product
16. customwere transferred to a separatory funnel with EtOAc
17. extractionextracted with a saturated, aqueous NaHCO3 solution
18. customThe aqueous layer was separated
19. extractionextracted with EtOAc
20. dry with materialthe combined organic phases were dried over MgSO4
21. filtrationfiltered
22. concentrationconcentrated under reduced pressure