反应详情

A solution of n-BuLi (2.5 M in hexanes, 0.49 mL, 1.2 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (0.500 g, 1.23 mmol, Intermediate 5: step d) in dry THF (20.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (230.9 mg, 1.233 mmol, Intermediate 6: step b) in dry THF (1.5 mL) was added dropwise. The reaction was stirred for 2 minutes, then moved into an ice bath for 7 minutes, and finally allowed to warm to ambient temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water/brine and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc), followed by reverse phase chromatography (ACN/H20+0.05% TFA). Product fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54 (d, J=3.9 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.84 (dd, J=9.5, 7.7 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J=14.1, 5.4 Hz, 3H), 7.05 (t, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J=7.8 Hz, 2H), 6.22 (d, J=1.1 Hz, 1H), 3.51 (q, J=14.6, 7.3 Hz, 4H), 3.25 (s, 3H), 1.05 (t, J=7.0 Hz, 6H); MS m/e 514.3 [M+H]+.

1. waitmoved into an ice bath for 7 minutes
2. customThe reaction was quenched with saturated aqueous ammonium chloride
3. customThe mixture was partitioned between water/brine and dichloromethane
4. extractionThe separated aqueous phase was further extracted with dichloromethane
5. dry with materialThe organic phase was dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated
8. customThe crude product was purified by flash column chromatography (silica gel, 100% EtOAc)
9. extractionextracted with DCM
10. dry with materialbefore being dried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated