反应详情

A suspension of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (214.5 mg, 0.495 mmol, Intermediate 3: step c) in dry THF (5 mL) was heated with a heat gun to form a solution. The solution was cooled in a dry ice-acetone bath for 2 minutes, then a solution of n-BuLi (2.5 M in hexanes, 0.18 mL, 0.45 mmol) was added dropwise by syringe. After 1 minute, a solution of (4-chlorophenyl)(pyridin-3-yl)methanone (0.117 mg, 0.541 mmol) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath that was allowed to warm to room temperature. The reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 50-100% EtOAc-hexanes) followed by reverse-phase chromatography (acetonitrile with 0.05% TFA in water). Product fractions were mixed with saturated aqueous sodium bicarbonate and DCM, the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated to provide the title compound as a clear oil.

1. temperaturewas heated with a heat gun
2. customto form a solution
3. temperatureThe solution was cooled in a dry ice-acetone bath for 2 minutes
4. customthe reaction flask was placed into an ice-water bath
5. customThe reaction was quenched with saturated ammonium chloride
6. customThe mixture was partitioned between water and ethyl acetate
7. extractionThe separated aqueous phase was further extracted with ethyl acetate
8. dry with materialThe organic phase was dried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated
11. customThe crude product was purified by flash column chromatography (silica gel, 50-100% EtOAc-hexanes)
12. additionProduct fractions were mixed with saturated aqueous sodium bicarbonate and DCM
13. customthe layers were separated
14. extractionthe aqueous layer was extracted with DCM
15. dry with materialThe combined organic layers were dried (Na2SO4)
16. filtrationfiltered
17. concentrationconcentrated