4-Chlorophenyl pyridin-3-yl ketone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol

HRID 926506Notes

Reaction equation

HRID 926506 reaction equation
[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:39])=[CH:34][CH:33]=1>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1

Participants

5

Reactant 3

HCID 845184-Chlorophenyl pyridin-3-yl ketoneHCID 867155943-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline2×HCID 178418339Butyllithium

Product 1

HCID 74220747(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-3191e6a7cb6a4472a7151a6f31b467df
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

Loading…