(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-(diethylamino)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

HRID 928857Notes

Reaction equation

HRID 928857 reaction equation
[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][C:11]3[C:12]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[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.[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[O:37])=[CH:34][N:33]=[CH:32]1.[Li]CCCC>>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][C:11]3[C:12]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:39]=[N:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=3)[OH:37])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1

Participants

4

Reactant 3

HCID 86715442(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone2×HCID 867156263-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-N,N-diethylquinolin-2-amine2×HCID 178418339Butyllithium

Product 1

HCID 74221398(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-(diethylamino)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

Conditions

Temperature
-78 °C

Procedure

A round bottom flask was charged with 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-N,N-diethylquinolin-2-amine (380 mg, 0.809 mmol, Intermediate 46) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (206 mg, 0.809 mmol, Intermediate 36, step c) and was evacuated and re-filled with argon. THF (13.5 mL) was added, and the solution was cooled in a dry ice acetone bath for 10 minutes. n-BuLi (1.6 M in hexane, 0.506 mL, 0.809 mmol), was added dropwise by syringe. The mixture was stirred at −78° C. for 30 minutes, then in an ice water bath for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 50-100% EtOAc-heptanes) to provide the title compound as a white foam.

Workup

  1. customwas evacuated
  2. additionre-filled with argon
  3. additionTHF (13.5 mL) was added
  4. temperaturethe solution was cooled in a dry ice acetone bath for 10 minutes
  5. waitin an ice water bath for 30 minutes
  6. customThe reaction was quenched by addition of saturated aqueous NH4Cl
  7. additiondiluted with water
  8. extractionextracted with EtOAc (3×)
  9. dry with materialThe organic phase was dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by flash column chromatography (silica gel, 50-100% EtOAc-heptanes)

Sources & evidence

ORD record
ord-f267505340264b9b89ed4728c9e7ba8e
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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