(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxy-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

HRID 928832Notes

Reaction equation

HRID 928832 reaction equation
C([Li])CCC.[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:33][N:34]1[C:38]([C:39]([C:41]2[CH:42]=[N:43][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:46]=2)=[O:40])=[CH:37][N:36]=[CH:35]1>C1COCC1>[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[N:34]([CH3:33])[CH:35]=[N:36][CH:37]=3)([C:41]3[CH:42]=[N:43][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:45][CH:46]=3)[OH:40])=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1

Participants

5

Reactant 3

HCID 86715442(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone2×HCID 867155993-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxy-8-methylquinoline2×HCID 178418339Butyllithium

Product 1

HCID 86715664(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxy-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

n-Butyllithium (1.6 M in hexane; 1.84 mL, 2.936 mmol) was added dropwise to a suspension of the 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxy-8-methylquinoline (1 g, 2.26 mmol, Intermediate 19: step b) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (0.63 g, 2.49 mmol, Intermediate 36: step c) in dry THF (23 mL) at −78° C. over a 2 minute period. After complete addition stirring was continued at −78° C. for 10 minutes then warmed in an ice bath to 0° C. The mixture was stirred for 1 hour then quenched with saturated aqueous NH4Cl and warmed to room temperature. After stirring for 10 minutes layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, evaporated in vacuo and chromatographed (0-5% MeOH in acetonitrile) to provide the title compound as an amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.00-8.07 (m, 1H), 7.92-7.99 (m, 2H), 7.87 (s, 1H), 7.72 (d, J=8.6 Hz, 3H), 7.57 (s, 1H), 7.33 (d, J=9.1 Hz, 2H), 7.16 (s, 1H), 6.40-6.59 (m, 1H), 4.29 (s, 2H), 4.07 (s, 3H), 3.53 (s, 3H) 2.65 (s, 3H); MS (ESI) 619.

Workup

  1. additionAfter complete addition
  2. stirringThe mixture was stirred for 1 hour
  3. customthen quenched with saturated aqueous NH4Cl
  4. temperaturewarmed to room temperature
  5. stirringAfter stirring for 10 minutes layers
  6. customwere separated
  7. extractionthe aqueous layer extracted with EtOAc
  8. dry with materialThe combined organic extracts were dried over Na2SO4
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customchromatographed (0-5% MeOH in acetonitrile)

Sources & evidence

ORD record
ord-42d6c2b5d3f74c5cbc3d8eac6745913e
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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