5-Bromo-2-(trifluoromethyl)pyridine → (4-Chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

HRID 928840Notes

Reaction equation

HRID 928840 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)([C:2]3[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([CH3:43])(=[O:41])=[O:42])=[CH:38][CH:39]=1

Participants

4

Reactant 2

HCID 27611975-Bromo-2-(trifluoromethyl)pyridineHCID 86715613(4-Chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone2×

Product 1

HCID 74220878(4-Chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Isopropyl magnesium chloride LiCl complex (1.3 M in THF, 0.7 mL, 0.904 mmol) was added dropwise to a solution of 5-bromo-2-(trifluoromethyl)pyridine (0.2 g, 0.904 mmol) in dry THF 5 mL) at 0° C. The mixture was stirred at 0° C. for five minutes then at room temperature for 30 minutes. A suspension of (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.085 g, 0.181 mmol, Intermediate 38: step b) in THF (5 mL) was added rapidly at 0° C. and the reaction mixture was stirred and allowed to warm to room temperature. The homogeneous amber solution was stirred at room temperature for 4 hours, then heated at 45° C. for 12 hours. Once cooled the reaction mixture was quenched with saturated aqueous NH4Cl, diluted with H2O and extracted with EtOAc (2×). The EtOAc extracts were washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (DCM/MeOH) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.87-8.00 (m, 1H), 7.78-7.87 (m, 3H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.32 (s, 1H), 6.33 (s, 1H), 5.30 (s, 1H), 4.37 (s, 2H), 4.08 (s, 3H), 3.36 (s, 3H), 3.01 (s, 3H); MS (ESI) 617.9.

Workup

  1. waitat room temperature for 30 minutes
  2. additionwas added rapidly at 0° C.
  3. stirringthe reaction mixture was stirred
  4. temperatureto warm to room temperature
  5. stirringThe homogeneous amber solution was stirred at room temperature for 4 hours
  6. temperatureheated at 45° C. for 12 hours
  7. temperatureOnce cooled the reaction mixture
  8. customwas quenched with saturated aqueous NH4Cl
  9. additiondiluted with H2O
  10. extractionextracted with EtOAc (2×)
  11. washThe EtOAc extracts were washed with brine
  12. dry with materialdried (Na2SO4)
  13. filtrationfiltered
  14. customevaporated in vacuo
  15. customchromatographed (DCM/MeOH)

Sources & evidence

ORD record
ord-7b1f55f93558476cbf4a0004fc3aa9c8
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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