Tetrahydrofuran → (4-Chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol.TFA

HRID 627571Notes

Reaction equation

HRID 627571 reaction equation
C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([O:18][CH3:19])[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[C:10]2[Cl:31].[CH3:32][N:33]1[C:37]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:45]=2)=[O:39])=[CH:36][N:35]=[CH:34]1.[NH4+].[Cl-].C1[CH2:56][O:55]CC1>O>[Cl:31][C:10]1[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:38]([C:37]3[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=3)([C:40]3[CH:41]=[N:42][C:43]([C:46]([F:48])([F:47])[F:49])=[CH:44][CH:45]=3)[OH:39])[CH:8]=2)[N:13]=[C:12]([O:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.[C:56]([OH:55])([C:27]([F:28])([F:29])[F:30])=[O:39]

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 86715442(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone2×HCID 867161006-Bromo-4-chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline2×HCID 178418339Butyllithium

Product 1

HCID 86716151(4-Chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol.TFA

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

n-Butyllithium (2.0 mL, 3.202 mmol) was added to a −78° C. mixture of 6-bromo-4-chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline (1.1 g, 2.463 mmol, Intermediate 58, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (0.691 g, 2.709 mmol, Intermediate 15, step c) in dry THF (25 mL) over a 2 min period. After complete addition stirring was continued at −78° C. for 10 min then the reaction was warmed up to 0° C. and stirred for 1 hour. Saturated NH4Cl was added and the reaction mixture slowly warmed to room temperature. Water was added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts was dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (DCM/10% MeOH in EtOAc) to provide product. Further purification using reverse phase HPLC provided the TFA salt of the title compound. MS (ESI) 623.1

Workup

  1. additionAfter complete addition
  2. stirringstirred for 1 hour
  3. temperaturethe reaction mixture slowly warmed to room temperature
  4. customthe layers were separated
  5. extractionThe aqueous layer was extracted with EtOAc
  6. dry with materialThe combined organic extracts was dried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customchromatographed (DCM/10% MeOH in EtOAc)
  10. customto provide product
  11. customFurther purification

Sources & evidence

ORD record
ord-fad3f48f9c444cd69b62cb8acdc9be05
Source dataset
uspto-grants-2016_04
Patent number
US09309222B2

Reaction notes

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