5-bromo-1,2-dimethyl-1H-imidazole → (4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(2,6-dimethylpyridin-3-yl)methanol

HRID 926599Notes

Reaction equation

HRID 926599 reaction equation
[Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1

Participants

5

Reactant 3

HCID 72048795-bromo-1,2-dimethyl-1H-imidazoleHCID 118006456(4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 118006104(4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(2,6-dimethylpyridin-3-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.90 mL, 2.2 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (408.9 mg, 2.336 mmol) in dry THF (12 mL) in a dry ice-acetone bath. After 1-2 minutes, (4-chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.505 g, 1.16 mmol, Intermediate 48: step b) in dry THF (12 mL) was added to the mixture via syringe. After 5 minutes, the reaction was removed from the cold bath and was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the aqueous mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM). Due to remaining impurities, the material was dissolved in ethyl acetate and washed several times with minimal water. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness. The material was purified by reverse phase chromatography (acetonitrile/H2O+0.05% TFA), basified with saturated aqueous sodium bicarbonate, and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=2.2 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28-7.24 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.96-6.89 (m, 3H), 6.00 (s, 1H), 4.23 (s, 2H), 4.07 (s, 3H), 3.36 (s, 3H), 2.51 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H); MS m/e 531.2 [M+H]+.

Workup

  1. waitAfter 5 minutes
  2. customthe reaction was removed from the cold bath
  3. customThe reaction was quenched with saturated aqueous ammonium chloride
  4. additionWater was added
  5. extractionthe aqueous mixture was extracted with dichloromethane
  6. dry with materialThe combined organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM)
  10. dissolutionthe material was dissolved in ethyl acetate
  11. washwashed several times with minimal water
  12. dry with materialThe organic layer was dried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated to dryness
  15. customThe material was purified by reverse phase chromatography (acetonitrile/H2O+0.05% TFA)
  16. extractionextracted with DCM
  17. dry with materialbefore being dried (Na2SO4)
  18. filtrationfiltered
  19. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-157362bbab234a93aaf77bc0f3b7fdac
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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