5-bromo-1,2-dimethyl-1H-imidazole → (4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(2,6-dimethylpyridin-3-yl)methanol

HRID 926596Notes

Reaction equation

HRID 926596 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:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=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]=[N:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=1

Participants

5

Reactant 3

HCID 72048795-bromo-1,2-dimethyl-1H-imidazoleHCID 118006248(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 118006117(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-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, 1.2 mL, 3.0 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (570.8 mg, 3.261 mmol) in dry THF (6 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.790 g, 1.626 mmol, Intermediate 47: step b) in dry THF (2 mL) was added dropwise. The reaction was stirred for 5 minutes, then was moved into an ice bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase HPLC (acetonitrile/H2O+0.05% TFA). The product fractions were 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 (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.57 (dd, J=8.1, 0.9 Hz, 1H), 7.41 (dd, J=8.7, 2.2 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.04 (s, 1H), 4.35 (s, 2H), 4.08 (s, 3H), 3.39 (s, 3H), 2.53 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H); MS m/e 582.2 [M+H]+.

Workup

  1. customwas moved into an ice bath
  2. customThe reaction was quenched with saturated aqueous ammonium chloride
  3. customThe mixture was partitioned between water and dichloromethane
  4. extractionThe separated aqueous phase was further extracted with dichloromethane
  5. dry with materialThe organic phase was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM)
  9. extractionextracted with DCM
  10. dry with materialbefore being dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-550a9d4d09a5448cabe7e8b17c794b8b
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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