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

HRID 1507327Notes

Reaction equation

HRID 1507327 reaction equation
[Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1)=[C:10]2[Cl:30].[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[C:33]1[CH3:39]>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:37]([C:36]3[N:32]([CH3:31])[C:33]([CH3:39])=[N:34][CH:35]=3)[OH:38])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 31596101,2-dimethyl-1H-imidazole-5-carbaldehydeHCID 86715658HCID 86715658, compound2×HCID 178418339Butyllithium

Product 1

HCID 118005815(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.9 mL, 2.25 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (1.009 g, 2.338 mmol, Intermediate 9: step c) in dry THF (12.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (359.6 mg, 2.897 mmol) in dry THF (5 mL) was added dropwise. The reaction was stirred for 10 minutes, then was moved into an ice bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the separated aqueous layer was extracted with EtOAc/THF 10:1. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude was triturated with EtOAc/ether 1:1 and filtered, rinsing with additional ether. The collected solids were purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (d, J=2.0 Hz, 1H), 8.24-8.22 (m, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.67-7.62 (m, 1H), 7.56 (dd, J=8.2, 0.9 Hz, 1H), 6.54 (d, J=0.7 Hz, 1H), 6.03 (s, 1H), 4.37 (s, 2H), 4.09 (s, 3H), 3.49 (s, 3H), 2.35 (s, 3H); MS m/e 477.0 [M+H]+.

Workup

  1. customwas moved into an ice bath
  2. customThe reaction was quenched with saturated aqueous ammonium chloride
  3. additionWater was added
  4. extractionthe separated aqueous layer was extracted with EtOAc/THF 10:1
  5. dry with materialThe organic phase was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude was triturated with EtOAc/ether 1:1
  9. filtrationfiltered
  10. washrinsing with additional ether
  11. customThe collected solids were purified by flash column chromatography (silica gel, 0-5% MeOH-DCM)

Sources & evidence

ORD record
ord-3ff847a1702148e5b851403bf2afa68b
Source dataset
uspto-grants-2015_12
Patent number
US09221804B2

Reaction notes

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