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

HRID 926594Notes

Reaction equation

HRID 926594 reaction equation
[Li][CH2:2]CCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([C:19]3[N:23]([CH3:24])[C:22](C)=[N:21][CH:20]=3)[OH:18])[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.[C:39]([CH:52]1[CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53]1)([CH:41]1[CH2:44]N(C(OC(C)(C)C)=O)C1)=O>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:18])([C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[C:44]3[CH:41]=[CH:39][C:52]([C:53]#[N:54])=[CH:55][CH:2]=3)[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=1

Participants

5

Reactant 3

HCID 118005815(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol2×HCID 118006144Di-tert-butyl 3,3'-carbonylbis(azetidine-1-carboxylate)2×HCID 178418339Butyllithium

Product 1

HCID 1180063224-((4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.7 mL, 1.75 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (0.755 g, 0.175 mmol, Intermediate 45: step d) in dry THF (9 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 4-(1-methyl-1H-imidazole-5-carbonyl)benzonitrile (0.370 g, 1.75 mmol, Intermediate 43: step c) in dry THF (17 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to room 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) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.1 Hz, 1H), 7.88-7.82 (m, 4H), 7.81-7.77 (m, 1H), 7.73-7.71 (m, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.52 (dt, J=8.5, 2.0 Hz, 2H), 7.27 (s, 1H), 6.17 (d, J=1.2 Hz, 1H), 4.37 (s, 2H), 4.03 (s, 3H), 3.32 (s, 3H); MS m/e 564.5 [M+H]+.

Workup

  1. customwas removed from the cold 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)

Sources & evidence

ORD record
ord-a3e651546b01410a80c06523b315ba4e
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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