2,6-Dimethylnicotinaldehyde → (4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol

HRID 1507328Notes

Reaction equation

HRID 1507328 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:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]2[Cl:27].[CH3:28][C:29]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>C1COCC1>[Cl:27][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:31]([C:30]3[C:29]([CH3:28])=[N:36][C:35]([CH3:37])=[CH:34][CH:33]=3)[OH:32])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1

Participants

5

Reactant 3

HCID 27847532,6-DimethylnicotinaldehydeHCID 867155816-Bromo-4-chloro-3-(4-fluorobenzyl)-2-methoxyquinoline2×HCID 178418339Butyllithium

Product 1

HCID 118006066(4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.84 mL, 2.1 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-3-(4-fluorobenzyl)-2-methoxyquinoline (0.826 g, 2.17 mmol, Intermediate 7: step d) in dry THF (11 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 2,6-dimethylnicotinaldehyde (0.23 mL, 1.8 mmol) in dry THF (3 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 combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.06 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.45 (dd, J=8.6, 2.0 Hz, 1H), 7.26-7.21 (m, 2H), 6.97 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 2H), 6.07 (s, 1H), 4.22 (s, 2H), 4.05 (s, 3H), 3.77 (s, 1H), 2.46 (s, 3H), 2.40 (s, 3H).

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 combined organic phases were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM)

Sources & evidence

ORD record
ord-47e9605248d744f181fe70b45e5d6f7d
Source dataset
uspto-grants-2015_12
Patent number
US09221804B2

Reaction notes

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