Sodium hydride → HCID 59316615, compound

HRID 1845937Notes

Reaction equation

HRID 1845937 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[NH:20][C:19](=[O:26])[CH2:18][CH2:17]3)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36]>CN(C)C=O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[CH2:28][N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:4]([F:3])[CH:5]=3)=[C:23]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:26]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 902971-(Bromomethyl)-2,4-difluorobenzeneHCID 59316620HCID 59316620, compound

Product 1

HCID 59316615HCID 59316615, compoundYield 52%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a suspension of 95% sodium hydride in anhydrous N,N-dimethylformamide (2 mL) at room temperature in a dry flask equipped with an inlet of dry nitrogen was added a solution of 6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one, prepared a shown above (53 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL) with stirring. The reaction mixture was stirred for 30 minutes, followed by addition of 1-(bromomethyl)-2,4-difluorobenzene (207 mg, 1.0 mmol), and the reaction mixture stirred overnight. The reaction was followed by LCMS and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase was successively washed with 2N sodium carbonate (20 mL), 30% aqueous ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (25 mg, 0.05 mmol, 52%). LCMS mz 466.0 (M+H), 487.9 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; CDCl3) δ7.58 (t, J=7.8 Hz, 1H); 7.34 (m, 2H); 7.21 (m, 1H); 7.10 (s, 1H); 6.80-6.89 (m, 2H); 6.57 (s, 1H); 5.24 (s, 2H); 3.70 (s, 3H); 2.94 (m, 2H); 2.81 (m, 2H).

Workup

  1. customequipped with an inlet of dry nitrogen
  2. customprepared
  3. stirringThe reaction mixture was stirred for 30 minutes
  4. stirringthe reaction mixture stirred overnight
  5. stirringstirring
  6. customwas consumed
  7. customThe reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL)
  8. stirringwith stirring
  9. concentrationconcentrated under reduced pressure
  10. additiondiluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL)
  11. extractionThe aqueous phase was extracted with ethyl acetate (3×20 mL)
  12. washthe combined organic phase was successively washed with 2N sodium carbonate (20 mL), 30% aqueous ammonium chloride (20 mL), brine (20 mL)
  13. dry with materialdried over magnesium sulfate
  14. customEvaporation of the solvent under reduced pressure
  15. customgave a crude mixture that
  16. customwas purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%)

Sources & evidence

ORD record
ord-d41b7720f0fc4cbf85c023602f2a2eb6
Source dataset
uspto-grants-2015_02
Patent number
US08952007B2

Reaction notes

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