Sodium hydride → 2-Chloro-4-{[(2-fluorophenyl)methyl][(3S)-1-(1-methylethyl)-5-oxo-3-pyrrolidinyl]amino}benzonitrile

HRID 1160416Notes

Reaction equation

HRID 1160416 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([NH:12][C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 67968alpha-Bromo-o-fluorotolueneHCID 59516187Chloro-4-{[(3S)-1-(1-methylethyl)-5-oxo-3-pyrrolidinyl]amino}benzonitrile

Product 1

HCID 595162082-Chloro-4-{[(2-fluorophenyl)methyl][(3S)-1-(1-methylethyl)-5-oxo-3-pyrrolidinyl]amino}benzonitrileYield 79%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-20 °C

Procedure

NaH (60% in mineral oil, 0.026 g, 0.65 mmol) was washed free of mineral oil and then suspended in DMF (3 mL) and cooled to −20° C. To this suspension was added a solution of 2-chloro-4-{[(3S)-1-(1-methylethyl)-5-oxo-3-pyrrolidinyl]amino}benzonitrile (0.120 g, 0.43 mmol). After stirring at −20° C. for 20 min, 1-(bromomethyl)-2-fluorobenzene (0.12 g, 0.65 mmol) in DMF (2 mL) was added and the reaction was stirred at −20° C. for 5 min and then at 0° C. for 5 min. The reaction was quenched with aqueous NH4Cl, diluted with H2O, and extracted with Et2O (2×). The organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 25% EtOAc in hexane grading to 100% EtOAc in hexane to afford the product (0.13 g, 79%) as a white solid. 1H-NMR (CDCl3) δ: 1.137 (6H, dd, J=16.8 Hz, 6.8 Hz), 2.547 (1H, m), 2.842 (1H, m), 3.349 (1H, m), 3.749 (1H, m), 4.465 (1H, m), 4.588 (2H, m), 4.755 (1H, m), 6.566 (1H, d, J=8.8 Hz), 6.747 (1H, s), 7.031 (1H, m), 7.130 (2H, m), 7.325 (1H, m), 7.455 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 386.4 (M+H)+.

Workup

  1. stirringthe reaction was stirred at −20° C. for 5 min
  2. waitat 0° C. for 5 min
  3. customThe reaction was quenched with aqueous NH4Cl
  4. additiondiluted with H2O
  5. extractionextracted with Et2O (2×)
  6. washThe organic extracts were washed with H2O
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified via silica gel chromatography with 25% EtOAc in hexane grading to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-81dfe94f1014492ea1e1e555b311bddb
Source dataset
uspto-grants-2010_10
Patent number
US07816395B2

Reaction notes

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