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

HRID 1160402Notes

Reaction equation

HRID 1160402 reaction equation
[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C@H:4]([NH:8][C:9](=O)OC(C)(C)C)[CH2:3]1.[Cl:16][C:17]1[CH:24]=C(F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[Cl:16][C:17]1[CH:24]=[C:9]([NH:8][C@H:4]2[CH2:5][C:6](=[O:7])[N:2]([CH3:1])[CH2:3]2)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]

Participants

6

Reactant 3

HCID 1090002-Chloro-4-fluorobenzonitrileHCID 516892Sodium BicarbonateHCID 45092180(S)-tert-Butyl (1-methyl-5-oxopyrrolidin-3-yl)carbamate

Product 1

HCID 595161672-Chloro-4-{[(3S)-1-methyl-5-oxo-3-pyrrolidinyl]amino}benzonitrileYield 53.2%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 312751,4-DioxaneSolvent

Procedure

1,1-Dimethylethyl [(3S)-1-methyl-5-oxo-3-pyrrolidinyl]carbamate (0.96 g, 4.5 mmol) was suspended in 4N HCl in dioxane (3 mL) and the mixture was stirred at room temperature for 12 h. Solvent was removed and the residue was dissolved in DMSO (27 mL) and H2O (3 mL). To this solution, 2-chloro-4-fluorobenzonitrile (0.77 g, 4.90 mmol) and NaHCO3 (1.89 g, 22.5 mmol) were added and the reaction mixture was stirred at 75° C. for 18 h. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to give the titled product (0.598 g, 53%) as a white solid. 1H-NMR (CDCl3) δ: 2.350 (1H, m), 2.914 (4H, m), 3.305 (1H, m), 3.825 (1H, m), 4.200 (1H, m), 4.835 (1H, d, J=6.8 Hz), 6.492 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.626 (1H, d, J=2.4 Hz), 7.454 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 250.0 (M+H)+.

Workup

  1. customSolvent was removed
  2. dissolutionthe residue was dissolved in DMSO (27 mL)
  3. stirringthe reaction mixture was stirred at 75° C. for 18 h
  4. temperatureAfter cooling to room temperature
  5. customthe reaction mixture was partitioned between H2O and EtOAc
  6. dry with materialthe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-7d7f03882295436b962076c77d5ac091
Source dataset
uspto-grants-2010_10
Patent number
US07816395B2

Reaction notes

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