Pentafluorophenol → 2-Anilino-4-(2,5-dioxopyrrolidin-1-ylmethyl)pyrimidine

HRID 2105131Notes

Reaction equation

HRID 2105131 reaction equation
[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F>CN(C=O)C>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:15]2[C:16](=[O:22])[CH2:17][CH2:18][C:19]2=[O:21])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 13041PentafluorophenolHCID 69061560HCID 69061560, compound

Product 1

HCID 690590132-Anilino-4-(2,5-dioxopyrrolidin-1-ylmethyl)pyrimidineYield 47%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

1-[3-(Dimethylamino)propyl]3-ethylcarbodiimnide hydrochloride (4.44 g, 22 mmol) was added in one portion to a stirred mixture of 4-{[(2-anilinopyrimidin-4-yl)methyl]amino}-4-oxobutanoic acid (Method 13; 6.0 g, 20mmol) and pentafluorophenol (4.05 g, 22 mmol) in DMF (180 ml) under nitrogen. The reaction was stirred at ambient temperature under nitrogen for 20 hours and then the reaction mixture was concentrated by evaporation. The residue was partitioned between EtOAc and water. The layers were separated and the organic layer washed with water (2×) and saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The crude pentafluoroester was stirred in dry TBF (218 ml) under nitrogen at 0° C. and sodium hydride (528 mg of a 60 % dispersion in oil, 22 mmol) added in one portion. The reaction mixture was stirred at 0° C. for 15 minutes and then 72 hours at ambient temperature. Acetic acid (1.32 ml) was added and the reaction mixture was concentrated by evaporation. The residue was partitioned between EtOAc and water and the layers separated. The organic layer was washed with dilute aqueous sodium hydrogen carbonate solution (2×), water and saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The crude product was purified by chromatography eluting with EtOAc/isohexane (60:40 and then 100:0). The purified product was triturated with isohexane, collected by filtration and dried to give the title compound (2.65 g, 47%) as a white solid. NMR: 2.75 (s, 4H), 4.55 (s, 2H), 6.75 (d, 1H), 6.93 (t, 1H), 7.25 (t, 2H), 7.64 (d, 2H), 8.37 (d, 1H), 9.53 (s, 1H); m/z 283.

Workup

  1. concentrationthe reaction mixture was concentrated by evaporation
  2. customThe residue was partitioned between EtOAc and water
  3. customThe layers were separated
  4. washthe organic layer washed with water (2×) and saturated brine
  5. dry with materialdried (Na2SO4)
  6. customthe volatiles removed by evaporation
  7. stirringThe crude pentafluoroester was stirred in dry TBF (218 ml) under nitrogen at 0° C.
  8. additionsodium hydride (528 mg of a 60 % dispersion in oil, 22 mmol) added in one portion
  9. stirringThe reaction mixture was stirred at 0° C. for 15 minutes
  10. custom72 hours
  11. customat ambient temperature
  12. additionAcetic acid (1.32 ml) was added
  13. concentrationthe reaction mixture was concentrated by evaporation
  14. customThe residue was partitioned between EtOAc and water
  15. customthe layers separated
  16. washThe organic layer was washed with dilute aqueous sodium hydrogen carbonate solution (2×), water and saturated brine
  17. dry with materialdried (Na2SO4)
  18. customthe volatiles removed by evaporation
  19. customThe crude product was purified by chromatography
  20. washeluting with EtOAc/isohexane (60:40
  21. customThe purified product was triturated with isohexane
  22. filtrationcollected by filtration
  23. customdried

Sources & evidence

ORD record
ord-5ec9bfe9152f4edaaae9e8d6e276095f
Source dataset
uspto-grants-2009_08
Patent number
US07579344B2

Reaction notes

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