Potassium hydride → 4-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide

HRID 1670320Notes

Reaction equation

HRID 1670320 reaction equation
[H-].[K+].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=1>CN(C=O)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)=[C:6]([F:12])[CH:5]=1

Participants

5

Reactant 3

HCID 82127Potassium hydrideHCID 3035434-Chloropyridine-2-carboxamideHCID 27787624-Amino-2,5-difluorophenol

Product 1

HCID 247886284-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a mixture of potassium hydride (30-35% dispersion in mineral oil, 1.9 g, 13.9 mmol) in DMF (30 mL) was added 4-amino-2,5-difluorophenol (1.7 g, 11.6 mmol) as a solution in DMF (5 mL). After one hour of stirring at ambient temperature, 4-chloropicolinamide (1.8 g, 11.6 mmol) was added and the reaction mixture was heated to 100° C. for 135 h. The mixture was cooled to room temperature, quenched with 10% aqueous lithium chloride and then extracted three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was partitioned between chloroform and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a solid (3.0 g, 98%). 1H NMR (DMSO-d6) δ 8.51-8.57 (m, 1H), 8.14 (br s, 1H), 7.74 (br s, 1H), 7.37-7.38 (m, 1H), 7.17-7.30 (m, 2H), 6.74-6.80 (m, 1H), 5.62 (s, 2H); MS (ESI+) m/z 266 (M+H)+.

Workup

  1. temperaturethe reaction mixture was heated to 100° C. for 135 h
  2. temperatureThe mixture was cooled to room temperature
  3. customquenched with 10% aqueous lithium chloride
  4. extractionextracted three times with EtOAc
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe resultant solid was partitioned between chloroform and water
  9. washThe organic layer was washed with brine
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo to a solid (3.0 g, 98%)

Sources & evidence

ORD record
ord-86440cafd7be4f3f83564a6630019667
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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