Acetic Anhydride → 4-bromo-6-(2,4-difluoro-phenoxy)-1H-indazole

HRID 1818742Notes

Reaction equation

HRID 1818742 reaction equation
[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH2:17])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N+:31]([O-])(OCCC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]2[C:3]=1[CH:18]=[N:31][NH:17]2

Participants

6

Reactant 4

HCID 7918Acetic AnhydrideHCID 10985Isoamyl nitrateHCID 517044Potassium AcetateHCID 578868113-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine

Product 1

HCID 578867874-bromo-6-(2,4-difluoro-phenoxy)-1H-indazoleYield 57.9%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Conditions

Temperature
80 °C

Procedure

3-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine (5.31 g, 16.9 mmol) was dissolved in 50 mL dry benzene, and acetic anhydride (5.17 g, 50.7 mmol) and potassium acetate (1.69 g, 17.2 mmol) were added. The reaction mixture was placed under nitrogen atmosphere and heated to 80° C. with stirring for 10 minutes. Isoamyl nitrate (3.39 mL, 25.4 mmol) was added dropwise over 30 minutes, after which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Water (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added, and the mixture was heated to 55° C. Methanol (100 mL) was added, and the mixture was heated to 80° C. The mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was partitioned betwee methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 3.18 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1H-indazole.

Workup

  1. stirringafter which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours
  2. temperatureThe reaction mixture was cooled
  3. filtrationfiltered
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. additionWater (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added
  6. temperaturethe mixture was heated to 55° C
  7. additionMethanol (100 mL) was added
  8. temperaturethe mixture was heated to 80° C
  9. temperatureThe mixture was cooled
  10. concentrationconcentrated under reduced pressure
  11. customthe residue was partitioned between water and ethyl acetate
  12. customThe organic layer was separated
  13. concentrationconcentrated under reduced pressure
  14. customThe residue was partitioned betwee methylene chloride and saturated sodium bicarbonate
  15. customThe organic layer was separated
  16. washwashed with brine
  17. dry with materialdried (MgSO4)
  18. filtrationfiltered
  19. concentrationconcentrated under reduced pressure
  20. customThe residue was chromatographed through silica (0%-25% EtOAc in hexanes)

Sources & evidence

ORD record
ord-3c6a1e50bdbb473b8405867f63eab7d0
Source dataset
uspto-grants-2009_10
Patent number
US07601726B2

Reaction notes

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