Hydrochloric Acid → 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol

HRID 253261Notes

Reaction equation

HRID 253261 reaction equation
[H-].[Na+].[F:3][C:4]1[C:9]([O:10]COC)=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15][C:16]#[N:17].[C:18](N1C=CN=C1)(=O)[CH3:19].Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[C:40]([NH:44][NH2:45])([CH3:43])([CH3:42])[CH3:41]>C1COCC1.ClCCl.CO.CCO.C(OCC)(=O)C>[NH2:17][C:16]1[N:44]([C:40]([CH3:43])([CH3:42])[CH3:41])[N:45]=[C:18]([CH3:19])[C:15]=1[C:5]1[C:4]([F:3])=[C:9]([OH:10])[CH:8]=[C:7]([F:14])[CH:6]=1

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 171741-(1H-Imidazol-1-yl)ethanoneHCID 24758Sodium hydrideHCID 81889tert-Butylhydrazine monohydrochlorideHCID 521998p-Toluenesulfonic acid monohydrateHCID 66889518HCID 66889518, compound

Product 1

HCID 668903693-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenolYield 81%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
40 °C

Procedure

To NaH (60 wt. % dispersion in oil; 0.09 g, 2.25 mmol) suspended in THF (4 mL) was added (2,5-difluoro-3-{[(methyloxy)methyl]oxy}phenyl)acetonitrile (0.240 g, 1.13 mmol) and then 1-acetylimidazole (0.186 g, 1.69 mmol). The mixture was stirred at 40° C. for 0.3 h. The mixture was cooled to room temperature, was acidified with 1 N HCl and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was dissolved in dichloromethane:MeOH (1:1, 8 mL) and treated with para-toluenesulfonic acid monohydrate (0.045 g, 0.237 mmol) at 40° C. for 15 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was dissolved in EtOH (4 mL) and treated with tert-butylhydrazine hydrochloride (0.136 g, 1.09 mmol) at 75° C. for 18 h and at room temperature for 38 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol as a pale brown solid (0.248 g, 0.883 mmol, 78% yield). MS (EI) for C14H17F2N3O: 282 (MH+).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. washThe organic portion was washed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto afford a yellow oil which
  7. customThe mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution
  8. extractionThe aqueous portion was extracted with ethyl acetate
  9. washThe combined organic portion was washed with brine
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto afford a yellow oil which
  14. concentrationThe mixture was concentrated in vacuo
  15. customthe residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution
  16. extractionThe aqueous portion was extracted with ethyl acetate
  17. washThe combined organic portion was washed with brine
  18. dry with materialdried over sodium sulfate
  19. filtrationfiltered
  20. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-44318e2b4b954c92b185fdeedabd404e
Source dataset
uspto-grants-2011_01
Patent number
US07872014B2

Reaction notes

Loading…