Potassium Carbonate → 5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-fluoro-phenol

HRID 60627

Reaction equation

HRID 60627 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:13]=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>C1(C)C=CC=CC=1.CCOC(C)=O.O.[Cu]I>[NH2:10][C:8]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 183421Phenol, 5-bromo-2-fluoro-HCID 13822957(1S,2S)-(+)-N,N'-Dimethylcyclohexane-1,2-diamineHCID 178441179HCID 178441179, compound

Product 1

HCID 1177294775-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-fluoro-phenolYield 70%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 3-(tert-butyl)-1H-pyrazol-5-amine (1.00 g, 7.20 mmol) in toluene (13 mL) was added 5-bromo-2-fluorophenol (1.51 g, 7.90 mmol), potassium carbonate (2.08 g, 15.1 mmol), (1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.20 g, 1.40 mmol) then copper (I) iodide (0.07 g, 0.36 mmol). The mixture was degassed then heated at 150° C. for 1 h using microwave irradiation. Another portion of copper (I) iodide (0.07 g, 0.36 mmol) was added and the reaction mixture heated at 150° C. for a further 1 h using microwave irradiation. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give an impure solid. The residue was partitioned between DCM and water and the phases separated. The organic layer was evaporated in vacuo and the residue was purified by FCC, using 0-5% MeOH in DCM. Further purification by FCC, using 0-25% EtOAc in DCM, gave the title compound as an orange gum (1.25 g, 70%). LCMS (Method 3): Rt 2.33 min, m/z 250.3 [MH+].

Workup

  1. customThe mixture was degassed
  2. custommicrowave irradiation
  3. temperaturethe reaction mixture heated at 150° C. for a further 1 h
  4. custommicrowave irradiation
  5. customthe phases separated
  6. extractionThe aqueous layer was then extracted with EtOAc (2×)
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customto give an impure solid
  12. customThe residue was partitioned between DCM and water
  13. customthe phases separated
  14. customThe organic layer was evaporated in vacuo
  15. customthe residue was purified by FCC
  16. customFurther purification by FCC

Sources & evidence

ORD record
ord-95f6bda1339647beb5249d396b41337a
Source dataset
uspto-grants-2016_09
Patent number
US09440974B2

Linked notes

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