Sodium hydride → 6-Difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine

HRID 982647Notes

Reaction equation

HRID 982647 reaction equation
Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11]C)=[N:6]2.Cl.N1C=CC=CC=1.[H-].[Na+].Br[CH:30]([F:32])[F:31]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH:30]([F:32])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[CH:2]=2)[N:6]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 62407BromodifluoromethaneHCID 10176127Pyridinium chlorideHCID 225623443-Bromo-2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine

Product 1

HCID 225623316-Difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazineYield 60%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Portions of 3-bromo-2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (400 mg, 2.1 g total) were placed in individual Reactivials equipped with a magnetic stirrer bar. Pyridine hydrochloride (10 eq) was added to each vial, the vials sealed, and heated to 200° for 3 hours. The vials were allowed to cool to ˜140° before opening and the contents poured into ice/water. The resulting mixture was extracted into ethyl acetate (3×100 ml) and the combined organic extracts washed with water (7×75 ml), dried (Na2SO4) and evaporated to give the des-bromo phenol as a brown solid (1.0 g, MH+ 230). This solid was dissolved in anhydrous DMF (10 ml) and sodium hydride (60% dispersion in mineral oil, 200 mg) added portionwise. After stirring for 20 minutes at ambient temperature the solution was transferred to a small cooled autoclave and bromodifluoromethane (5 ml, xs, condensed at −30°) added. The autoclave was then sealed, allowed to warm to ambient temperature and stirred for 36 hours. The resulting solution was diluted with ethyl acetate (200 ml), washed with water (10×20 ml), dried (Na2SO4), concentrated and the residual gum purified by flash column chromatography with cyclohexane:ethyl acetate (4:1) as eluant. This gave the title compound as a solid (652 mg, 60%).

Workup

  1. customequipped with a magnetic stirrer bar
  2. customsealed
  3. temperatureheated to 200° for 3 hours
  4. temperatureto cool to ˜140° before opening
  5. extractionThe resulting mixture was extracted into ethyl acetate (3×100 ml)
  6. washthe combined organic extracts washed with water (7×75 ml)
  7. dry with materialdried (Na2SO4)
  8. customevaporated
  9. customto give the des-bromo phenol as a brown solid (1.0 g, MH+ 230)
  10. additionadded
  11. customThe autoclave was then sealed
  12. temperatureto warm to ambient temperature
  13. stirringstirred for 36 hours
  14. washwashed with water (10×20 ml)
  15. dry with materialdried (Na2SO4)
  16. concentrationconcentrated
  17. customthe residual gum purified by flash column chromatography with cyclohexane:ethyl acetate (4:1) as eluant

Sources & evidence

ORD record
ord-7a1ee2c4a962419281256ba770290bae
Source dataset
uspto-grants-2005_03
Patent number
US06861429B2

Reaction notes

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