Potassium Hydroxide → 1-{3,5-Difluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indazole-6-carbonitrile

HRID 2423091Notes

Reaction equation

HRID 2423091 reaction equation
Br[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:13]1[CH:18]=[C:17]([F:19])[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([F:28])[CH:14]=1.[OH-:29].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[F:19][C:17]1[CH:18]=[C:13]([N:6]2[C:7]3[C:3](=[C:2]([OH:29])[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=3)[CH:4]=[N:5]2)[CH:14]=[C:15]([F:28])[C:16]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1

Participants

8

Reactant 2

HCID 14797Potassium HydroxideHCID 672458554-Bromo-1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole-6-carbonitrile

Product 1

HCID 1363814391-{3,5-Difluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indazole-6-carbonitrileYield 76.6%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 4-bromo-1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole-6-carbonitrile (D36) (940 mg, 2.135 mmol) in dioxane (20 mL) and water (20 mL) was added potassium hydroxide (479 mg, 8.54 mmol). The mixture was degassed with argon and then treated with 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (54.4 mg, 0.128 mmol) and tris(dibenzylideneacetone)dipalladium(0) (39.1 mg, 0.043 mmol). The reaction mixture was heated to 90° C. for 1 hour. The reaction was diluted with ethyl acetate and water. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to give the title compound (D37) (617 mg).

Workup

  1. customThe mixture was degassed with argon
  2. customAfter separation of the layers
  3. extractionthe aqueous phase was re-extracted with ethyl acetate
  4. dry with materialThe combined organic layers were dried over magnesium sulphate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe product was purified by silica gel chromatography
  8. washeluting with 10-100% ethyl acetate in hexane

Sources & evidence

ORD record
ord-78dd4fc176ba4a7a8ba4c45a434dd3d8
Source dataset
uspto-grants-2011_06
Patent number
US07960563B2

Reaction notes

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