Hydrochloric Acid → 1-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazol-4-ol

HRID 2423064Notes

Reaction equation

HRID 2423064 reaction equation
Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([F:27])[CH:14]=1.[OH-:28].[K+].Cl>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].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>[F:27][C:15]1[CH:14]=[C:13]([N:6]2[C:7]3[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([OH:28])[C:3]=3[CH:4]=[N:5]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

9

Reactant 3

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 592729754-Bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazole

Product 1

HCID 1360852391-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazol-4-olYield 79%

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-fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazole (D3) (176 mg, 0.41 mmol) in dioxane (5 mL) and water (5 mL) was added potassium hydroxide (92 mg, 1.64 mmol). The reaction mixture was degassed with argon and then treated with bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (10 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.009 mmol). After heating at 90° C. for 1 hour, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate and water. The pH was adjusted to 7 by the addition of 1M hydrochloric acid. 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 5-70% ethyl acetate in hexane to yield the title compound (D4) (118 mg).

Workup

  1. customThe reaction mixture was degassed with argon
  2. temperatureto cool to room temperature
  3. customAfter separation of the layers
  4. extractionthe aqueous phase was re-extracted with ethyl acetate
  5. dry with materialThe combined organic layers were dried over magnesium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe product was purified by silica gel chromatography
  9. washeluting with 5-70% ethyl acetate in hexane

Sources & evidence

ORD record
ord-0857f7534e5843848a641c0ee3c83762
Source dataset
uspto-grants-2011_06
Patent number
US07960563B2

Reaction notes

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