Hydrochloric Acid → 5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid

HRID 912465Notes

Reaction equation

HRID 912465 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([F:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](=O)([O-:56])[O-:55].[K+].[K+].Cl>CO.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:54]([OH:56])=[O:55])[N:8]([CH2:11][C:12]([F:15])([CH3:14])[CH3:13])[N:7]=[CH:6]2

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 812191,3-Bis(diphenylphosphino)propaneHCID 67417764HCID 67417764, compound

Product 1

HCID 674162635-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acidYield 48.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 22242641Methanol--water (1/1)Solvent

Conditions

Temperature
60 °C

Procedure

6-Bromo-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole (1.64 g, 4.11 mmol) was dissolved in 9:1 methanol/water degassed with carbon monoxide (27 mL). To this was added 1-((3-(diphenylphosphino)propyl)(phenyl)phosphino)benzene (85 mg, 0.21 mmol), palladium (II) acetate (46 mg, 0.21 mmol), and potassium carbonate (1.70 g, 12.3 mmol). The reaction mixture was heated to 60° C. for 20 hours. The reaction mixture was then acidified to pH 1 by the addition of 5M hydrochloric acid, and the crude reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether, and the combined organic layers were washed with brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column, eluting with a gradient of 0.2-10% methanol/dichloromethane to yield 5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (7a) (724 mg, 48%).

Workup

  1. customdegassed with carbon monoxide (27 mL)
  2. customthe crude reaction mixture
  3. customwas partitioned between ether and water
  4. extractionThe aqueous layer was extracted with ether
  5. washthe combined organic layers were washed with brine
  6. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified on a silica gel column
  10. washeluting with a gradient of 0.2-10% methanol/dichloromethane

Sources & evidence

ORD record
ord-68208b3c6ac5406eb9b4a5903122d489
Source dataset
uspto-grants-2011_09
Patent number
US08026233B2

Reaction notes

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