Benzo(B)Thiophene-2-Boronic Acid → 3-benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methyl ester

HRID 503185Notes

Reaction equation

HRID 503185 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:6]([F:34])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:9]=[C:8]2Br)=[O:4].[S:35]1[C:39](B(O)O)=[CH:38][C:37]2[CH:43]=[CH:44][CH:45]=[CH:46][C:36]1=2.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](C(C)C)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:34])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:39]1[S:35][C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[CH:38]=1)=[O:4]

Participants

11

Reactant 7

HCID 2359Benzo(B)Thiophene-2-Boronic AcidHCID 6422Trifluoroacetic acidHCID 138754Silane, tris(1-methylethyl)-HCID 516892Sodium BicarbonateHCID 522689Potassium FluorideHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 684205673-Bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic Acid Methyl Ester

Product 1

HCID 684211323-benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methyl esterYield 47.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
55 °C

Procedure

To a solution of 515 mg of 3-bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl ester obtained in Production Example II-13-e in 7.5 ml dimethylformamide were sequentially added 267 mg of 2-benzo[b]thiopheneboronic acid, 1 ml of an aqueous solution of 291 mg of potassium fluoride, 30 mg of 2-(di-tert-butylphosphino)biphenyl and 12 mg of palladium(II) acetate, and the mixture was stirred at 55° C. for 1 hour. The reaction mixture was ice-cooled, and then the precipitated crystals were collected by filtration. The resulting crystals were dissolved in a mixture solution of ethyl acetate and tetrahydrofuran, and the mixture was sequentially washed with water, half-saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 504 mg of a crude coupling product. A total of 350 mg of the resulting crude coupling product was suspended in 4 ml of methylene chloride, 2 ml of trifluoroacetic acid and 0.1 ml of triisopropylsilane were added, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution and it was extracted with 50 ml of ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9), to give 154 mg of the title compound as pale yellow crystals.

Workup

  1. temperaturecooled
  2. filtrationthe precipitated crystals were collected by filtration
  3. dissolutionThe resulting crystals were dissolved in a mixture solution of ethyl acetate and tetrahydrofuran
  4. washthe mixture was sequentially washed with water, half-saturated aqueous sodium hydrogencarbonate solution and brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. customthe solvent was evaporated
  7. customto give 504 mg of a crude coupling product
  8. stirringthe mixture was stirred at room temperature for 15 minutes
  9. extractionwas extracted with 50 ml of ethyl acetate
  10. washThe organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine
  11. dry with materialdried over anhydrous magnesium sulfate
  12. customthe solvent was evaporated
  13. customThe crude product was purified
  14. customseparated by silica gel column chromatography (ethyl acetate:toluene=1:9)

Sources & evidence

ORD record
ord-a2853cfb3d444932b5cc14db49fc5be8
Source dataset
uspto-grants-2010_08
Patent number
US07776890B2

Reaction notes

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