Lithium Hydroxide → 3-{[4-(4,5-Difluorobenzofuran-7-yl)-2-fluoro-phenoxy]methyl}benzoic acid

HRID 928675Notes

Reaction equation

HRID 928675 reaction equation
[F:1][C:2]1C=[C:6](O)[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[C:21]2[O:20][CH:19]=[CH:18][C:17]=2[C:16]([F:22])=[C:15]([F:23])[CH:14]=1.[C:24](=[O:27])([O-])[O-:25].[Na+].[Na+].BrC[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1.O.CO.CN(C=O)C.O1CCOCC1>[F:22][C:16]1[C:17]2[CH:18]=[CH:19][O:20][C:21]=2[C:13]([C:4]2[CH:5]=[CH:6][C:38]([O:37][CH2:35][C:34]3[CH:39]=[C:40]([CH:41]=[CH:32][CH:33]=3)[C:24]([OH:25])=[O:27])=[C:2]([F:1])[CH:3]=2)=[CH:14][C:15]=1[F:23]

Participants

14

Reactant 6

HCID 3939Lithium HydroxideHCID 10340Sodium CarbonateHCID 11430Potassium CarbonateHCID 517981Methyl 3-(bromomethyl)benzoateHCID 221448747-Bromo-4,5-difluorobenzofuranHCID 567376732-Fluoro-4-hydroxyphenylboronic acid

Product 1

HCID 903843853-{[4-(4,5-Difluorobenzofuran-7-yl)-2-fluoro-phenoxy]methyl}benzoic acidYield 24%

Reagents, catalysts & solvents 7

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

1,4-Dioxane (12 mL) and water (4 mL) were added to 2-fluoro-4-hydroxyphenylboronic acid (475 mg, 3.0 mmol), 7-bromo-4,5-difluoro-1-benzofuran (590 mg, 2.53 mmol), sodium carbonate (540 mg, 5.1 mmol), and Pd(dppf)Cl2 (catalytic amount), and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Then, to the resulting residue, methyl 3-(bromomethyl)benzoate (595 mg, 2.6 mmol), potassium carbonate (414 mg, 3.0 mmol), and DMF (4 mL) were added, and stirred overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, methanol (5 mL), water (2 mL), THF (5 mL), and lithium hydroxide (210 mg, 5.0 mmol) were added, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the resulting solid was collected by filtration to thus obtain the title compound.

Workup

  1. concentrationThe reaction solution was concentrated under reduced pressure
  2. additionTo the residue, ethyl acetate and 1 N hydrochloric acid were added
  3. stirringstirred
  4. filtrationAfter that, the insoluble material was filtered off
  5. extractionextraction
  6. washThe organic phase was washed with saturated brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. distillationThe solvent was distilled away under reduced pressure
  9. stirringstirred overnight
  10. washthe resultant was washed with water and saturated brine
  11. dry with materialdried over anhydrous magnesium sulfate
  12. distillationThe solvent was distilled away under reduced pressure
  13. stirringstirred at room temperature overnight
  14. concentrationThe reaction solution was concentrated under reduced pressure, and extraction
  15. washThe organic phase was washed with saturated brine
  16. dry with materialdried over anhydrous magnesium sulfate
  17. distillationAfter the solvent was distilled away under reduced pressure
  18. filtrationthe resulting solid was collected by filtration

Sources & evidence

ORD record
ord-f277e21dedb7467cb1c83838cfee3267
Source dataset
uspto-grants-2016_03
Patent number
US09290487B2

Reaction notes

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