Sodium Carbonate → 3-{[4-(5-Fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl}benzoic acid

HRID 928645Notes

Reaction equation

HRID 928645 reaction equation
Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41]C)=[O:40]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CN(C=O)C.O.O1CCOCC1>[F:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:35][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([OH:41])=[O:40])=[CH:14][CH:15]=2)[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1

Participants

11

Reactant 5

HCID 10340Sodium CarbonateHCID 11430Potassium CarbonateHCID 517981Methyl 3-(bromomethyl)benzoateHCID 27343604-Hydroxyphenylboronic acidHCID 833974101432609-54-5

Product 1

HCID 903843973-{[4-(5-Fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl}benzoic acidYield 29%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To the compound (300 mg, 1.4 mmol) obtained in Step 2, 4-hydroxyphenylboronic acid (230 mg, 1.7 mmol), sodium carbonate (292 mg, 2.8 mmol), tetrakis(triphenylphosphine)palladium(0) (hereinafter, Pd(PPh3)4) (catalytic amount), 1,4-dioxane (10 mL), water (3 mL) were added, and stirred at 90° C. for 2 hours. The solvent was distilled away under reduced pressure. Ethyl acetate was used as an extraction solvent, and after washing with a 1 N hydrochloric acid aqueous solution and saturated brine, the resultant was dried over magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, DMF (10 ml), potassium carbonate (280 mg, 2.8 mmol), and methyl 3-(bromomethyl)benzoate (470 mg, 2.1 mmol) were added, and stirred at 50° C. overnight. Ethyl acetate was used as an extraction solvent, and after washing with water, a 1 N sodium hydroxide aqueous solution, and saturated brine, the resultant was dried over magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, THF (5 mL), methanol (5 mL), and a 1 N sodium hydroxide aqueous solution (10 mL) were added, and stirred at room temperature for 4 hours. The solvent was distilled away under reduced pressure. Ethyl acetate was used as an extraction solvent, and after washing with a 1 N hydrochloric acid aqueous solution and saturated brine, the resultant was dried over magnesium sulfate. After the solvent was distilled away under reduced pressure, the resulting residue was washed with a water-acetonitrile mixture solvent, and then dried to thus obtain the title compound.

Workup

  1. distillationThe solvent was distilled away under reduced pressure
  2. washafter washing with a 1 N hydrochloric acid aqueous solution and saturated brine
  3. dry with materialthe resultant was dried over magnesium sulfate
  4. distillationThe solvent was distilled away under reduced pressure
  5. stirringstirred at 50° C. overnight
  6. washafter washing with water
  7. dry with materiala 1 N sodium hydroxide aqueous solution, and saturated brine, the resultant was dried over magnesium sulfate
  8. distillationThe solvent was distilled away under reduced pressure
  9. additionTo the resulting residue, THF (5 mL), methanol (5 mL), and a 1 N sodium hydroxide aqueous solution (10 mL) were added
  10. stirringstirred at room temperature for 4 hours
  11. distillationThe solvent was distilled away under reduced pressure
  12. washafter washing with a 1 N hydrochloric acid aqueous solution and saturated brine
  13. dry with materialthe resultant was dried over magnesium sulfate
  14. distillationAfter the solvent was distilled away under reduced pressure
  15. washthe resulting residue was washed with a water-acetonitrile mixture solvent
  16. customdried

Sources & evidence

ORD record
ord-940439196c974a2da29360adf6897c92
Source dataset
uspto-grants-2016_03
Patent number
US09290487B2

Reaction notes

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