Citric Acid → HCID 67341262, compound

HRID 1673559Notes

Reaction equation

HRID 1673559 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:42]([NH:50][C:51]1[CH:63]=[C:62](Br)[CH:61]=[CH:60][C:52]=1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=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].C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:42]([NH:50][C:51]1[CH:63]=[C:62]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:61]=[CH:60][C:52]=1[C:53]([O:55][C:56]([CH3:58])([CH3:59])[CH3:57])=[O:54])(=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1

Participants

11

Reactant 6

HCID 311Citric AcidHCID 24758Sodium hydride3×HCID 1230512,4-Difluorophenol2×HCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphane3×HCID 44558591Tri-t-butylphosphine fluoroborateHCID 67343005Tert-butyl 2-(benzamido)-4-bromobenzoate

Product 1

HCID 67341262HCID 67341262, compound

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalyst3×HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

0.018 mL of 2,4-difluorophenol was added to 1 mL of toluene suspension containing 10 mg of 60% sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 0.5 mL of toluene solution containing 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 1.7 mg of palladium acetate and 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate was added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 4.5 mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 0.018 mL of 2,4-difluorophenol, 7.4 mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 5.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour and 30 minutes. 10% citric acid aqueous solution and ethyl acetate were added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(benzamido)-4-(2,4-difluorophenoxy)benzoate.

Workup

  1. temperaturethe resulting mixture was heated
  2. temperatureto reflux under nitrogen atmosphere for 15 minutes
  3. additionwas added
  4. temperaturethe resulting mixture was heated
  5. temperatureto reflux under nitrogen atmosphere for 4 hours
  6. temperatureAfter the reaction mixture was cooled to room temperature
  7. temperaturethe resulting mixture was heated
  8. temperatureto reflux under nitrogen atmosphere for 2 hours
  9. temperatureAfter the reaction mixture was cooled to room temperature
  10. temperaturethe resulting mixture was heated
  11. temperatureto reflux under nitrogen atmosphere for 2 hours
  12. temperatureAfter the reaction mixture was cooled to room temperature
  13. temperaturethe resulting mixture was heated
  14. temperatureto reflux under nitrogen atmosphere for 1 hour and 30 minutes
  15. temperaturewas cooled to room temperature
  16. customThe organic layer was separated
  17. dry with materialdried over anhydrous magnesium sulfate
  18. washafter washed with a saturated sodium chloride aqueous solution
  19. customthe solvent was evaporated under reduced pressure
  20. customThe obtained residue was purified with silica gel column chromatography [Flash Tube 2008

Sources & evidence

ORD record
ord-8ff5976756e241fd9ec8c6e4e98a9ecd
Source dataset
uspto-grants-2011_08
Patent number
US07999132B2

Reaction notes

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