Ethyl Acetate → HCID 66616497, compound

HRID 1889633Notes

Reaction equation

HRID 1889633 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.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.[Pd].O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)=[CH:19][CH:18]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 1039541,3-Benzenedicarboxylic acid, 5-bromo-, 1,3-dimethyl ester2×HCID 2856454-Fluorophenylboronic acid

Product 1

HCID 66616497HCID 66616497, compound

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of dimethyl 5-bromoisophthalate (5.47 g, 20.03 mmol), 4-fluorophenylboronic acid (4.20 g, 30.0 mmol) and cesium carbonate (9 g, 27.6 mmol) in dioxane (60 mL) was purged with Ar gas for a few minutes, to the mixture was added Pd(PPh3)4 (1 g, 0.865 mmol). The reaction mixture was heated at 90° C. overnight. The next morning additional Pd-catalyst (˜300 mg) was added, and the reaction mixture was heated at 90° C. for an additional 7 h. To the reaction mixture was added EtOAc and water, and the insoluble material was filtered. The EtOAc layer was separated, dried over MgSO4, concentrated in vacuo and the residual solid was mixed with ether. The insoluble solid was filtered and the filtrate was concentrated. To the residue was added ether, the insoluble solid was filtered (this solid was mostly boronic acid) and the filtrate solution was concentrated. The residue was purified by flash column chromatography on SiO2 which provided a mixture of desired product and dimethyl 5-bromoisophthalate (3.4 g). This mixture was carried on into the same coupling reaction again repeating the same procedure except it was heated at 77° C. for 16 h. The solid was filtered, washed with EtOAc, and the filtrate solution was washed with water, dried, concentrated, and the residue was passed through a flash column on SiO2 eluting with 3:1/Hex:EtOAc, which provided the desired product (3.0 g, 10.41 mmol, 52%) as a white solid. 1H NMR (CDCl3): δ 8.62 (d, J=1.7 Hz, 1H), 8.39 (d, J=1.7 Hz, 2H), 7.61 (dd, J=8.8, 5.5 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 3.96 (s, 6H).

Workup

  1. customwas purged with Ar gas for a few minutes, to the mixture
  2. temperaturethe reaction mixture was heated at 90° C. for an additional 7 h
  3. filtrationthe insoluble material was filtered
  4. customThe EtOAc layer was separated
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo
  7. additionthe residual solid was mixed with ether
  8. filtrationThe insoluble solid was filtered
  9. concentrationthe filtrate was concentrated
  10. additionTo the residue was added ether
  11. filtrationthe insoluble solid was filtered (this solid
  12. concentrationwas concentrated
  13. customThe residue was purified by flash column chromatography on SiO2 which
  14. customprovided

Sources & evidence

ORD record
ord-86d7f28ac3a64fdf8764089e0652ddc0
Source dataset
uspto-grants-2013_08
Patent number
US08501992B2

Reaction notes

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