3,4-Dichlorophenol → 2-(3,4-Dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester

HRID 497528Notes

Reaction equation

HRID 497528 reaction equation
Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=1)[CH3:8]

Participants

6

Reactant 3

HCID 72583,4-DichlorophenolHCID 10796Cesium carbonateHCID 11390082Ethyl 2-chloro-5-fluoronicotinate

Product 1

HCID 208726362-(3,4-Dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Ethyl 2-chloro-5-fluoronicotinate (5.09 g, 25 mmol see reference J. Med. Chem., 1993, 36(18) 267-88) and 3,4-dichlorophenol (6.11 g, 37.5 mmol) were dissolved in 1,4-dioxane and the solution was purged with argon. Anhydrous caesium carbonate (12.21 g, 37.5 mmol) was added and the mixture was heated under reflux for 17 hours. The reaction mixture was partitioned between water (300 ml) and ethyl acetate (300 ml). The aqueous layer was acidified to pH 3 by addition of 2M hydrochloric acid and the phases were separated. The aqueous layer was extracted with ethyl acetate (2-fold 100 ml) and the combined organic solutions were dried over magnesium sulphate and concentrated in-vacuo to give a red oil. The material isolated was redissolved in ethyl acetate and was washed with 5% potassium carbonate solution (2-fold 200 ml), 0.5 M sodium hydroxide solution (2-fold 200 ml) and saturated sodium hydrogen carbonate solution (100 ml). The organic phase was dried over magnesium sulphate and concentrated in-vacuo. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (4:96) to give 2-(3,4-dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester as a colourless oil that crystallised on standing (4.95 g).

Workup

  1. customthe solution was purged with argon
  2. temperaturethe mixture was heated
  3. temperatureunder reflux for 17 hours
  4. customThe reaction mixture was partitioned between water (300 ml) and ethyl acetate (300 ml)
  5. additionThe aqueous layer was acidified to pH 3 by addition of 2M hydrochloric acid
  6. customthe phases were separated
  7. extractionThe aqueous layer was extracted with ethyl acetate (2-fold 100 ml)
  8. dry with materialthe combined organic solutions were dried over magnesium sulphate
  9. concentrationconcentrated in-vacuo
  10. customto give a red oil
  11. customThe material isolated
  12. washwas washed with 5% potassium carbonate solution (2-fold 200 ml), 0.5 M sodium hydroxide solution (2-fold 200 ml) and saturated sodium hydrogen carbonate solution (100 ml)
  13. dry with materialThe organic phase was dried over magnesium sulphate
  14. concentrationconcentrated in-vacuo
  15. customThe residue was purified by chromatography on silica gel

Sources & evidence

ORD record
ord-636c9eb61d4143e4a02af8a0566cc1a5
Source dataset
uspto-grants-2005_09
Patent number
US06949573B2

Reaction notes

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