Toluene → Ethyl 2,6-dichloro-5-fluoropyridine-3-carboxylate

HRID 901245Notes

Reaction equation

HRID 901245 reaction equation
[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]1(C)C=CC=C[CH:14]=1>S(Cl)(Cl)=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([Cl:11])=[N:10][C:2]=1[Cl:1])[CH3:14]

Participants

4

Reactant 2

HCID 1140TolueneHCID 27336592,6-Dichloro-5-fluoronicotinic acid

Product 1

HCID 13210747Ethyl 2,6-dichloro-5-fluoropyridine-3-carboxylateYield 99%

Reagents, catalysts & solvents 1

HCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
0 °C

Procedure

A suspension of 2,6-dichloro-5-fluoronicotinic acid (43 g, 205 mmol) in thionyl chloride (200 mL) and toluene (200 mL) was refluxed for 3 h to yield a clear solution. The solution was cooled and the solvent was evaporated under vacuum. The residue was cooled in an ice bath and cold anhydrous ethanol was added slowly. After stirring 15 min at 0° C., the solution was refluxed for 30 min under argon. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 48.5 g (99%) of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (65) as colorless viscous oil. 1H-NMR (DMSO-d6): δ 1.32 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2 Hz, 2H), 8.46 (d, J=8.0 Hz, 1H); EIMS m/z 238 (M).

Workup

  1. temperaturewas refluxed for 3 h
  2. customto yield a clear solution
  3. temperatureThe solution was cooled
  4. customthe solvent was evaporated under vacuum
  5. temperatureThe residue was cooled in an ice bath
  6. additioncold anhydrous ethanol was added slowly
  7. temperaturethe solution was refluxed for 30 min under argon
  8. temperatureThe solution was cooled
  9. customthe solvent was removed under vacuum
  10. dissolutionThe residue was dissolved in ethyl acetate
  11. washwashed subsequently by saturated NaHCO3 solution, water and brine
  12. dry with materialThe organic phase was dried over MgSO4
  13. customevaporated

Sources & evidence

ORD record
ord-c6c7bbfad3e34185a14b9509271e0ea0
Source dataset
uspto-grants-2008_04
Patent number
US07361760B2

Reaction notes

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