Acetic Acid → 2-Chloro-5-fluoronicotinic acid

HRID 2219785Notes

Reaction equation

HRID 2219785 reaction equation
CO.[Cl:3][C:4]1[N:12]=[C:11](Cl)[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].C(O)(=O)C.Cl>[Zn].O>[Cl:3][C:4]1[N:12]=[CH:11][C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 887Methanol2×HCID 27336592,6-Dichloro-5-fluoronicotinic acid

Product 1

HCID 114352432-Chloro-5-fluoronicotinic acidYield 70.4%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 962WaterSolvent

Conditions

Temperature
35 °C

Procedure

Into a 2 L round bottomed flask, zinc powder (847 g) and methanol (4,080 mL) were charged and dispersed with stirring. A methanol (2,720 mL) solution of 2,6-dichloro-5-fluoronicotinic acid (1,700 g) was slowly added dropwise thereto, and then, acetic acid (535 g) was further added dropwise thereto. The internal temperature was raised to 35° C., followed by stirring at that temperature for 5 hours. After confirming that the starting material became at most 3% by the HPLC analysis, the residue of zinc powder was removed by filtration. Methanol was distilled off under reduced pressure, and then, water (3,000 mL) was added, whereby crystals precipitated. Then, the crude reaction product containing the crystals was transferred to a 20 L reactor by means of water (3,750 mL). The internal temperature was heated to at least 50° C., and then, 6 mol/L hydrochloric acid (1,960 g) was dropwise added thereto. After stirring for 3 hours as it was, the mixture was gradually cooled to room temperature, and a precipitated solid was collected by filtration and washed with water. The obtained crystals were dried under reduced pressure (60° C., 30.7 Pa, 12 hours) to obtain a salt of 2-chloro-5-fluoronicotinic acid (1,000 g).

Workup

  1. additiondispersed
  2. stirringby stirring at that temperature for 5 hours
  3. customthe residue of zinc powder was removed by filtration
  4. distillationMethanol was distilled off under reduced pressure
  5. additionwater (3,000 mL) was added
  6. customwhereby crystals precipitated
  7. customThen, the crude reaction product
  8. additioncontaining the crystals
  9. temperatureThe internal temperature was heated to at least 50° C.
  10. stirringAfter stirring for 3 hours as it
  11. temperaturethe mixture was gradually cooled to room temperature
  12. filtrationa precipitated solid was collected by filtration
  13. washwashed with water
  14. customThe obtained crystals were dried under reduced pressure (60° C., 30.7 Pa, 12 hours)

Sources & evidence

ORD record
ord-9a44f1174ee34b0591ddd19f27e169e7
Source dataset
uspto-grants-2008_08
Patent number
US07414136B2

Reaction notes

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