Toluene → Ethyl 2-chloro-5-fluoronicotinate

HRID 2219786Notes

Reaction equation

HRID 2219786 reaction equation
[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1(C)C=CC=C[CH:13]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]

Participants

7

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 24386Thionyl ChlorideHCID 114352432-Chloro-5-fluoronicotinic acid2×

Product 1

HCID 11390082Ethyl 2-chloro-5-fluoronicotinate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 702EthanolSolvent

Conditions

Temperature
95 °C

Procedure

Into a 5 L four-necked flask, the salt (1,000 g) of 2-chloro-5-fluoronicotinic acid obtained in Example 5-1 was put and dissolved by adding toluene (3,000 mL), thionyl chloride (617 g) and N,N-dimethylformamide (0.95 g). The flask was heated by dipping it in an oil bath set at 80° C. Six hours later, after confirming by the HPLC analysis that 2-chloro-5-fluoronicotinic acid became at most 5%, ethanol (2,173 g) was added. The temperature of the oil bath was raised to 95° C., and the reaction was carried out for 14 hours. Then, concentration under reduced pressure was carried out, and to the obtained crude liquid, ethyl acetate (4,000 mL) and a 7.5% sodium carbonate aqueous solution (4,000 mL) were added, followed by stirring. After confirming that the pH of the aqueous layer was at least 8, filtration and separation were carried out, and an organic layer was recovered. An aqueous layer was extracted with ethyl acetate (2,000 mL), and the extract was put together with the previous organic layer, followed by washing with water (2,000 mL) and then with a 5% sodium chloride aqueous solution (2,000 mL). The organic solvent was distilled off under reduced pressure to obtain a reddish brown oil (1,234.7 g). It was purified by distillation under reduced pressure to obtain ethyl 2-chloro-5-fluoronicotinate (624.8 g). The yield from 2,6-dichloro-5-fluoronicotinic acid was 66%. As a result of the HPLC analysis, the purity of ethyl 2-chloro-5-fluoronicotinate was 99%.

Workup

  1. dissolutiondissolved
  2. temperatureThe flask was heated
  3. customset at 80° C
  4. customSix hours
  5. additionwas added
  6. concentrationThen, concentration under reduced pressure
  7. customto the obtained crude liquid, ethyl acetate (4,000 mL)
  8. filtrationwas at least 8, filtration and separation
  9. customan organic layer was recovered
  10. extractionAn aqueous layer was extracted with ethyl acetate (2,000 mL)
  11. washby washing with water (2,000 mL)
  12. distillationThe organic solvent was distilled off under reduced pressure
  13. customto obtain a reddish brown oil (1,234.7 g)
  14. distillationIt was purified by distillation under reduced pressure

Sources & evidence

ORD record
ord-ae45c90db35247a592eb01fe4b596634
Source dataset
uspto-grants-2008_08
Patent number
US07414136B2

Reaction notes

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