Formic Acid → Methyl 5-fluoro-6-methoxynicotinate

HRID 1510682Notes

Reaction equation

HRID 1510682 reaction equation
Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(O)=O.Cl>CN(C)C=O.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.O.C(OCC)(=O)C>[F:14][C:9]1[C:10]([O:12][CH3:13])=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]

Participants

9

Reactant 4

HCID 284Formic Acid2×HCID 313Hydrochloric AcidHCID 8471Triethylamine2×HCID 40148026Methyl 2-chloro-5-fluoro-6-methoxynicotinate

Product 1

HCID 46311253Methyl 5-fluoro-6-methoxynicotinateYield 23.7%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

To a solution of 1.5 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate in 15 mL of N,N-dimethylformamide, 0.38 g of tetrakis(triphenylphosphine)palladium(0), 1.4 mL of triethylamine, and 0.38 mL of formic acid were added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour under a nitrogen atmosphere, and then stirred at 90 to 100° C. for 2 hours 20 minutes. Thereto were further added 1.4 mL of triethylamine, 0.38 g of tetrakis(triphenylphosphine)palladium(0) and 0.38 mL of formic acid at room temperature, and the mixture was stirred at 90 to 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was charged with ethyl acetate and water, and adjusted to pH 4.8 with 2 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution. A mixed solvent of chloroform:methanol was added to the organic layer to dissolve the insoluble substance, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resultant residue, and the solid was filtered off to obtain 0.30 g of methyl 5-fluoro-6-methoxynicotinate as a yellow solid.

Workup

  1. stirringstirred at 90 to 100° C. for 2 hours 20 minutes
  2. customat room temperature
  3. stirringthe mixture was stirred at 90 to 100° C. for 1 hour
  4. temperatureAfter cooling to room temperature
  5. customThe organic layer was separated
  6. extractionthe aqueous layer was extracted with ethyl acetate
  7. washthe resultant solution was washed with a saturated aqueous sodium chloride solution
  8. additionA mixed solvent of chloroform:methanol was added to the organic layer
  9. dissolutionto dissolve the insoluble substance
  10. dry with materialdried over anhydrous magnesium sulfate
  11. distillationthe solvent was distilled off under reduced pressure
  12. additionEthyl acetate was added to the resultant residue
  13. filtrationthe solid was filtered off

Sources & evidence

ORD record
ord-75175b0a60c94482b2305944fed5550e
Source dataset
uspto-grants-2012_07
Patent number
US08211908B2

Reaction notes

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