Citric Acid → Benzyl 2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

HRID 1436891Notes

Reaction equation

HRID 1436891 reaction equation
[Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].C[O:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:19]([O:26][C:27]([N:16]1[CH:17]=[CH:18][C:13](=[O:12])[CH2:14][CH:15]1[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

7

Reactant 5

HCID 311Citric AcidHCID 10387Benzyl chloroformateHCID 692784-MethoxypyridineHCID 967432-Bromo-5-fluorotolueneHCID 5462224Magnesium

Product 1

HCID 21927686Benzyl 2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-50 °C

Procedure

To Grignard reagent prepared from 14.2 g of magnesium, 93.1 g of 2-bromo-5-fluorotoluene and 500 ml of tetrahydrofuran was added dropwise 50 ml of 4-methoxypyridine at −20° C. under nitrogen atmosphere. After completion of dripwise addition, the mixture was stirred at the same temperature for 20 minutes. Further, the reaction mixture was cooled down to −50° C., and 85 ml of benzylchlorocarbonate was added dropwise, while keeping the temperature at −40° C. or below. After completion of dropwise addition, the temperature of the reaction mixture was slowly raised, 200 g of ice was added thereto at −15C, and the mixture was stirred for 30 minutes. Further, 200 ml of a 5M aqueous citric acid solution was added thereto and the mixture was stirred at room temperature for an hour. From the reaction mixture tetrahydrofuran was removed by distillation under reduced pressure. To the residue was added 200 ml of ethyl acetate and the mixture was extracted twice. The organic layers were combined and washed with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was collected by filtration and washed with isopropyl ether, to give 146.5 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine as shown in Table 125 below.

Workup

  1. additionAfter completion of dripwise addition
  2. customat −40° C. or below
  3. additionAfter completion of dropwise addition
  4. temperaturethe temperature of the reaction mixture was slowly raised
  5. stirringat −15C, and the mixture was stirred for 30 minutes
  6. stirringthe mixture was stirred at room temperature for an hour
  7. customFrom the reaction mixture tetrahydrofuran was removed by distillation under reduced pressure
  8. additionTo the residue was added 200 ml of ethyl acetate
  9. extractionthe mixture was extracted twice
  10. washwashed with an aqueous sodium hydrogen carbonate solution and saturated brine
  11. dry with materialdried over magnesium sulfate
  12. customthe solvent was removed by distillation under reduced pressure
  13. filtrationThe residue was collected by filtration
  14. washwashed with isopropyl ether

Sources & evidence

ORD record
ord-d9a29ce1ee374b3b888a56afa748a80a
Source dataset
uspto-grants-2009_11
Patent number
US07619092B2

Reaction notes

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