Acetic Acid → 2-Tert-butyl 4-ethyl 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate

HRID 1888971Notes

Reaction equation

HRID 1888971 reaction equation
[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C.[N:16]([O-])=O.[Na+].[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O>[Zn].O>[CH2:27]([O:26][C:20]([C:21]1[C:3]([CH3:5])=[C:2]([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH:16][C:22]=1[CH3:24])=[O:25])[CH3:28]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 8868Ethyl AcetoacetateHCID 15538Tert-butyl acetoacetateHCID 23668193Sodium Nitrite

Product 1

HCID 43476602-Tert-butyl 4-ethyl 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate

Reagents, catalysts & solvents 2

HCID 23994ZincCatalyst2×HCID 962WaterSolvent

Conditions

Temperature
2.5 °C

Procedure

Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket and an air condenser, were charged tertiary butyl acetoacetate (1.0 Kg; 6.3 mole) and acetic acid (3.0 Lt). The solution was cooled to 0-5° C. and a previously dissolved solution of sodium nitrite (0.436 Kg; 6.3 mole) in 640 mL DM water into an addition funnel and added to the flask at a rate that the temperature does not exceed 5° C. After the addition, the solution was maintained for 90 minutes at 0-5° C. and slowly brought the reaction mixture to room temperature (25-30° C.) over a period of 4 hours. At this temperature, ethyl acetoacetate (0.824 Kg; 6.3 mole) was charged at once followed by Zinc powder (0.94 Kg; 14.4 mole) in ten equal lots below 70° C. After addition of zinc powder, the reaction mixture was maintained for 1-2 hours at 65-70° C. The resulting solution was cooled to 60° C. and quenched in a carboy containing 25.0 Lt DM water under stirring. The product was extracted with ethyl acetate and separated using separating funnel. The organic layer was then clarified by treating the product solution with activated charcoal followed by filtration through hyflow. The solvent was then recovered by distillation under diminished pressure and the traces were removed by the addition of methanol (500 ml) to the distillation flask and continued distillation under diminished pressure. The resulting product was triturated in 95% aqueous methanol (1.5 L) at 0-5° C. for 2 hours to get a crystalline product of formula-II.

Workup

  1. customdoes not exceed 5° C
  2. additionAfter the addition
  3. temperaturethe solution was maintained for 90 minutes at 0-5° C.
  4. customto room temperature
  5. custom(25-30° C.)
  6. customof 4 hours
  7. temperaturethe reaction mixture was maintained for 1-2 hours at 65-70° C
  8. temperatureThe resulting solution was cooled to 60° C.
  9. customquenched in a carboy
  10. additioncontaining 25.0 Lt DM water
  11. extractionThe product was extracted with ethyl acetate
  12. customseparated
  13. customusing separating funnel
  14. additionby treating the product solution with activated charcoal
  15. filtrationfollowed by filtration through hyflow
  16. distillationThe solvent was then recovered by distillation under diminished pressure
  17. customthe traces were removed by the addition of methanol (500 ml) to the distillation flask
  18. distillationdistillation under diminished pressure
  19. customThe resulting product was triturated in 95% aqueous methanol (1.5 L) at 0-5° C. for 2 hours
  20. customto get a crystalline product of formula-II

Sources & evidence

ORD record
ord-9a80d25e57f744b9805ae7021f598a07
Source dataset
uspto-grants-2013_08
Patent number
US08501962B2

Reaction notes

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