Water → 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester

HRID 2364978Notes

Reaction equation

HRID 2364978 reaction equation
[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[C:15]([O:19][C:20](=[O:27])[C:21](=[N:25]O)[C:22](=O)[CH3:23])([CH3:18])([CH3:17])[CH3:16].O>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:22]([CH3:23])=[C:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[NH:25][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14])[CH3:2]

Participants

6

Reactant 3

HCID 962WaterHCID 66045Diethyl acetonedicarboxylateHCID 178468384tert-butyl 2-hydroxyimino-3-oxobutanoate

Product 1

HCID 498403265-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl esterYield 88.5%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 176Acetic AcidSolvent

Conditions

Temperature
75 °C

Procedure

A stirred solution of 3-oxo-butyric acid tert-butyl ester (32 g, 0.2 mol) in glacial acetic acid was added dropwise with an aqueous solution of sodium nitrite (13.8 g, 0.2 mol sodium nitrite in 20 ml of water) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the reaction mixture was stirred in an ice-water bath for 1 hour and at room temperature for another 3 hours. The solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester was obtained which was used as such. A mixture of 3-oxo-glutaric acid diethyl ester (40 g, 0.2 mol) in 90 ml of glacial acetic acid was added with the above solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester and zinc dust (26 g, 0.4 mol) alternatively at a rate to maintain the reaction temperature below 65° C. Upon completion of the addition, the mixture was stirred at 75° C. for 2 hours, added with cold water (100 ml), and the mixture was stirred at room temperature for 1 hour. The zinc dust was removed by filtration and the filtrate was extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml×3), saturated sodium bicarbonate solution (100 ml×4), and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (60 g, 88.5%) as a yellow oil.

Workup

  1. temperatureto maintain the reaction temperature below 65° C
  2. additionUpon completion of the addition
  3. stirringthe mixture was stirred at room temperature for 1 hour
  4. customThe zinc dust was removed by filtration
  5. extractionthe filtrate was extracted with ethyl acetate (100 ml×3)
  6. washThe combined organic extracts were washed with water (100 ml×3), saturated sodium bicarbonate solution (100 ml×4), and brine (100 ml)
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-ab46ff4778e44e3bac4333379de09f74
Source dataset
uspto-grants-2014_04
Patent number
US08697692B2

Reaction notes

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