Acetic Acid → Ethyl 4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

HRID 1372386Notes

Reaction equation

HRID 1372386 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6](C(=O)C)[C:7](=O)[CH3:8])[CH3:2].[C:14](O)(=O)C.Cl.[NH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21](OCC)=O.C([O-])(=O)C.[Na+]>O.C(O)C.C(OCC)(=O)C.CCCCCC>[CH2:29]([O:28][C:26]([C:20]1[NH:19][C:7]([CH3:8])=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[C:21]=1[CH3:14])=[O:27])[CH3:30]

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 87820Ethyl 3-acetyl-4-oxopentanoateHCID 517045Sodium AcetateHCID 3084143Propanedioic acid, 2-amino-, 1,3-diethyl ester, hydrochloride (1:1)

Product 1

HCID 14840862Ethyl 4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylateYield 93%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
105 °C

Procedure

3-Acetyl-4-oxo-pentanoic acid ethyl ester (710 g, 3.81 mol), 533 mL of acetic acid and 847 g (4.00 mol) of diethyl aminomalonate hydrochloride salt were heated in an oil bath while 344 g (4.19 mol) of sodium acetate were slowly added. The internal temperature at the end of the addition was 55° C. and the mixture was thick with solids but could be stirred. The mixture was heated to 105° C. Gas evolution was vigorous. The temperature was allowed to fall to 98° C. and the reaction was stirred at this temperature for 30 minutes. Thin layer chromatography (ethyl acetate:hexane 1:2) showed the product at Rf 0.6 and a small impurity at Rf 0.7. The reaction was cooled to 50° C. and 1000 mL of ethanol and 1000 mL of water were added with stirring. The mixture was cooled in an ice bath and 3000 mL of ice water were added with stirring. The solids were collected by vacuum filtration and washed two times with 500 mL of 30% ethanol in water each time. The solids were air dried to give 870 g (93% yield) of 4-ethoxycarbonylmethyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H-NMR (dimethylsulfoxide-d6) δ 1.15, 1.26 (2×t, 2×3H, 2×CH3), 2.15 (2×s, 2×3H, 2×CH3), 3.32 (s, 2H, CH2), 4.01, 4.18 (2×d, 2×2H, 2×CH2O), 11.20 (br s, 1H, NH). MS m/z 254 [M+1].

Workup

  1. additionwere slowly added
  2. additionThe internal temperature at the end of the addition
  3. customwas 55° C.
  4. customto fall to 98° C.
  5. stirringthe reaction was stirred at this temperature for 30 minutes
  6. temperatureThe reaction was cooled to 50° C.
  7. stirringwith stirring
  8. temperatureThe mixture was cooled in an ice bath
  9. stirringwith stirring
  10. filtrationThe solids were collected by vacuum filtration
  11. washwashed two times with 500 mL of 30% ethanol in water each time
  12. customdried

Sources & evidence

ORD record
ord-570f32b313654796950508928961673a
Source dataset
uspto-grants-2007_01
Patent number
US07157577B2

Reaction notes

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