2-Propenoic acid, 2-cyano-3-ethoxy-, ethyl ester → Methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate

HRID 1178619Notes

Reaction equation

HRID 1178619 reaction equation
[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([NH2:12])=[CH:10][CH:11]=1.C([O:16][CH:17]=[C:18]([C:24]#[N:25])[C:19](OCC)=O)C>C1(C)C=CC=CC=1>[C:24]([C:18]1[C:17](=[O:16])[C:10]2[CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13])[S:8][C:9]=2[NH:12][CH:19]=1)#[N:25]

Participants

4

Reactant 2

HCID 789432-Propenoic acid, 2-cyano-3-ethoxy-, ethyl esterHCID 692355624-(5-Amino-thiophen-2-yl)-butyric acid methyl ester

Product 1

HCID 22256643Methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoateYield 9.8%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester (1.00 g, 5.0 mmol) and ethyl (ethoxymethylene)cyanoacetate (930 mg, 5.5 mmol) in 50 mL of toluene is heated at reflux for 1 hour. The reaction mixture is concentrated and 50 mL of Dowtherm-A is added. The mixture is heated at reflux for 3 hours and cooled to room temperature. The crude reaction mixture is passed through a short pad of silica gel, eluting with dichloromethane followed by 10% methanol in dichloromethane. The crude product is further purified by flash column chromatography eluting with 10% methanol in dichloromethane followed by another flash column chromatography eluting with 10% methanol in ethyl acetate to provide 136 mg of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate as a tan solid.

Workup

  1. temperatureis heated
  2. temperatureat reflux for 1 hour
  3. concentrationThe reaction mixture is concentrated
  4. addition50 mL of Dowtherm-A is added
  5. temperatureThe mixture is heated
  6. temperatureat reflux for 3 hours
  7. customThe crude reaction mixture
  8. washeluting with dichloromethane
  9. customThe crude product is further purified by flash column chromatography
  10. washeluting with 10% methanol in dichloromethane
  11. washeluting with 10% methanol in ethyl acetate

Sources & evidence

ORD record
ord-9b55b64e04ab47fcb73c0d141af9226c
Source dataset
uspto-grants-2007_10
Patent number
US07276519B2

Reaction notes

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