Ethyl cyanoacetate → Ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)-3-thiophenecarboxylate

HRID 390780Notes

Reaction equation

HRID 390780 reaction equation
[C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:21](=O)[CH3:22])[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18].N1CCOCC1.BrC1C=CC2OC(C(NC3[S:43]C=C(C4C=CC(Cl)=CC=4)C=3C(O)=O)=O)=NC=2C=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[S:43][CH:22]=[C:21]([C:13]2[CH:12]=[C:11]([O:10][CH3:9])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]

Participants

6

Reactant 4

HCID 7764Ethyl cyanoacetateHCID 8083MorpholineHCID 143453',4',5'-TrimethoxyacetophenoneHCID 595359892-(5-Bromobenzo[d]oxazole-2-carboxamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid

Product 1

HCID 299299Ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)-3-thiophenecarboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Ethyl cyanoacetate (5 mmol), and 1-(3,4,5-trimethoxyphenyl)ethanone (5 mmol) are dissolved in toluene (5 mL). Morpholine (5 mmol) is added followed by activated molecular sieves (4A). The reaction is stirred at 80° C. for 12 hours. The reaction is cooled to room temperature, filtered and concentrated. The residue is taken up in toluene (5 mL), ethanol (5 mL) and sulfur is added (0.16 g; 5 mmol). The reaction mixture is heated with mixing at 70° C. for 12 hours. The reaction is cooled to room temperature and the solvents are evaporated. The residue is purified by HPLC to provide ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiophene-3-carboxylate. Ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiophene-3-carboxylate (5 mmol) is treated with 4-methylbenzoyl chloride (5 mmol) in THF (10 mL). The reaction is stirred at room temperature for 10 hours. The reaction is diluted with 1N NaOH (10 mL) and ethyl acetate (15 mL). The layers are separated, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography to provide ethyl 4-p-tolyl-2-(3,4,5-trimethoxybenzamido)thiophene-3-carboxylate. Ethyl 4-p-tolyl-2-(3,4,5-trimethoxybenzamido)thiophene-3-carboxylate is hydrolyzed under a variety of conditions (e.g. LiOH, water; LiOH, H2O2, water; or NaOH, water) to provide the title compound

Workup

  1. temperatureThe reaction is cooled to room temperature
  2. filtrationfiltered
  3. concentrationconcentrated
  4. additionethanol (5 mL) and sulfur is added (0.16 g; 5 mmol)
  5. temperatureThe reaction mixture is heated
  6. additionwith mixing at 70° C. for 12 hours
  7. temperatureThe reaction is cooled to room temperature
  8. customthe solvents are evaporated
  9. customThe residue is purified by HPLC

Sources & evidence

ORD record
ord-ef6b093adf224dd288c563da39d2dda3
Source dataset
uspto-grants-2013_02
Patent number
US08383670B2

Reaction notes

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