4-Fluorobenzoyl chloride → Ethyl 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate

HRID 38892Notes

Reaction equation

HRID 38892 reaction equation
[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])=[CH:22][CH:21]=1

Participants

6

Reactant 2

HCID 678794-Fluorobenzoyl chlorideHCID 616598Ethyl 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate

Product 1

HCID 1724388Ethyl 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 14798Sodium HydroxideSolvent

Procedure

Ethyl cyanoacetate (5 mmol), and p-chloro-acetophenone (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-(4-chlorophenyl)-thiophene-3-carboxylate. Ethyl 2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate (5 mmol) is treated with 4-fluorobenzoyl 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 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate. Ethyl 2-(fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate is hydrolyzed under a variety of conditions (e.g. LiOH, water; LiOH, H2O2, water; or NaOH, water) to provide 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid.

Workup

  1. customThe layers are separated
  2. dry with materialthe organic layer is dried with anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue is purified by flash chromatography

Sources & evidence

ORD record
ord-69de4cbd449141a9a4b0cdf5c1f29634
Source dataset
uspto-grants-2013_09
Patent number
US08524765B2

Reaction notes

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