Dimethylformamide → 4-Trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butyl ester

HRID 860599Notes

Reaction equation

HRID 860599 reaction equation
[H-].[Na+].CN(C)C=O.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.[CH2:21]([O:23][C:24](=[O:32])[CH:25](Cl)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH3:22]>O>[CH2:21]([O:23][C:24]([CH:25]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:9]([F:19])([F:20])[F:8])=[CH:11][CH:12]=1)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:32])[CH3:22]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 99664-(Trifluoromethyl)benzoic acidHCID 24758Sodium hydrideHCID 9877606Ethyl 2-chloro-4-methyl-3-oxopentanoate

Product 1

HCID 690607214-Trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butyl ester

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

Sodium Hydride, 60% mineral oil (1.9 g, 46.3 mmol) and dimethylformamide (50 mL) are stirred at room tmperature and 4-(trifluoromethyl)benzoic acid (8.0 g, 42.1 mmol) is added. To the resulting slurry is added 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (8.5 g, 44.2 mmol) and the resulting mixture is heated to 90° C. for 3 hr. The reaction mixture is cooled, diluted with water (100 mL), and product is extracted with ethyl acetate (100 mL). The organic layer is washed with water (three 100 mL portions) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to constant weight to give 4-trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butyl ester as a colorless oil, 14.6 g, 100%. The resulting oil is stirred in a mixture of acetic acid (100 mL) and ammonium acetate (9.75 g, 126.5 mmol) at reflux 1 hr, then 20 hr at room temperature. The solvent is removed in vacuo and the residue is partioned between aqueous saturated sodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL. The layers are separated, the aqueous layer is washed with ethyl acetate (100 mL). The organic extracts are combined, washed with water and brine (100 mL each) dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is purified over silica eluting with 9:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester as a white solid, 8.1 g, 60%. MS (M++1) 328.

Workup

  1. additionis added
  2. temperatureThe reaction mixture is cooled
  3. extractionis extracted with ethyl acetate (100 mL)
  4. washThe organic layer is washed with water (three 100 mL portions) and brine (100 mL)
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to constant weight

Sources & evidence

ORD record
ord-33f6b784a3e7417cb2f3b658e5dad465
Source dataset
uspto-grants-2006_12
Patent number
US07153878B2

Reaction notes

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