Citric Acid → 2-Ethoxycarbonyl-3-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-4-methyl-pentanedioic acid 1-tert-butyl ester 5-ethyl ester

HRID 238589

Reaction equation

HRID 238589 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[K+].[CH2:20]([O:22][C:23](=[O:35])[C:24]([CH3:34])=[C:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH3:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[CH2:20]([O:22][C:23](=[O:35])[CH:24]([CH3:34])/[C:25](=[CH:26]\[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)/[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:21]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 96345tert-Butyl ethyl malonateHCID 11481404HCID 11481404, compoundHCID 23665647Potassium tert-butoxide

Product 1

HCID 593265542-Ethoxycarbonyl-3-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-4-methyl-pentanedioic acid 1-tert-butyl ester 5-ethyl ester

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
25 °C

Procedure

Malonic acid tert-butyl ester ethyl ester (30.08 g, 151.8 mmol) was added to a solution of potassium tert-butoxide (16.30 g, 138.0 mmol) in 200 mL of N,N-dimethyl acetamide, while the reaction temperature was maintained at ˜25° C. To the resulting mixture was then added the solution of 4-(4-fluoro-phenyl)-2-methyl-buta-2,3-dienoic acid ethyl ester prepared above, at such a rate that the reaction temperature was maintained between 20-28° C. After the addition was complete, the reaction mixture was stirred at room temperature for 20 minutes, when HPLC indicated completed reaction. The mixture was then treated with 100 mL of 1M citric acid and 150 mL of ice-water, and then extracted with 400 mL of methyl tert-butyl ether. The organic extract was separated and washed with 2×200 mL of water, and then concentrated to produce 56.36 g of a yellow oil, which was used in the next step without further purification.

Workup

  1. customprepared above, at such a rate that the reaction temperature
  2. temperaturewas maintained between 20-28° C
  3. additionAfter the addition
  4. customreaction
  5. extractionextracted with 400 mL of methyl tert-butyl ether
  6. extractionThe organic extract
  7. customwas separated
  8. washwashed with 2×200 mL of water
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-31ad60e175554caea484eb2808af43d8
Source dataset
uspto-grants-2014_02
Patent number
US08642629B2

Linked notes

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