Citric Acid → 1,3-Diethyl 2-[2-(4-bromo-2-chlorophenyl)ethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]propanedioate

HRID 1641536Notes

Reaction equation

HRID 1641536 reaction equation
[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[Na+].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]I)=[C:29]([Cl:36])[CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:5]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])([C:4]([O:3][CH2:1][CH3:2])=[O:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:29]([Cl:36])[CH:28]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 382219Diethyl 2-((tert-butoxycarbonyl)amino)malonateHCID 23676156Sodium t-butoxideHCID 462025614-Bromo-2-chloro-1-(2-iodoethyl)benzene

Product 1

HCID 462028801,3-Diethyl 2-[2-(4-bromo-2-chlorophenyl)ethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]propanedioateYield 64.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Diethyl(tert-butoxycarbonyl)aminomalonate (202 g) was dissolved in a mixed solution of tetrahydrofuran (6000 mL) and N,N-dimethylformamide (714 mL), and sodium tert-butoxide (70.5 g) was added. After heating the mixture to the refluxing temperature, a solution of 2-(4-bromo-2-chlorophenyl)ethyl iodide (246 g) of Reference Example 18 in tetrahydrofuran (940 mL) was added to the reaction mixture, and the mixture was refluxed with stirring for 15 hr. After cooling, the reaction mixture was poured into 25% aqueous citric acid solution. After partitioning and extraction with ethyl acetate, the organic layer was washed with water and 25% brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (227 g) as a pale-yellow oil.

Workup

  1. additionwas added
  2. temperatureAfter heating the mixture to the refluxing temperature
  3. temperaturethe mixture was refluxed
  4. temperatureAfter cooling
  5. customAfter partitioning
  6. extractionextraction with ethyl acetate
  7. washthe organic layer was washed with water and 25% brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. customThe solvent was evaporated under reduced pressure
  10. customthe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-f3f013c304cb47b3b7d2812bd2c0b21b
Source dataset
uspto-grants-2012_02
Patent number
US08114902B2

Reaction notes

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