Citric Acid → HCID 66784733, compound

HRID 1096570Notes

Reaction equation

HRID 1096570 reaction equation
IC.[H-].[Na+].[C:5]([CH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])([CH3:8])([CH3:7])[CH3:6].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:5]([CH:9]1[C@@:13]([CH3:26])([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])([CH3:6])([CH3:7])[CH3:8]

Participants

6

Reactant 4

HCID 311Citric Acid2×HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 66784856HCID 66784856, compound

Product 1

HCID 66784733HCID 66784733, compoundYield 33.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
30 °C

Procedure

Under a nitrogen gas atmosphere, iodomethane (26.0 mL, 59.28 g, 0.418 mol) and sodium hydride (oil content: 55%, 11.35 g, 0.260 mol) were sequentially added at room temperature to a solution of t-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL) with stirring. When the internal temperature reached to about 50° C., the mixture was cooled to 30° C. in an ice-water bath. Subsequently, the bath was changed to a water bath having an external temperature of 17° C., followed by stirring for 23 hours. The reaction mixture was poured into cold aqueous citric acid (a mixture of 10% citric acid (1 L) and ice (500 g)), followed by stirring for 30 minutes and extracting with ethyl acetate (800 mL, 500 mL). The organic layers were combined. The combined organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and filtration. The filtrate was evaporated to dryness under reduced pressure. The residue was purified through flash silica gel column chromatography (eluent; hexane:ethyl acetate=5:1 to 4:1), to thereby yield the title compound as white solid (10.63 g, 33.7%) as a high-polar isomer. In addition, t-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (14.91 g, 47.3%) was produced as a low-polar isomer.

Workup

  1. customreached to about 50° C.
  2. customSubsequently, the bath was changed to a water bath
  3. customan external temperature of 17° C.
  4. stirringby stirring for 23 hours
  5. stirringby stirring for 30 minutes
  6. extractionextracting with ethyl acetate (800 mL, 500 mL)
  7. washThe combined organic layer was washed with saturated brine
  8. dry with materialby drying over sodium sulfate anhydrate and filtration
  9. customThe filtrate was evaporated to dryness under reduced pressure
  10. customThe residue was purified through flash silica gel column chromatography (eluent; hexane:ethyl acetate=5:1 to 4:1)

Sources & evidence

ORD record
ord-57486a3d1fc6423fae8899feafbfee36
Source dataset
uspto-grants-2012_03
Patent number
US08138352B2

Reaction notes

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