Citric Acid → 1,1-Dimethylethyl (3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate

HRID 1176712Notes

Reaction equation

HRID 1176712 reaction equation
IC.[H-].[Na+].[O:5]=[C:6]1[N:10]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:9][CH:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7]1.[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:26][C@:8]1([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:7][C:6](=[O:5])[N:10]([C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH2:9]1

Participants

6

Reactant 4

HCID 311Citric Acid2×HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 57758674HCID 57758674, compound

Product 1

HCID 577587301,1-Dimethylethyl (3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylateYield 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 (55% in oil, 11.35 g, 0.260 mol) were sequentially added at room temperature to a solution of tert-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL) under 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 mL, 500 mL). The organic layers were combined and 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, tert-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (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 mL
  7. washwashed 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-38d0058281064eea822fde9c0e541f9e
Source dataset
uspto-grants-2010_11
Patent number
US07842818B2

Reaction notes

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