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

HRID 229523Notes

Reaction equation

HRID 229523 reaction equation
[O:1]=[C:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][N:3]1[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].IC.[H-].[Na+].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:26][C@:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][C:2](=[O:1])[N:3]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:4]1

Participants

6

Reactant 4

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

Product 1

HCID 577587301,1-Dimethylethyl (3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of tert-butyl 2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate (30.05 g, 0.104 mol) in N,N-dimethylformamide (210 mL), iodomethane (26.0 mL, 59.28 g, 0.418 mol), and then, sodium hydride (55%, in oil, 11.35 g, 0.260 mol) was added at room temperature in nitrogen atmosphere while stirring the mixture. When inner temperature increased to about 50° C., the reaction mixture was cooled to 30° C. by adding ice water to the outer bath. After changing the bath to a water bath at an outer temperature of 17° C., the mixture was stirred for 23 hours. The reaction mixture was poured into cold aqueous solution of citric acid (1 L of 10% citric acid and 500 g of ice), and after stirring the mixture for 30 minutes, the mixture was extracted with ethyl acetate (800 mL, 500 mL). The organic layers were combined, and washed with saturated aqueous solution of sodium chloride. After drying with anhydrous sodium sulfate, the mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash silica gel column chromatography (elution was started at hexane ethyl acetate of 5:1, and after elution of the low polarity isomer, hexane:ethyl acetate was changed to 4:1) to obtain 10.63 g (33.7%) of high polarity isomer of tert-butyl(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate as a white solid. 14.91 g (47.3%) of low polarity isomer of tert-butyl(3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate was also obtained.

Workup

  1. temperaturethe reaction mixture was cooled to 30° C.
  2. customat an outer temperature of 17° C.
  3. stirringthe mixture was stirred for 23 hours
  4. stirringafter stirring the mixture for 30 minutes
  5. extractionthe mixture was extracted with ethyl acetate (800 mL, 500 mL)
  6. washwashed with saturated aqueous solution of sodium chloride
  7. dry with materialAfter drying with anhydrous sodium sulfate
  8. filtrationthe mixture was subjected to filtration
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe concentrate was purified by flash silica gel column chromatography (
  11. washelution
  12. washafter elution of the low polarity isomer, hexane

Sources & evidence

ORD record
ord-cf916102c23043da8d307ca5a61012bc
Source dataset
uspto-grants-2009_07
Patent number
US07563805B2

Reaction notes

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