p-Toluenesulfonic acid → (R)-methyl 5-oxo-1-((R)-1-phenylethyl)pyrrolidine-3-carboxylate

HRID 1468759Notes

Reaction equation

HRID 1468759 reaction equation
[C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5](OC)=[O:6])=[CH2:3].[C:12]1([C@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:6]=[C:5]1[N:20]([C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:19])[CH2:3][C@@H:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4]1.[O:6]=[C:5]1[N:20]([C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:19])[CH2:3][C@H:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4]1

Participants

6

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 69240Dimethyl itaconateHCID 6431891-Phenethylamine, (+)-

Product 2

HCID 11637375(R)-methyl 5-oxo-1-((R)-1-phenylethyl)pyrrolidine-3-carboxylateYield 48%HCID 13772852Methyl (3S)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylateYield 36%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of dimethyl itaconate (25 g, 158 mmol) in methanol (150 ml) was added (R)-1-phenylethylamine (20 ml, 158 mmol) at room temperature. The resulting mixture was stirred for 18 hours and concentrated. The residue was dissolved in toluene (100 ml) and p-toluenesulfonic acid (3.0 g, 16 mmol) was added at room temperature. The mixture was refluxed for 16 hours and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1 to 1/3) to afford methyl (3S)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate as a white solid (14.0 g, 56.5 mmol, 36%) and methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate as a yellow oil (18.7 g, 75.5 mmol, 48%). Each stereochemistry was determined by the data based on the literature (J. Med. Chem. 1990, 33, 71-77).

Workup

  1. concentrationconcentrated
  2. dissolutionThe residue was dissolved in toluene (100 ml)
  3. temperatureThe mixture was refluxed for 16 hours
  4. concentrationconcentrated
  5. customThe residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1 to 1/3)

Sources & evidence

ORD record
ord-4fff014cbccd481b88797842ffa1f866
Source dataset
uspto-grants-2015_04
Patent number
US09006232B2

Reaction notes

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