p-Toluenesulfonic acid monohydrate → HCID 10065017, compound

HRID 2050941Notes

Reaction equation

HRID 2050941 reaction equation
O=C1CCN(CC2C=CC=CC=2)[C@H]1CC1CC(=O)CC(=O)C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:35]([O:37][C:38]1[CH2:39][C@@H:40]([CH2:45][C@H:46]2[N:50]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:49](=[O:58])[CH2:48][CH2:47]2)[CH2:41][C:42](=[O:44])[CH:43]=1)[CH3:36]>C(O)C.C1(C)C=CC=CC=1>[CH2:35]([O:37][C:38]1[CH2:39][C@H:40]([CH2:45][C@H:46]2[N:50]([CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:49](=[O:58])[CH2:48][CH2:47]2)[CH2:41][C:42](=[O:44])[CH:43]=1)[CH3:36]

Participants

6

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10245891HCID 10245891, compoundHCID 54362083HCID 54362083, compound

Product 1

HCID 10065017HCID 10065017, compoundYield 57%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 1140TolueneSolvent

Procedure

A solution of (S)-5-[[oxo-1-(phenylmethyl)-2-pyrrolidinyl]methyl]-1,3-cyclohexanedione (60 g, 0.20 mol) and p-toluenesulfonic acid monohydrate (3.8 g, 0.02 mol) in 600 mL of ethanol and 1200 mL of toluene was stirred and refluxed for 1.5 h. The solvent was removed on a rotary evaporator and the residue dissolved in methylene chloride. The methylene chloride solution was washed with saturated sodium bicarbonate solution, brine, and dried over Na2SO4. The solvent was removed on a rotary evaporator to give 57.6 g of a crude oil. The crude product was chromatographed on silica gel (800 g) eluting with 2-4% methanol in ethyl acetate to give a 1:1 mixture of diastereomeric products: (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone and (5s,1S)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone (37.5 g, 57% yield). A total of 25.5 g of mixture (from this and a similar preparation) was chromatographed using a Waters Prep 500 high pressure liquid chromatograph, eluting with 1:24:25 methanol:ethyl acetate:hexane, and recovering and rechromatographing the mixed fractions. A total of 24.3 g (25.0% yield) of the more polar diastereomer, (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone, and a total of 23.9 g (24.6% yield) of the less polar diastereomer, (5S,1S)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone was obtained.

Workup

  1. temperaturerefluxed for 1.5 h
  2. customThe solvent was removed on a rotary evaporator
  3. dissolutionthe residue dissolved in methylene chloride
  4. washThe methylene chloride solution was washed with saturated sodium bicarbonate solution, brine
  5. dry with materialdried over Na2SO4
  6. customThe solvent was removed on a rotary evaporator
  7. customto give 57.6 g of a crude oil
  8. customThe crude product was chromatographed on silica gel (800 g)
  9. washeluting with 2-4% methanol in ethyl acetate
  10. customto give
  11. additiona 1:1 mixture of diastereomeric products

Sources & evidence

ORD record
ord-ec668b123a28457b914e740e6c891a27
Source dataset
uspto-grants-1991_05
Patent number
US05015653

Reaction notes

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