Methyl iodide → (+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]4-[4-(dimethylamino)phenyl]-1-methylpyrrolidin-2-one

HRID 1838005Notes

Reaction equation

HRID 1838005 reaction equation
[OH:1][C@H:2]([C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][CH:11]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+].C[O-].[Na+]>C(#N)C.O.CO>[OH:1][C@H:2]([C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH3:31])[CH3:17])=[CH:14][CH:15]=1

Participants

8

Reactant 4

HCID 6328Methyl iodide2×HCID 11430Potassium CarbonateHCID 10942334Sodium MethoxideHCID 59066505(+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]methyl-4-[4-(methylamino)phenyl]pyrrolidin-2-one

Product 1

HCID 59066457(+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]4-[4-(dimethylamino)phenyl]-1-methylpyrrolidin-2-oneYield 14%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

A mixture of (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-[4-(methylamino)phenyl]pyrrolidin-2-one (Example 18, 70 mg, 0.18 mmol), methyl iodide (26 mg, 0.18 mmol) and potassium carbonate (49 mg, 0.36 mmol) in acetonitrile (1 mL) was stirred for 3 h. More methyl iodide (0.26 mg, 0.18 mmol) was added and the mixture was heated at the reflux temperature for 2 h. The reaction mixture was treated with sodium methoxide (20 mg, 0.36 mmol) and methanol (1 mL) and heated at the reflux temperature overnight. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to give a colorless oil, which was sequentially triturated with EtOAc, Et2O and hexane to provide (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]4-[4-(dimethylamino)phenyl]-1-methylpyrrolidin-2-one (10 mg, 14%) as an off-white solid: TLC (EtOAc) Rf 0.40; HPLC ES-MS m/z (rel abundance) 407 (MH+, 100%).

Workup

  1. temperaturethe mixture was heated at the reflux temperature for 2 h
  2. temperatureheated at the reflux temperature overnight
  3. extractionextracted with EtOAc (2×10 mL)
  4. washThe combined organic layers were washed with a saturated NaCl solution
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product was purified by flash chromatography (EtOAc)
  8. customto give a colorless oil, which
  9. customwas sequentially triturated with EtOAc, Et2O and hexane

Sources & evidence

ORD record
ord-8d6afd8de7af419d94d07a5bffe919c6
Source dataset
uspto-grants-2004_08
Patent number
US06784167B2

Reaction notes

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