Iodine → (+/-)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-iodophenyl)pyrrolidin-2-one

HRID 1837974Notes

Reaction equation

HRID 1837974 reaction equation
N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C@@H:10]1[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]1[C:17]1[CH:22]=[CH:21][C:20](N)=[CH:19][CH:18]=1)=[O:9])[CH3:6].[I-:24].[K+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH2:5]([O:7][C:8]([C@@H:10]1[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]1[C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][CH:18]=1)=[O:9])[CH3:6]

Participants

9

Reactant 5

HCID 807IodineHCID 4875Potassium IodideHCID 24477Sodium ThiosulfateHCID 23668193Sodium NitriteHCID 59066479(+/-)-(4R*,5R)-5-ethoxycarbonyl-1-methyl-4-(4-aminophenyl)pyrrolidin-2-one

Product 1

HCID 59066478(+/-)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-iodophenyl)pyrrolidin-2-oneYield 44%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×HCID 1118Sulfuric AcidSolvent

Procedure

To a 0° C. solution of sodium nitrite (80 mg, 1.15 mmol) in sulfuric acid (2 mL) was added dropwise a solution of (±)-(4R*,5R)-5-ethoxycarbonyl-1-methyl-4-(4-aminophenyl)pyrrolidin-2-one (prepared according to the procedure for Intermediate U, 200 mg, 0.763 mmol) in glacial acetic acid (2 mL). The mixture was allowed to warm to room temperature and stirred for 40 min. The reaction was then cooled to 0° C. and a solution of potassium iodide (300 mg) and iodine (233 mg) in water (2 mL) was added in one portion. The dark mixture was stirred for 10 min at 0° C., followed by addition of enough aqueous solution of saturated sodium thiosulfate to lighten the reaction color. The mixture was then diluted with water (10 mL) and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The oily residue was purified by flash chromatography (gradient from 75% EtOAc/hex to 100% EtOAc) to give (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-iodophenyl)pyrrolidin-2-one (125 mg, 44%) as a white powder: mp 120-121° C.; TLC (EtOAc) Rf0.59; HPLC ES-MS m/z (rel abundance) 374 (MH+, 100%).

Workup

  1. customprepared
  2. temperatureThe reaction was then cooled to 0° C.
  3. stirringThe dark mixture was stirred for 10 min at 0° C.
  4. extractionextracted with EtOAc
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe oily residue was purified by flash chromatography (gradient from 75% EtOAc/hex to 100% EtOAc)

Sources & evidence

ORD record
ord-eec59de20340411bb457fb048316848a
Source dataset
uspto-grants-2004_08
Patent number
US06784167B2

Reaction notes

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