Ethyl Acetate → (4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one

HRID 1799199

Reaction equation

HRID 1799199 reaction equation
N[C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:25].O>O.[Cu]Br>[Br:25][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 22326455Hydrobromide monohydrate2×HCID 23668193Sodium NitriteHCID 66724932(4R)-4-(3-amino-4-chlorophenyl)pyrrolidin-2-one

Product 1

HCID 66724952(4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one

Reagents, catalysts & solvents 2

HCID 24593copper(I) bromideCatalystHCID 962WaterSolvent3×

Procedure

(4R)-4-(3-Amino-4-chlorophenyl)pyrrolidin-2-one (12 g, 57.14 mmol) was added to a mixture of 75 mL of 48% HBr/water and 150 mL of water. The solution was cooled in ice. Sodium nitrite (4.33 g, 62.85 mmol) in 10 mL of water was added dropwise. The resulting mixture was stirred for 10 min. Copper(I) bromide (8.9 g, 62.85 mmol) was dissolved in a mixture of 75 mL of 48% HBr/water and 150 mL of water and added dropwise to the reaction mixture. The mixture was then stirred overnight at room temperature. Ethyl acetate (250 mL) was added to the reaction mixture and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with 200 mL of ethyl acetate. The combined ethyl acetate layers were washed with water (3 times), brine and then concentrated to give the desired product as a brownish yellow oil, which was purified by silica gel column chromatography eluting with methylene chloride/methanol to provide 7.2 g of the title compound (60% yield). 1H-NMR (400 MHz, CD3OD): δ 7.62-7.63 d, J=2.0 Hz, 1H), 7.45-7.47 (m, 1H), 7.26-7.30 (m, 1H), 3.69-3.79 (m, 2H), 3.33-3.37 (m, 1H) 2.67-2.74 (dd, J=16.4, 8.8 Hz, 1H), 2.40-2.47 (dd, J=16.4, 8.4 Hz, 1H); MS (ESI) m/z 275.89 (M+H)+.

Workup

  1. temperatureThe solution was cooled in ice
  2. additionadded dropwise to the reaction mixture
  3. stirringThe mixture was then stirred overnight at room temperature
  4. stirringstirred for 10 min
  5. customThe organic layer was separated
  6. extractionthe aqueous layer was extracted with 200 mL of ethyl acetate
  7. washThe combined ethyl acetate layers were washed with water (3 times), brine
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-fb5850c05d604911b10caf694ebca7a3
Source dataset
uspto-grants-2013_01
Patent number
US08344028B2

Linked notes

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