Water → 2-(4-Chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1h-isoindole-1,3(2h)-dione

HRID 380786Notes

Reaction equation

HRID 380786 reaction equation
[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2.O.C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:10](=[O:15])[C:11]3[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=3[C:13]2=[O:14])=[C:4]([F:9])[CH:3]=1

Participants

6

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 124753,4,5,6-Tetrahydrophthalic anhydrideHCID 938984-Chloro-2-fluoroaniline2×

Product 1

HCID 1859312-(4-Chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1h-isoindole-1,3(2h)-dioneYield 69.3%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A solution of 4-chloro-2-fluoroaniline (19.0 g, 130.6 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid is refluxed for 2 hours, treated with additional 4-chloro-2-fluoroaniline (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15 to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, 69% yield, mp 81-82° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.

Workup

  1. temperaturerefluxed for 90 minutes
  2. extractionThe resultant aqueous mixture is extracted with ethyl acetate
  3. extractionThe organic extract
  4. washis washed sequentially with water, saturated sodium hydrogen carbonate solution and brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customto obtain a purple oil

Sources & evidence

ORD record
ord-323391b5e491496e9e3132e1849d2043
Source dataset
uspto-grants-2001_10
Patent number
US06303783B1

Reaction notes

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