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

HRID 2258107Notes

Reaction equation

HRID 2258107 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(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 8857Ethyl AcetateHCID 124753,4,5,6-Tetrahydrophthalic anhydrideHCID 938984-Chloro-2-fluoroaniline2×HCID 22728543Water ethylacetate

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 mixture 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 (150 mL) 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 a water/ethyl acetate mixture. The organic phase 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, mp 81°-82° C.).

Workup

  1. temperatureis refluxed for 2 hours
  2. temperaturerefluxed for 90 minutes
  3. washThe organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. concentrationconcentrated in vacuo
  6. customto obtain a purple oil

Sources & evidence

ORD record
ord-145a5b672d94481aa03313c972109ca0
Source dataset
uspto-grants-1997_08
Patent number
US05659031

Reaction notes

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