1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 6-bromo-2-(4-methylsulfanylbenzyl)-4-phenyl-3-propionyl-2H-isoquinolin-1-one

HRID 750327Notes

Reaction equation

HRID 750327 reaction equation
[CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:16]([C:24]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Br:33][C:31]1[CH:32]=[C:24]2[C:25](=[CH:29][CH:30]=1)[C:26](=[O:27])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:15][CH:14]=1)[C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1

Participants

7

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 3467342-Benzoyl-4-bromobenzoic acidHCID 23060965HCID 23060965, compound

Product 1

HCID 230610156-bromo-2-(4-methylsulfanylbenzyl)-4-phenyl-3-propionyl-2H-isoquinolin-1-oneYield 35.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Procedure

To a solution of 1-(4-methylsulfanylbenzylamino)butan-2-ol (8.5 g) and 2-benzoyl-4-bromobenzoic acid (14.7 g) and 1-hydroxy-1H-benzotriazole (7.4 g) in DMF (100 ml) was added triethylamine (8.4 ml) and then WSC (11.5 g) was added at room temperature. The mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and the residue was partitioned between dichloromethane and water, washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1-+13/7). The resulting colorless amorphous form was dissolved in dimethyl sulfoxide (100 ml) and triethylamine (25.3 ml) was added. Under ice-cooling, pyridine sulfur trioxide complex (14.5 g) was added, and the mixture was stirred at room temperature for 8 hrs. Water (300 ml) was added, and the mixture was extracted with ethyl acetate and washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine. Sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→2/3). The obtained colorless amorphous form was dissolved in 0.1N potassium hydroxide-ethanol solution (75 ml) and heated under reflux for 12 hrs. 1N Hydrochloric acid (7.5 ml) was added and the mixture was stirred under ice-cooling for 1 hr. The crystals were collected by filtration and washed with 70% ethanol-water to give the title compound (6.58 g, 34%).

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. customthe residue was partitioned between dichloromethane and water
  3. washwashed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine
  4. customdried
  5. additionby adding sodium sulfate
  6. customThe solvent was evaporated under reduced pressure
  7. customthe obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1-+13/7
  8. dissolutionThe resulting colorless amorphous form was dissolved in dimethyl sulfoxide (100 ml)
  9. additiontriethylamine (25.3 ml) was added
  10. temperatureUnder ice-cooling
  11. additionpyridine sulfur trioxide complex (14.5 g) was added
  12. stirringthe mixture was stirred at room temperature for 8 hrs
  13. additionWater (300 ml) was added
  14. extractionthe mixture was extracted with ethyl acetate
  15. washwashed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine
  16. additionSodium sulfate was added
  17. customto dry the mixture
  18. customThe solvent was evaporated under reduced pressure
  19. customthe obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→2/3)
  20. dissolutionThe obtained colorless amorphous form was dissolved in 0.1N potassium hydroxide-ethanol solution (75 ml)
  21. temperatureheated
  22. temperatureunder reflux for 12 hrs
  23. addition1N Hydrochloric acid (7.5 ml) was added
  24. stirringthe mixture was stirred under ice-
  25. temperaturecooling for 1 hr
  26. filtrationThe crystals were collected by filtration
  27. washwashed with 70% ethanol-water

Sources & evidence

ORD record
ord-4e627c222df149999ee5008c05780078
Source dataset
uspto-grants-2008_07
Patent number
US07402595B2

Reaction notes

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