Methanol → HCID 69157468, compound

HRID 750370Notes

Reaction equation

HRID 750370 reaction equation
[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1.CO.N12CCCN=C1CCCCC2>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:12]([C:13](=[O:15])[CH3:14])=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]3[C:17](=[CH:22][CH:21]=[C:20]([Cl:23])[CH:19]=3)[C:16]2=[O:32])=[CH:8][CH:9]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 69157139HCID 69157139, compound

Product 1

HCID 69157468HCID 69157468, compoundYield 57.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

[Step 1] To a solution (100 ml) of 2-benzoyl-4-chlorobenzoic acid (7.0 g) in THF were added 4-[(2-hydroxypropylamino)methyl]benzoic acid methyl ester (6.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.7 g), 1-hydroxy-1H-benzotriazole monohydrate (4.1 g), acetonitrile (100 ml) and triethylamine (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hrs. and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-hexane:ethyl acetate=1:2) to give 4-[[(2-benzoyl-4-chlorobenzoyl)(2-hydroxypropyl)amino]methyl]benzoic acid methyl ester (6.7 g). [Step 2] To a solution (64 ml) of 4-[[(2-benzoyl-4-chlorobenzoyl)(2-hydroxypropyl)amino]methyl]benzoic acid methyl ester (6.4 g) in DMSO was added triethylamine (16 ml), and pyridine sulfur trioxide complex (8.7 g) was added at room temperature. The mixture was stirred for 1 hr. and added to water. 10% Hydrochloric acid was added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-hexane:ethyl acetate=1:2) to give 4-[[(2-benzoyl-4-chlorobenzoyl)(2-oxopropyl)amino]methyl]benzoic acid methyl ester (5.8 g). [Step 3] To a solution (60 ml) of 4-[[(2-benzoyl-4-chlorobenzoyl)(2-oxopropyl)amino]methyl]benzoic acid methyl ester (5.6 g) in THF were added methanol (60 ml) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (3.7 g), and the mixture was heated under reflux for 72 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with methanol to give the title compound (3.1 g).

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux for 72 hrs
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. additionthe residue was diluted with ethyl acetate
  5. washThe organic layer was washed with 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. customThe solvent was evaporated under reduced pressure
  8. washthe obtained crystals were washed with methanol

Sources & evidence

ORD record
ord-893923169ddc4443b17ec50a5264eee3
Source dataset
uspto-grants-2008_07
Patent number
US07402595B2

Reaction notes

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