Fumaric Acid → (2S,4S,5S)-5-Amino-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2-carbamoyl-2-methylpropyl)amide fumarate

HRID 1694917Notes

Reaction equation

HRID 1694917 reaction equation
[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([C:12]([CH3:44])([CH3:43])[CH2:13][NH:14][C:15](=[O:42])[C@H:16]([CH:39]([CH3:41])[CH3:40])[CH2:17][C@H:18]([OH:38])[C@@H:19]([NH2:37])[CH2:20][N:21]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:23][C:22]1([CH3:36])[CH3:35])(=[O:11])[NH2:10]>[Cl-].[Na+].O.CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([C:12]([CH3:43])([CH3:44])[CH2:13][NH:14][C:15](=[O:42])[C@H:16]([CH:39]([CH3:40])[CH3:41])[CH2:17][C@H:18]([OH:38])[C@@H:19]([NH2:37])[CH2:20][N:21]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:23][C:22]1([CH3:36])[CH3:35])(=[O:11])[NH2:10]

Participants

5

Reactant 2

HCID 444972Fumaric AcidHCID 66645756HCID 66645756, compound

Product 1

HCID 66645755(2S,4S,5S)-5-Amino-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropylhexanoic acid (2-carbamoyl-2-methylpropyl)amide fumarateYield 67%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

196 mg of cesium carbonate (0.6 mmol) was added to a solution of 345 mg of (2S,4S,5S)-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-5-(2-nitrobenzenesulfonylamino)hexanoic acid (2-carbamoyl-2-methylpropyl)amide obtained in the above reaction (0.5 mmol) and 0.15 ml of thiophenol (content: 95%) (1.5 mmol) in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for four hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=20/1/0-10/1/0-100/10/1). 38.7 mg of fumaric acid (0.33 mmol) was added to a solution of 168 mg of (2S,4S,5S)-5-amino-6-(2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl)-4-hydroxy-2-isopropylhexanoic acid (2-carbamoyl-2-methylpropyl)amide obtained above (0.33 mmol) in methanol (3 ml), and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (2 ml) was added to the residue. Diethyl ether (5 ml) was further added and the solid was collected by filtration to obtain 132 mg of the title compound (yield: 67%).

Workup

  1. extractionfollowed by extraction with methylene chloride
  2. dry with materialThen, the organic layer was dried over anhydrous sodium sulfate
  3. filtrationAfter filtration
  4. customthe solvent was evaporated under reduced pressure
  5. customthe residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=20/1/0-10/1/0-100/10/1)
  6. stirringthe mixture was stirred at room temperature for five minutes
  7. concentrationThe reaction mixture was concentrated under reduced pressure, and methylene chloride (2 ml)
  8. additionwas added to the residue
  9. additionDiethyl ether (5 ml) was further added
  10. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-734b5befccbe4389bfb5b5cd197a4a37
Source dataset
uspto-grants-2012_04
Patent number
US08158790B2

Reaction notes

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