Citric Acid → (E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepine

HRID 452163Notes

Reaction equation

HRID 452163 reaction equation
[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]\[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.NO.C([N:37](CC)CC)C.[C:42](Cl)(=[O:46])[O:43]CC.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C1COCC1.O>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]\[C:29]5[NH:37][C:42](=[O:46])[O:43][N:30]=5)/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1

Participants

10

Reactant 6

HCID 311Citric AcidHCID 787HydroxylamineHCID 8471TriethylamineHCID 10928Ethyl chloroformateHCID 23665647Potassium tert-butoxideHCID 67210398(E)-2-{8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile

Product 1

HCID 136337400(E)-8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-11-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-6,11-dihydrodibenzo[b,e]oxepineYield 73.1%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

[step 1] Using (E)-2-(8-bromomethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitrile (1.5 g, 4.6 mmol) obtained in Reference Example B13 and 4-methyl-2-propylbenzimidazole (EP400835; 842 mg, 4.83 mmol) and in the same manner as in Example 92, step 1, (E)-2-{8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (1.47 g, 76%) was obtained. [step 2] (E)-2-{8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (150 mg, 0.34 mmol) obtained in step 1 was dissolved in ethanol (1.8 mL), hydroxylamine (50% aqueous solution, 1.1 mL, 17.9 mmol) was added, and the mixture was stirred under reflux for 18 hr. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (1.8 mL), triethylamine (75 μL, 0.54 mmol) and ethyl chlorocarbonate (51 μL, 0.54 mmol) were added at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene (0.9 mL) and THF (0.9 mL), potassium tert-butoxide (80 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 20 min. 5% Aqueous citric acid solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 10/90) to give the title compound (compound 104) (119 mg, 70%).

Workup

  1. temperatureunder reflux for 18 hr
  2. extractionthe mixture was extracted with chloroform
  3. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe obtained residue was dissolved in dichloromethane (1.8 mL)
  6. stirringthe mixture was stirred at room temperature for 30 min
  7. extractionthe mixture was extracted with chloroform
  8. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. dissolutionThe obtained residue was dissolved in toluene (0.9 mL)
  11. stirringthe mixture was stirred at room temperature for 20 min
  12. extractionthe mixture was extracted with chloroform
  13. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 10/90)

Sources & evidence

ORD record
ord-b2ce2fd3ac724ee7a4fb60dafd2f421e
Source dataset
uspto-grants-2013_07
Patent number
US08486980B2

Reaction notes

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