Potassium Hydroxide → Emedastine EP Impurity E

HRID 1584428Notes

Reaction equation

HRID 1584428 reaction equation
ClCCl.CO.C(OC([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:22]([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:21]3[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=O)C.O.NN.[OH-].[K+]>C(O)CO.O>[CH2:26]([O:25][CH2:24][CH2:23][N:22]1[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[N:19]=[C:18]1[N:14]1[CH2:15][CH2:16][CH2:17][NH:11][CH2:12][CH2:13]1)[CH3:27]

Participants

7

Reactant 4

HCID 14797Potassium HydroxideHCID 24654Hydrazine hydrate (1:1)HCID 143561191-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHCID 21226129Dichloromethane methanol

Product 1

HCID 9984168Emedastine EP Impurity E

Reagents, catalysts & solvents 2

HCID 174Ethylene GlycolSolventHCID 962WaterSolvent

Procedure

Combine 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20 mL). Heat to 80° C. After 2 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.87 (silica gel, dichloromethane/methanol, 90/10). Combine 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5 hours, cool the reaction mixture and dilute with water (500 mL). Extract three times with dichloromethane. Combine the dichloromethane layers and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.25 (silica gel, dichloromethane/methanol, 90/10).

Workup

  1. temperatureHeat to reflux
  2. temperaturecool the reaction mixture
  3. extractionExtract three times with dichloromethane
  4. extractionextract with a saturated aqueous sodium bicarbonate solution
  5. dry with materialDry the organic layer over MgSO4
  6. filtrationfilter
  7. customevaporate in vacuo

Sources & evidence

ORD record
ord-f02fb888a4904d47bc2cada9bd94c057
Source dataset
uspto-grants-1999_08
Patent number
US05932571

Reaction notes

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