Hydrochloric Acid → Ethyl 1,4-diazepane-1-carboxylate

HRID 1584440Notes

Reaction equation

HRID 1584440 reaction equation
[NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C([O-])(=O)C.[Na+].[OH-].[Na+]>O>[CH2:34]([O:33][C:31]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:32])[CH3:35]

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 10928Ethyl chloroformateHCID 11037Benzenesulfonic acid, 4-(2-(4-(dimethylamino)phenyl)diazenyl)-HCID 14798Sodium Hydroxide2×HCID 68163Hexahydro-1,4-diazepineHCID 517045Sodium Acetate

Product 1

HCID 15289249Ethyl 1,4-diazepane-1-carboxylate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Combine [1,4]diazepane (33.9 g, 340 mmol) and water (250 mL). Add methyl orange and adjust the pH using 3 M aqueous hydrochloric acid solution until the indicator turns red. Add dropwise, ethyl chloroformate (38 mL, 400 mmol) over about 2.5 hours while maintaining the pH using first aqueous sodium acetate and then aqueous sodium hydroxide solution. After the addition is complete adjust the pH to 8 using aqueous sodium hydroxide solution and extract three times with diethyl ether. Discard the organic extracts and saturate the aqueous layer with potassium carbonate. Extract three times with diethyl ether. Combine the organic layers from the second extraction, dry the over Na2SO4, filter, and evaporate in vacuo to give a 1-ethoxycarbonyl[1,4]diazepane. Combine 1-ethoxycarbonyl[1,4]diazepane (36.6 g, 212 mmol) and 2-chlorobenzimidazole (18.0 g, 106 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Partition the methanol solution between dichloromethane (700 mL) and a solution of sodium hydroxide (20 g) in water (500 mL). Separate the layers and extract the aqueous layer three times with dichloromethane. Combine the organic layers, extract with brine, dry over Na2SO4, filter, and evaporate in vacuo to give a solid. Triturate the solid with ethyl acetate (100 mL) and cool to 0° C. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane.

Workup

  1. additionAdd dropwise
  2. additionAfter the addition
  3. extractionextract three times with diethyl ether
  4. concentrationsaturate the aqueous layer with potassium carbonate
  5. extractionExtract three times with diethyl ether
  6. extractionCombine the organic layers from the second extraction
  7. dry with materialdry the over Na2SO4
  8. filtrationfilter
  9. customevaporate in vacuo

Sources & evidence

ORD record
ord-c9815839df974e06841abab5c916493c
Source dataset
uspto-grants-1999_08
Patent number
US05932571

Reaction notes

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