ethyl 1,4-diazepane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium carbonate (0.80 g) was added to a solution of 0.86 g of ethyl 1-homopiperazinecarboxylate and 0.90 g of benzylbromide in 5 ml of tetrahydrofuran, and the mixture was refluxed for 4 hours. Thereafter, water was added, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Elution with a hexane-ethyl acetate (2:1) mixture gave 1.06 g of ethyl 4-benzylhomopiperazine-1-carboxylate. the mixture was refluxed for 4 hours the mixture was extracted with ethyl acetate the organic layer was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate concentrated under reduced pressure Elution with a hexane-ethyl acetate (2:1) mixture

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2N Hydrochloric acid was added to a solution of 1.10 g of homopiperazine in 15 ml of water at room temperature until a pH of 2 was attained. Then, 40% aqueous sodium acetate and 1.28 g of ethyl chloroformate were added alternately in portions within the pH range of 2.0 to 3.5, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate, and the aqueous layer was saturated with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.27 g of ethyl 1-homopiperazinecarboxylate. The reaction mixture was washed with ethyl acetate extracted with ethyl acetate The organic layer was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2N Hydrochloric acid was added to a solution of 1.10 g of homopiperazine in 15 ml of water at room temperature until a pH of 2 was attained. Then, 40% aqueous sodium acetate and 1.28 g of ethyl chloroformate were added alternately in portions within the pH range of 2.0 to 3.5, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate, and the aqueous layer was saturated with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.27 g of ethyl 1-homopiperazinecarboxylate. The reaction mixture was washed with ethyl acetate extracted with ethyl acetate The organic layer was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate concentrated under reduced pressure

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol) and 2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Add a saturated aqueous solution of sodium bicarbonate (150 mL) and concentrate in vacuo to remove most of the methanol. Combine the aqueous reaction mixture and 95/5 diethyl ether/ethyl acetate. Separate the aqueous layer and extract three times with dichloromethane. Combine the dichloromethane layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with ethyl acetate (100 mL) to give a solid. Chromatograph on silica gel eluting with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp; 161-162° C. cool to ambient temperature to dissolve the reaction mixture concentrate in vacuo to remove most of the methanol Separate the aqueous layer extract three times with dichloromethane dry over Na2SO4 filter evaporate in vacuo to give a residue Triturate the residue with ethyl acetate (100 mL) to give a solid Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid Collect solid by filtration dry in vacuo

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol) and 2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Add a saturated aqueous solution of sodium bicarbonate (150 mL) and concentrate in vacuo to remove most of the methanol. Combine the aqueous reaction mixture and 95/5 diethyl ether/ethyl acetate. Separate the aqueous layer and extract three times with dichloromethane. Combine the dichloromethane layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with ethyl acetate (100 mL) to give a solid. Chromatograph on silica gel eluting with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp; 161-162° C. cool to ambient temperature to dissolve the reaction mixture concentrate in vacuo to remove most of the methanol Separate the aqueous layer extract three times with dichloromethane dry over Na2SO4 filter evaporate in vacuo to give a residue Triturate the residue with ethyl acetate (100 mL) to give a solid Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid Collect solid by filtration dry in vacuo

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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. cool to ambient temperature to dissolve the reaction mixture Partition the methanol solution between dichloromethane (700 mL) Separate the layers extract the aqueous layer three times with dichloromethane extract with brine dry over Na2SO4 filter evaporate in vacuo to give a solid Triturate the solid with ethyl acetate (100 mL) cool to 0° C Collect solid by filtration dry in vacuo

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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. cool to ambient temperature to dissolve the reaction mixture Partition the methanol solution between dichloromethane (700 mL) Separate the layers extract the aqueous layer three times with dichloromethane extract with brine dry over Na2SO4 filter evaporate in vacuo to give a solid Triturate the solid with ethyl acetate (100 mL) cool to 0° C Collect solid by filtration dry in vacuo