cyclopropylmethyl carbonochloridate

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

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

Procedure: To a solution of silver salt of 2,2,2-trichloroethyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (695 mg) in hexamethyl phoshorotriamide (8 ml) is added a mixture of cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg), and the mixture is stirred for 1 hour. The reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated in leave residue. Purification of the residue by chromatography over silica gel to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate (650 mg). Yield: 64.4%. is extracted with benzene The extract solution is washed with water dried evaporated in leave residue Purification of the residue by chromatography over silica gel

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of cyclopropylmethyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 6 h. The crude product was purified using chromatographic methods. The reaction solution was then stirred at RT for a further 6 h The crude product was purified

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of cyclopropylmethyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 6 h. The crude product was purified using chromatographic methods. The reaction solution was then stirred at RT for a further 6 h The crude product was purified

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

Procedure: To a solution of silver salt of 2,2,2-trichloroethyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (695 mg) in hexamethyl phoshorotriamide (8 ml) is added a mixture of cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg), and the mixture is stirred for 1 hour. The reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated in leave residue. Purification of the residue by chromatography over silica gel to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate (650 mg). Yield: 64.4%. is extracted with benzene The extract solution is washed with water dried evaporated in leave residue Purification of the residue by chromatography over silica gel

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

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-[(R)-1-{3-(1-tertbutoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine (207 mg, 0.45 mmol) in acetonitrile (7 mL) was added monosilylacetamide (0.8 g), then the mixture was stirred for 30 minutes at 45° C. After the mixture was allowed to cool to room temperature, N-methylmorpholine (50 mL, 0.45 mmol) and a solution of cyclopropylmethyl chloroformate (1 mmol) in dichloromethane (2 mL), which was prepared from cyclopropanemethanol, triphosgene and pyridine, was added successively via syringe. After stirring for 2 hours, the mixture was acidified with 20% aqueous KHSO4 solution, extracted with ethyl acetate and dried over sodium sulfate. After evaporation of the solvent, the residue was treated with 4N hydrochloric acid in ethyl acetate. The insoluble material was collected by filtration, dried and dissolved in water. The solution was neutralized with a saturated aqueous NaHCO3 solution, purified by an ODS column chromatography using Daisogel-120SP (10% CH3CN/water) and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(cyclopropylmethyloxycarbonyl)amino-β-alanine (120 mg, 47.4%) as a white powder. to cool to room temperature was added successively via syringe After stirring for 2 hours extracted with ethyl acetate dried over sodium sulfate After evaporation of the solvent the residue was treated with 4N hydrochloric acid in ethyl acetate The insoluble material was collected by filtration dried dissolved in water purified by an ODS column chromatography freeze-dried

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-[(R)-1-{3-(1-tertbutoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine (207 mg, 0.45 mmol) in acetonitrile (7 mL) was added monosilylacetamide (0.8 g), then the mixture was stirred for 30 minutes at 45° C. After the mixture was allowed to cool to room temperature, N-methylmorpholine (50 mL, 0.45 mmol) and a solution of cyclopropylmethyl chloroformate (1 mmol) in dichloromethane (2 mL), which was prepared from cyclopropanemethanol, triphosgene and pyridine, was added successively via syringe. After stirring for 2 hours, the mixture was acidified with 20% aqueous KHSO4 solution, extracted with ethyl acetate and dried over sodium sulfate. After evaporation of the solvent, the residue was treated with 4N hydrochloric acid in ethyl acetate. The insoluble material was collected by filtration, dried and dissolved in water. The solution was neutralized with a saturated aqueous NaHCO3 solution, purified by an ODS column chromatography using Daisogel-120SP (10% CH3CN/water) and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(cyclopropylmethyloxycarbonyl)amino-β-alanine (120 mg, 47.4%) as a white powder. to cool to room temperature was added successively via syringe After stirring for 2 hours extracted with ethyl acetate dried over sodium sulfate After evaporation of the solvent the residue was treated with 4N hydrochloric acid in ethyl acetate The insoluble material was collected by filtration dried dissolved in water purified by an ODS column chromatography freeze-dried

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

Procedure: 3.2 g (44.4 millimoles) of (hydroxymethyl)cyclopropane, dissolved in 50 ml of absolute ether, are added dropwise to a stirred solution of 8.8 g (89.0 millimoles) of phosgene in 50 ml of absolute ether at 10°-15° C. The reaction solution is then stirred for 3 hours at room temperature. The excess phosgene is removed by means of a dry stream of nitrogen, and the ether is then removed under reduced pressure at room temperature. The cyclopropylmethyl chloroformate which remains is mixed with 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 100 ml of absolute toluene and the mixture is kept for 7 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized twice from dimethylformamide/water. 3.0 g (34% of theory) of 6-(p-cyclopropylmethoxycarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals of melting point 240°-241° C. The excess phosgene is removed by means of a dry stream of nitrogen the ether is then removed under reduced pressure at room temperature the mixture is kept for 7 hours at 80° C The product is filtered off at 10° C. washed first with toluene with water, and recrystallized twice from dimethylformamide/water

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of cyclopropylmethyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 6 h. The crude product was purified using chromatographic methods. The reaction solution was then stirred at RT for a further 6 h The crude product was purified

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

Procedure: To a solution of silver salt of 2,2,2-trichloroethyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (695 mg) in hexamethyl phoshorotriamide (8 ml) is added a mixture of cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg), and the mixture is stirred for 1 hour. The reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated in leave residue. Purification of the residue by chromatography over silica gel to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate (650 mg). Yield: 64.4%. is extracted with benzene The extract solution is washed with water dried evaporated in leave residue Purification of the residue by chromatography over silica gel