benzyl (2S,3aS,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrole-2-carboxylate;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In 10 ml of N,N-dimethylformamide are dissolved 0.56 g of benzyl (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylate.hydrochloride and 0.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine.hydrochloride, and 0.3 g of triethylamine is added to the solution under ice-cooling with stirring, followed by addition of 0.5 ml of diethyl phosphorocyanidate. After stirring for 30 minutes, there is added to the mixture 0.1 g of triethylamine, followed by stirring for 30 minutes and at room temperature for 1 hour. The reaction mixture is diluted with 100 ml of water and extracted with 100 ml of ethyl acetate. The extract is washed with 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:acetone=3:1) to give 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylate as a colorless oil. is added to the solution under ice- cooling After stirring for 30 minutes by stirring for 30 minutes and at room temperature for 1 hour extracted with 100 ml of ethyl acetate The extract is washed with 5% aqueous phosphoric acid and water successively, and dried over anhydrous magnesium sulfate The solvent is distilled off under reduced pressure the residue is purified by silica gel column chromatography (hexane:acetone=3:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.92 g (30 mmol) of 4-phenylbutyric acid are dissolved together with 8.4 ml of triethylamine in 200 ml of dry tetrahydrofuran. While cooling in ice, 2.9 ml of ethyl chloroformate are added dropwise. After stirring at 0° C. for 1 hour, 7.4 g of benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride are added, and the mixture is stirred at room temperature for a further 12 hours. Filtration is followed by concentration, and the residue is taken up in 3% NaHCO3 /ethyl acetate. The organic phase is separated off and washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine, once each, dried with MgSO4 and concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as mobile phase results in 9.05 g of the title compound as a colorless oil. While cooling in ice the mixture is stirred at room temperature for a further 12 hours Filtration is followed by concentration The organic phase is separated off washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine once each, dried with MgSO4 concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In 10 ml of N,N-dimethylformamide are dissolved 0.56 g of benzyl (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylate·hydrochloride and 0.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine·hydrochloride, and 0.3 g of triethylamine is added to the solution under ice-cooling with stirring, followed by addition of 0.5 ml of diethyl phosphorocyanidate. After stirring for 30 minutes, there is added to the mixture 0.1 g of triethylamine, followed by stirring for 30 minutes and at room temperature for 1 hour. The reaction mixture is diluted with 100 ml of water and extracted with 100 ml of ethyl acetate. The extract is washed with 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:acetone=3:1) to give 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo-[3,3,0]octane-3-carboxylate as a colorless oil. is added to the solution under ice- cooling After stirring for 30 minutes by stirring for 30 minutes and at room temperature for 1 hour extracted with 100 ml of ethyl acetate The extract is washed with 5% aqueous phosphoric acid and water successively, and dried over anhydrous magnesium sulfate The solvent is distilled off under reduced pressure the residue is purified by silica gel column chromatography (hexane:acetone=3:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of commercially available (2S,3aS,6aS)-benzyl octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride (4.70 g, 16.68 mmol) in methylene chloride (42 mL) was added Di-tert-butyl dicarbonate (7.28 g, 33.36 mmol), N,N-diisopropylethylamine (5.82 mL, 33.36 mmol) and 4-(Dimethylamino)pyridine (0.20 g, 1.67 mmol). The solution was stirred under air for 16 hours. Upon completion, the reaction was concentrated in vacuo, diluted in ethyl acetate, and washed with 1N HCl. The aqueous layers were backextracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (5-40% ethyl acetate in hexanes) to afford (2S,3aS,6aS)-1-tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid which was used without further purification. MS (ESI) m/z 368.47 [M+Na]+. Upon completion, the reaction was concentrated in vacuo diluted in ethyl acetate washed with 1N HCl the combined organic layers were dried over sodium sulfate filtered concentrated The resulting residue was purified by silica gel chromatography (5-40% ethyl acetate in hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In 10 ml of N,N-dimethylformamide are dissolved 0.56 g of benzyl (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylate. hydrochloride and 0.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine.hydrochloride, and 0.3 g of triethylamine is added to the solution under ice-cooling with stirring, followed by addition of 0.5 ml of diethyl phosphorocyanidate. After stirring for 30 minutes, there is added to the mixture 0.1 g of triethylamine, followed by stirring for 30 minutes and at room temperature for 1 hour. The reaction mixture is diluted with 100 ml of water and extracted with 100 ml of ethyl acetate. The extract is washed with 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:acetone=3:1) to give 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylate as a colorless oil. is added to the solution under ice- cooling After stirring for 30 minutes by stirring for 30 minutes and at room temperature for 1 hour extracted with 100 ml of ethyl acetate The extract is washed with 5% aqueous phosphoric acid and water successively, and dried over anhydrous magnesium sulfate The solvent is distilled off under reduced pressure the residue is purified by silica gel column chromatography (hexane:acetone=3:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In 10 ml of N,N-dimethylformamide are dissolved 0.56 g of benzyl (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylate.hydrochloride and 0.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine.hydrochloride, and 0.3 g of triethylamine is added to the solution under ice-cooling with stirring, followed by addition of 0.5 ml of diethyl phosphorocyanidate. After stirring for 30 minutes, there is added to the mixture 0.1 g of triethylamine, followed by stirring for 30 minutes and at room temperature for 1 hour. The reaction mixture is diluted with 100 ml of water and extracted with 100 ml of ethyl acetate. The extract is washed with 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:acetone=3:1) to give 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylate as a colorless oil. is added to the solution under ice- cooling After stirring for 30 minutes by stirring for 30 minutes and at room temperature for 1 hour extracted with 100 ml of ethyl acetate The extract is washed with 5% aqueous phosphoric acid and water successively, and dried over anhydrous magnesium sulfate The solvent is distilled off under reduced pressure the residue is purified by silica gel column chromatography (hexane:acetone=3:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.92 g (30 mmol) of 4-phenylbutyric acid are dissolved together with 8.4 ml of triethylamine in 200 ml of dry tetrahydrofuran. While cooling in ice, 2.9 ml of ethyl chloroformate are added dropwise. After stirring at 0° C. for 1 hour, 7.4 g of benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride are added, and the mixture is stirred at room temperature for a further 12 hours. Filtration is followed by concentration, and the residue is taken up in 3% NaHCO3 /ethyl acetate. The organic phase is separated off and washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine, once each, dried with MgSO4 and concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as mobile phase results in 9.05 g of the title compound as a colorless oil. While cooling in ice the mixture is stirred at room temperature for a further 12 hours Filtration is followed by concentration The organic phase is separated off washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine once each, dried with MgSO4 concentrated