tert-butyl 8-oxa-4-azabicyclo[5.1.0]octane-4-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 16.4 g 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester in 420 ml dichloromethane was added at −60° C. 35.8 g m-chloroperbenzoic acid (70% purity). The mixture was allowed to slowly warm to room temperature overnight, 1 l ethylacetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. Evaporation of the solvent and chromatography yielded 14.5 g (82%) 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester as colorless liquid; MS (EI): m/e=213 (M+,5%), 158 (22%), 140 (12%), 57 (100%). To a solution of 14.3 g 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in 750 ethanol was added 150 ml water, 35.8 g ammonium chloride and 43.6 g sodium azide. The mixture was stirred at 75° C. over night, the solvents were greatly removed by distillation under vacuum and the residue was suspended in ethanol and filtered. The ethanol was distilled off and the residue was suspended in ethylacetate and filtered. Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1, yielded 13.5 g (79%) 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as a viscous oil; MS (ISP): m/e=257 (M+H+). the solvents were greatly removed by distillation under vacuum filtered The ethanol was distilled off filtered Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1

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

実験手順: To a stirred solution of 16.4 g 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester in 420 ml dichloromethane was added at −60° C. 35.8 g m-chloroperbenzoic acid (70% purity). The mixture was allowed to slowly warm to room temperature overnight, 1 l ethylacetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. Evaporation of the solvent and chromatography yielded 14.5 g (82%) 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester as colorless liquid; MS (EI): m/e=213 (M+,5%), 158 (22%), 140 (12%), 57 (100%). To a solution of 14.3 g 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in 750 ethanol was added 150 ml water, 35.8 g ammonium chloride and 43.6 g sodium azide. The mixture was stirred at 75° C. over night, the solvents were greatly removed by distillation under vacuum and the residue was suspended in ethanol and filtered. The ethanol was distilled off and the residue was suspended in ethylacetate and filtered. Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1, yielded 13.5 g (79%) 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as a viscous oil; MS (ISP): m/e=257 (M+H+). the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine Evaporation of the solvent and chromatography

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: According to scheme 10, to a stirred solution of 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (XXX) in dichloromethane was added at −60° C. m-chloroperbenzoic acid (MCPBA). The mixture was allowed to slowly warm to room temperature overnight and 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester (XXXI) was obtained. To a solution of 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in ethanol was added water, ammonium chloride and sodium azide. The mixture was stirred at 75° C. over night, to give 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXII). 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in methanol was hydrogenated in the presence of palladium on charcoal (10%) to yield 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXIII). 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1,1′-carbonyl-diimidazole in dimethylformamide are stirred at room temperature for about 16 hours. 4-Amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester was added and stirring was continued for 16 hours at room temperature. It was obtained 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (XXXIV). To a solution of 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in dimethylsulfoxide was added triethylamine, dichloromethane and a solution of sulfur trioxide pyridine complex in dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. After purification 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester (VIII) was obtained.

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

実験手順: According to scheme 10, to a stirred solution of 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (XXX) in dichloromethane was added at −60° C. m-chloroperbenzoic acid (MCPBA). The mixture was allowed to slowly warm to room temperature overnight and 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester (XXXI) was obtained. To a solution of 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in ethanol was added water, ammonium chloride and sodium azide. The mixture was stirred at 75° C. over night, to give 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXII). 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in methanol was hydrogenated in the presence of palladium on charcoal (10%) to yield 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXIII). 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1,1′-carbonyl-diimidazole in dimethylformamide are stirred at room temperature for about 16 hours. 4-Amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester was added and stirring was continued for 16 hours at room temperature. It was obtained 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (XXXIV). To a solution of 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in dimethylsulfoxide was added triethylamine, dichloromethane and a solution of sulfur trioxide pyridine complex in dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. After purification 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester (VIII) was obtained.