ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A mixture of 3.4 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate, 2.1 parts of benzenemethanamine and 40 parts of ethanol was stirred and refluxed for 17 hours. Another 0.3 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate were added and stirring at reflux was continued for 4 hours. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (61.8%) of a mixture of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and ethyl trans-4-hydroxy-3-[(phenylmethyl)amino]-1-piperidinecarboxylate as an oily residue (intermediate 35 and 36). refluxed for 17 hours stirring at reflux The reaction mixture was evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: A mixture of 3.4 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate, 2.1 parts of benzenemethanamine and 40 parts of ethanol was stirred and refluxed for 17 hours. Another 0.3 parts of ethyl 7oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate were added and stirring at reflux was continued for 4 hours. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (61.8%) of a mixture of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and ethyl trans-4-hydroxy-3-[(phenylmethyl)amino]-1- piperidinecarboxylate as an oily residue (intermediates 35 and 36). refluxed for 17 hours stirring at reflux The reaction mixture was evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: (a-1) A mixture of 51.3 parts of ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. 36.4 parts of N-methylbenzenemethanamine and 480 parts of ethanol was stirred and refluxed for 42 hours. The reaction mixture was evaporated and the residue was taken up in a dilute hydrochloric acid solution. The aqueous phase was washed three times with 2,2'-oxybispropane and alkalized with a sodium hydroxide solution 50%. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 45 9 parts (52.3%) of a mixture of ethyl trans-4-hydroxy-3-[methyl(phenylmethyl)amino-]1-piperidinecarboxylate and ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate (interm. 6) in the proportion of 62.3% and 32.9%. Intermediate 6 was also prepared according to the following procedure: refluxed for 42 hours The reaction mixture was evaporated The aqueous phase was washed three times with 2,2'-oxybispropane The product was extracted with dichloromethane The extract was washed with water dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: (a-1) A mixture of 51.3 parts of ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. 36.4 parts of N-methylbenzenemethanamine and 480 parts of ethanol was stirred and refluxed for 42 hours. The reaction mixture was evaporated and the residue was taken up in a dilute hydrochloric acid solution. The aqueous phase was washed three times with 2,2'-oxybispropane and alkalized with a sodium hydroxide solution 50%. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 45 9 parts (52.3%) of a mixture of ethyl trans-4-hydroxy-3-[methyl(phenylmethyl)amino-]1-piperidinecarboxylate and ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate (interm. 6) in the proportion of 62.3% and 32.9%. Intermediate 6 was also prepared according to the following procedure: refluxed for 42 hours The reaction mixture was evaporated The aqueous phase was washed three times with 2,2'-oxybispropane The product was extracted with dichloromethane The extract was washed with water dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: To a stirred emulsion of 53.8 parts of ethyl 7-oxa-3-azabicyclo-[4.1,0]heptane-3-carboxylate, 17.6 parts of ethanol and 195 parts of water were added portionwise, during a 15 minutes-period, 28.6 parts of sodium azide while cooling in an ice bath. The mixture was warmed slowly to room temperature and stirring was continued overnight at room temperature. The aqueous phase was separated and extracted twice with dichloromethane. The combined organic phases were washed with a small amount of water, dried, filtered and evaporated, yielding 56.3 parts (82%) of a mixture of 80% of ethyl trans- 4-azido-3-hydroxy-1-piperidinecarboxylate (interm. 3) and 15% of ethyl trans-3-azido-4-hydroxy-1-piperidinecarboxylate. while cooling in an ice bath The aqueous phase was separated extracted twice with dichloromethane The combined organic phases were washed with a small amount of water dried filtered evaporated

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

実験手順: A mixture of 3.4 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate, 2.1 parts of benzenemethanamine and 40 parts of ethanol was stirred and refluxed for 17 hours. Another 0.3 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate were added and stirring at reflux was continued for 4 hours. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (61.8%) of a mixture of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and ethyl trans-4-hydroxy-3-[(phenylmethyl)amino]-1-piperidinecarboxylate as an oily residue (intermediate 35 and 36). refluxed for 17 hours stirring at reflux The reaction mixture was evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: A mixture of 3.4 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate, 2.1 parts of benzenemethanamine and 40 parts of ethanol was stirred and refluxed for 17 hours. Another 0.3 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate were added and stirring at reflux was continued for 4 hours. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (61.8%) of a mixture of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and ethyl trans-4-hydroxy-3-[(phenylmethyl)amino]-1-piperidinecarboxylate as an oily residue (intermediate 35 and 36). refluxed for 17 hours stirring at reflux The reaction mixture was evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: Reaction was carried out under a nitrogen atmosphere. Lithium hydride (95%) (0.036 mol) was suspended in THF (30 ml). A solution of 2-hydroxy-2-methyl-propanenitrile (0.636 mol) in THF (10 ml) was added dropwise (evolution of hydrogen gas). The mixture was stirred for 90 minutes at room temperature. A solution of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid, ethyl ester (0.03 mol) in THF (15 ml) for 90 minutes. The reaction mixture was cooled to 15° C. Diethyl sulfate (0.039 mol) was added (exothermic temperature rise to 25° C.). The reaction mixture was stirred for one hour at room temperature, then stirred and refluxed for 6 hours, cooled and a drop of water was added. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH from 100/0 to 99/1). The pure fractions were collected and the solvent was evaporated, yielding 4.3 g of ethyl (trans)-4-cyano-3-ethoxy-1-piperidine-carboxylate (intermediate 13). Reaction The reaction mixture was cooled to 15° C The reaction mixture was stirred for one hour at room temperature stirred refluxed for 6 hours cooled The solvent was evaporated The residue was partitioned between water and DCM The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH from 100/0 to 99/1) The pure fractions were collected the solvent was evaporated

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

実験手順: Reaction was carried out under a nitrogen atmosphere. Lithium hydride (95%) (0.036 mol) was suspended in THF (30 ml). A solution of 2-hydroxy-2-methyl-propanenitrile (0.036 mol) in TEF (10 ml) was added dropwise (evolution of hydrogen gas). The mixture was stirred for 90 minutes at room temperature. A solution of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid, ethyl ester (0.03 mol) in THF (15 ml) for 90 minutes. The reaction mixture was cooled to 15 ° C. Diethyl sulfate (0.039 mol) was added (exothermic temperature rise to 25 ° C.). The reaction mixture was stirred for one hour at room temperature, then stirred and refluxed for 6 hours, cooled and a drop of water was added. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C]2/CH3OH from 100/0 to 99/1). The pure fractions were collected and the solvent was evaporated, yielding 4.3 g of ethyl (trans)-4-cyano-3-ethoxy-1-piperidine-carboxylate (intermediate 13). Reaction The reaction mixture was cooled to 15 ° C The reaction mixture was stirred for one hour at room temperature stirred refluxed for 6 hours cooled The solvent was evaporated The residue was partitioned between water and DCM The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2C]2/CH3OH from 100/0 to 99/1) The pure fractions were collected the solvent was evaporated

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

実験手順: A mixture of 3.4 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate, 2.1 parts of benzenemethanamine and 40 parts of ethanol was stirred and refluxed for 17 hours. Another 0.3 parts of ethyl 7oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate were added and stirring at reflux was continued for 4 hours. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (61.8%) of a mixture of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and ethyl trans-4-hydroxy-3-[(phenylmethyl)amino]-1- piperidinecarboxylate as an oily residue (intermediates 35 and 36). refluxed for 17 hours stirring at reflux The reaction mixture was evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated

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

実験手順: (a-1) A mixture of 51.3 parts of ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. 36.4 parts of N-methylbenzenemethanamine and 480 parts of ethanol was stirred and refluxed for 42 hours. The reaction mixture was evaporated and the residue was taken up in a dilute hydrochloric acid solution. The aqueous phase was washed three times with 2,2'-oxybispropane and alkalized with a sodium hydroxide solution 50%. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 45 9 parts (52.3%) of a mixture of ethyl trans-4-hydroxy-3-[methyl(phenylmethyl)amino-]1-piperidinecarboxylate and ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate (interm. 6) in the proportion of 62.3% and 32.9%. Intermediate 6 was also prepared according to the following procedure: refluxed for 42 hours The reaction mixture was evaporated The aqueous phase was washed three times with 2,2'-oxybispropane The product was extracted with dichloromethane The extract was washed with water dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent The pure fractions were collected the eluent was evaporated