benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate

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

Procedure: To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert-butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2×50 mL). The combined organic layers were washed with water (3×40 mL) and concentrated under vacuum to provide the title compound. To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar The mixture was heated to reflux The reaction mixture was refluxed for another 2 hours The water layer was separated extracted with toluene (2×50 mL) The combined organic layers were washed with water (3×40 mL) concentrated under vacuum

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

Procedure: tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4a (2.80 g, 8.263 mmol) and benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.014 g, 7.767 mmol) were dissolved in a mixture of DCE (10 mL) and DME (10 mL) and placed under a nitrogen atmosphere. Triethylamine (1.149 mL, 834.5 mg, 8.263 mmol) was added, followed by Ti(OiPr)4 (7.2 mL, 6.9 g, 24.6 mmol) and the reaction was allowed to stir at room temperature for 60 h. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH4 (1.223 g, 33.051 mmol, 4.0 eq) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. until bubbling had subsided (approximately 3 h), was allowed to warm slowly back to room temperature and was stirred for 2 h. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide the crude product as a white foam. Unreacted starting material was converted to the corresponding ethyl carbamates by suspending the crude product in CH3CN (30 mL) and treating sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et2O (300 mL) and poured onto 1N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) and dried to provide tert-butyl 1′-(8-(benzyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4b as the hydrochloride salt (2.7 g, 56% yield). LC/MS m/z [M+H]+ 546.4, retention time 2.92 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). cooled to −40° C. to −50° C to stir at −40° C. until bubbling (approximately 3 h) to warm slowly back to room temperature was stirred for 2 h The sticky suspension was filtered through a pad of Celite the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL) The filtrate was separated into the corresponding layers the aqueous layer was extracted with Et2O (2×50 mL) The combined organic extracts were dried over Na2SO4 concentrated to provide the crude product as a white foam After 10 min The biphasic suspension was filtered the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) dried

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

Procedure: tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4a (2.80 g, 8.263 mmol) and benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.014 g, 7.767 mmol) were dissolved in a mixture of DCE (10 mL) and DME (10 mL) and placed under a nitrogen atmosphere. Triethylamine (1.149 mL, 834.5 mg, 8.263 mmol) was added, followed by Ti(OiPr)4 (7.2 mL, 6.9 g, 24.6 mmol) and the reaction was allowed to stir at room temperature for 60 h. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH4 (1.223 g, 33.051 mmol, 4.0 eq) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. until bubbling had subsided (approximately 3 h), was allowed to warm slowly back to room temperature and was stirred for 2 h. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide the crude product as a white foam. Unreacted starting material was converted to the corresponding ethyl carbamates by suspending the crude product in CH3CN (30 mL) and treating sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et2O (300 mL) and poured onto 1N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) and dried to provide tert-butyl 1′-(8-(benzyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4b as the hydrochloride salt (2.7 g, 56% yield). LC/MS m/z [M+H]+ 546.4, retention time 2.92 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). cooled to −40° C. to −50° C to stir at −40° C. until bubbling (approximately 3 h) to warm slowly back to room temperature was stirred for 2 h The sticky suspension was filtered through a pad of Celite the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL) The filtrate was separated into the corresponding layers the aqueous layer was extracted with Et2O (2×50 mL) The combined organic extracts were dried over Na2SO4 concentrated to provide the crude product as a white foam After 10 min The biphasic suspension was filtered the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) dried

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

Procedure: 8-azabicyclo[3.2.1]octan-3-one (5.10 g; 31.55 mmol) was dissolved in CH2Cl2 (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH2Cl2. The organic phase was washed with 1 N HCl (2×100 mL), dried on Na2SO4 and concentrated to provide the crude product (7.2 g). 1H-NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 5.22 (s, 2H), 4.62 (s, 2H), 2.67 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.12 (m, 2H), 1.71 (dd, J=15.0, 7.2 Hz, 2H). was added drop-wise (exothermic reaction) The organic phase was washed with 1 N HCl (2×100 mL) dried on Na2SO4 concentrated

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

Procedure: 8-azabicyclo[3.2.1]octan-3-one (5.10 g; 31.55 mmol) was dissolved in CH2Cl2 (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH2Cl2. The organic phase was washed with 1 N HCl (2×100 mL), dried on Na2SO4 and concentrated to provide the crude product (7.2 g). 1H-NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 5.22 (s, 2H), 4.62 (s, 2H), 2.67 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.12 (m, 2H), 1.71 (dd, J=15.0, 7.2 Hz, 2H). was added drop-wise (exothermic reaction) The organic phase was washed with 1 N HCl (2×100 mL) dried on Na2SO4 concentrated

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

Procedure: To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert-butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2×50 mL). The combined organic layers were washed with water (3×40 mL) and concentrated under vacuum to provide the title compound. To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar The mixture was heated to reflux The reaction mixture was refluxed for another 2 hours The water layer was separated extracted with toluene (2×50 mL) The combined organic layers were washed with water (3×40 mL) concentrated under vacuum

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

Procedure: To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert-butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2×50 mL). The combined organic layers were washed with water (3×40 mL) and concentrated under vacuum to provide the title compound. To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar The mixture was heated to reflux The reaction mixture was refluxed for another 2 hours The water layer was separated extracted with toluene (2×50 mL) The combined organic layers were washed with water (3×40 mL) concentrated under vacuum

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

Procedure: To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert-butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2×50 mL). The combined organic layers were washed with water (3×40 mL) and concentrated under vacuum to provide the title compound. To a 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar The mixture was heated to reflux The reaction mixture was refluxed for another 2 hours The water layer was separated extracted with toluene (2×50 mL) The combined organic layers were washed with water (3×40 mL) concentrated under vacuum

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

Procedure: tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4a (2.80 g, 8.263 mmol) and benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.014 g, 7.767 mmol) were dissolved in a mixture of DCE (10 mL) and DME (10 mL) and placed under a nitrogen atmosphere. Triethylamine (1.149 mL, 834.5 mg, 8.263 mmol) was added, followed by Ti(OiPr)4 (7.2 mL, 6.9 g, 24.6 mmol) and the reaction was allowed to stir at room temperature for 60 h. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH4 (1.223 g, 33.051 mmol, 4.0 eq) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. until bubbling had subsided (approximately 3 h), was allowed to warm slowly back to room temperature and was stirred for 2 h. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide the crude product as a white foam. Unreacted starting material was converted to the corresponding ethyl carbamates by suspending the crude product in CH3CN (30 mL) and treating sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et2O (300 mL) and poured onto 1N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) and dried to provide tert-butyl 1′-(8-(benzyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4b as the hydrochloride salt (2.7 g, 56% yield). LC/MS m/z [M+H]+ 546.4, retention time 2.92 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). cooled to −40° C. to −50° C to stir at −40° C. until bubbling (approximately 3 h) to warm slowly back to room temperature was stirred for 2 h The sticky suspension was filtered through a pad of Celite the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL) The filtrate was separated into the corresponding layers the aqueous layer was extracted with Et2O (2×50 mL) The combined organic extracts were dried over Na2SO4 concentrated to provide the crude product as a white foam After 10 min The biphasic suspension was filtered the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) dried

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

Procedure: 8-azabicyclo[3.2.1]octan-3-one (5.10 g; 31.55 mmol) was dissolved in CH2Cl2 (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH2Cl2. The organic phase was washed with 1 N HCl (2×100 mL), dried on Na2SO4 and concentrated to provide the crude product (7.2 g). 1H-NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 5.22 (s, 2H), 4.62 (s, 2H), 2.67 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.12 (m, 2H), 1.71 (dd, J=15.0, 7.2 Hz, 2H). was added drop-wise (exothermic reaction) The organic phase was washed with 1 N HCl (2×100 mL) dried on Na2SO4 concentrated

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

Procedure: 2.80 g of the entitled compound was obtained as a white powder in the same manner as in Production Example 8-3, for which, however, benzyl 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylate and phenylmagnesium bromide were used in place of tert-butyl 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylate and the lithium reagent prepared from and 2-bromobenzyl alcohol and n-butyllithium-hexane solution used in Production Example 8-3.

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

Procedure: 2.80 g of the entitled compound was obtained as a white powder in the same manner as in Production Example 8-3, for which, however, benzyl 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylate and phenylmagnesium bromide were used in place of tert-butyl 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylate and the lithium reagent prepared from and 2-bromobenzyl alcohol and n-butyllithium-hexane solution used in Production Example 8-3.