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

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

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

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 dry DMF (45 g, 0.6 mol) in dry CH2Cl2 (150 ml) was added POCl3 (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-one (57 g, 0.29 mol) dissolved in dry CH2Cl2 (60 ml) was added. The reaction mixture was stirred over night at room temperature, then added to ice water (1.000 ml). The phases were separated and the water phase extracted with CH2Cl2 (2×200 ml). The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water, dried and evaporated to give 70 g of the title compound, which was used in the next step without further purification. was added The phases were separated the water phase extracted with CH2Cl2 (2×200 ml) The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water dried evaporated

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

Procedure: To a solution of dry DMF (45 g, 0.6 mol) in dry CH2Cl2 (150 ml) was added POCl3 (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-one (57 g, 0.29 mol) dissolved in dry CH2Cl2 (60 ml) was added. The reaction mixture was stirred over night at room temperature, then added to ice water (1.000 ml). The phases were separated and the water phase extracted with CH2Cl2 (2×200 ml). The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water, dried and evaporated to give 70 g of the title compound, which was used in the next step without further purification. was added The phases were separated the water phase extracted with CH2Cl2 (2×200 ml) The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water dried evaporated

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

Procedure: To a solution of dry DMF (45 g, 0.6 mol) in dry CH2Cl2 (150 ml) was added POCl3 (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-one (57 g, 0.29 mol) dissolved in dry CH2Cl2 (60 mol) was added. The reaction mixture was stirred over night at room temperature, then added to ice water (1.000 ml). The phases were separated and the water phase extracted with CH (2×200 ml). The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water, dried and evaporated to give 70 g of the title compound, which was used in the next step without further purification. was added The phases were separated the water phase extracted with CH (2×200 ml) The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water dried evaporated

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

Procedure: To a solution of dry DMF (45 g, 0.6 mol) in dry CH2Cl2 (150 ml) was added POCl3 (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-one (57 g, 0.29 mol) dissolved in dry CH2Cl2 (60 mol) was added. The reaction mixture was stirred over night at room temperature, then added to ice water (1.000 ml). The phases were separated and the water phase extracted with CH (2×200 ml). The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water, dried and evaporated to give 70 g of the title compound, which was used in the next step without further purification. was added The phases were separated the water phase extracted with CH (2×200 ml) The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water dried evaporated

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 5a (2.071 g, 6.11 mmol) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.51 g, 7.66 mmol) were dissolved in anhydrous dichloromethane (10 mL) in a 100-mL round-bottom flask and treated with triethylamine (618 mg, 6.11 mmol), followed by titanium tetraisopropoxide (5.21 g, 18.3 mmol). The reaction was stirred under nitrogen at room temperature for 21 h, then cooled in a dry ice/isopropanol bath to −40° C. and quenched with methanol (10 mL). The reaction was stirred for several minutes at the same temperature and treated in one portion with sodium borohydride (462 mg, 12.2 mmol). The reaction was stirred at −40° C. for 30 minutes, then warmed to room temperature. The reaction was then treated with 1 N NaOH (12 mL), diluted with methanol (50 mL) and stirred vigorously at room temperature for 10 minutes. The reaction was filtered through Celite and the solids rinsed with dichloromethane (4×25 mL). The filtrate was washed with H2O, saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 3.641 g tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b as a pale yellow oil. LC/MS m/z [M+H]+ 484.3, retention time 2.32 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). cooled in a dry ice/isopropanol bath to −40° C. quenched with methanol (10 mL) The reaction was stirred for several minutes at the same temperature The reaction was stirred at −40° C. for 30 minutes warmed to room temperature stirred vigorously at room temperature for 10 minutes The reaction was filtered through Celite the solids rinsed with dichloromethane (4×25 mL) The filtrate was washed with H2O, saturated brine dried over Na2SO4 filtered The filtrate was concentrated under reduced pressure

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 5a (2.071 g, 6.11 mmol) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.51 g, 7.66 mmol) were dissolved in anhydrous dichloromethane (10 mL) in a 100-mL round-bottom flask and treated with triethylamine (618 mg, 6.11 mmol), followed by titanium tetraisopropoxide (5.21 g, 18.3 mmol). The reaction was stirred under nitrogen at room temperature for 21 h, then cooled in a dry ice/isopropanol bath to −40° C. and quenched with methanol (10 mL). The reaction was stirred for several minutes at the same temperature and treated in one portion with sodium borohydride (462 mg, 12.2 mmol). The reaction was stirred at −40° C. for 30 minutes, then warmed to room temperature. The reaction was then treated with 1 N NaOH (12 mL), diluted with methanol (50 mL) and stirred vigorously at room temperature for 10 minutes. The reaction was filtered through Celite and the solids rinsed with dichloromethane (4×25 mL). The filtrate was washed with H2O, saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 3.641 g tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b as a pale yellow oil. LC/MS m/z [M+H]+ 484.3, retention time 2.32 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). cooled in a dry ice/isopropanol bath to −40° C. quenched with methanol (10 mL) The reaction was stirred for several minutes at the same temperature The reaction was stirred at −40° C. for 30 minutes warmed to room temperature stirred vigorously at room temperature for 10 minutes The reaction was filtered through Celite the solids rinsed with dichloromethane (4×25 mL) The filtrate was washed with H2O, saturated brine dried over Na2SO4 filtered The filtrate was concentrated under reduced pressure

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

Procedure: To a solution of dry DMF (45 g, 0.6 mol) in dry CH2Cl2 (150 ml) was added POCl3 (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-one (57 g, 0.29 mol) dissolved in dry CH2Cl2 (60 ml) was added. The reaction mixture was stirred over night at room temperature, then added to ice water (1.000 ml). The phases were separated and the water phase extracted with CH2Cl2 (2×200 ml). The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water, dried and evaporated to give 70 g of the title compound, which was used in the next step without further purification. was added The phases were separated the water phase extracted with CH2Cl2 (2×200 ml) The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water dried evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (3.0 g, 15.23 mmol) in methanol (20 mL) was added 5 mL Raney Nickel (50% aq slurry). The resultant mixture was degassed and charged with hydrogen (g) three times, heated to 70° C. and stirred for 12 hrs. The suspension was filtered through celite, and concentrated to provide a white solid (3.0 g, 100%). 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.0 Hz, 3H), 1.57 (m, 2H), 1.72 (app dd, J=1.4, 15.1 Hz, 2H), 1.94 (m, 2H), 2.12 (m 4H), 4.13 (q, J=7.1 Hz, 2H), 4.25 (m, 2H); MS (ESI+Q1MS) m/z 200 [M+H]+ The resultant mixture was degassed charged with hydrogen (g) three times The suspension was filtered through celite concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (3.0 g, 15.23 mmol) in methanol (20 mL) was added 5 mL Raney Nickel (50% aq slurry). The resultant mixture was degassed and charged with hydrogen (g) three times, heated to 70° C. and stirred for 12 hrs. The suspension was filtered through celite, and concentrated to provide a white solid (3.0 g, 100%). 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.0 Hz, 3H), 1.57 (m, 2H), 1.72 (app dd, J=1.4, 15.1 Hz, 2H), 1.94 (m, 2H), 2.12 (m 4H), 4.13 (q, J=7.1 Hz, 2H), 4.25 (m, 2H); MS (ESI+Q1MS) m/z 200 [M+H]+ The resultant mixture was degassed charged with hydrogen (g) three times The suspension was filtered through celite concentrated