tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-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: 0.58 g (8.36 mmol) of hydroxylamine hydrochloride and 1.15 g (8.36 mmol) of potassium carbonate are added to a solution of 1.00 g (4.18 mmol) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (U.S. Pat. No. 6,498,159) in 60 mL of ethanol, and the mixture is then left stirring at room temperature for 12 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and water, the aqueous phase is separated out and extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia. 0.831 g of pure product is thus obtained in the form of a white powder. After evaporating off the solvent under reduced pressure water, the aqueous phase is separated out extracted twice with dichloromethane the combined organic phases are dried over sodium sulfate After evaporating off the solvent the residue obtained is purified by chromatography on silica gel eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia

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

Procedure: To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 2.5 mmol, 1.0 equiv) in MeOH (6.0 mL) was added sodium borohydride (190 mg, 5.0 mmol, 2.0 equiv) in portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 2.0 hrs. The solution was concentrated by evaporator to give the white solid. Saturated NaHCO3 solution (40 mL) was added. The aqueous phase was extracted with DCM (4×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated to give the crude which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane=0-60%) to afford 334 mg (yield 57%) of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate as a white solid. The solution was concentrated by evaporator to give the white solid The aqueous phase was extracted with DCM (4×30 mL) The combined organic phase was dried over anhydrous Na2SO4 concentrated to give the crude which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane=0-60%)

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

Procedure: To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 2.5 mmol, 1.0 equiv) in MeOH (6.0 mL) was added sodium borohydride (190 mg, 5.0 mmol, 2.0 equiv) in portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 2.0 hrs. The solution was concentrated by evaporator to give the white solid. Saturated NaHCO3 solution (40 mL) was added. The aqueous phase was extracted with DCM (4×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated to give the crude which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane=0-60%) to afford 334 mg (yield 57%) of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate as a white solid. The solution was concentrated by evaporator to give the white solid The aqueous phase was extracted with DCM (4×30 mL) The combined organic phase was dried over anhydrous Na2SO4 concentrated to give the crude which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane=0-60%)

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flame-dried RB flask with tert-butyl 4-methylenepiperidine-1-carboxylate (2.96 g, 15 mmol, 1.0 equiv) and Zn/Cu couple (6.54 g, 172.5 mmol, 11.5 equiv) under vacuum, t-BuOMe (60 mL) was charged and refilled the flask with N2 balloon. To the mixture thus obtained stirred at 15° C., a solution of 2,2,2-trichloroacetyl chloride in DME (20 mL) was added dropwise. The mixture was stirred at room temperature overnight after addition. To the reaction mixture stirred in an external ice-bath, a saturated solution of NH4Cl (60 mL) was added slowly and carefully (especially the first few drops). After addition, the mixture was stirred at room temperature for 4 h, filtered to remove the solid. The phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated to give the residue which was purified by CombiFlash (40 g silica gel column, EtOAc/Hexane: 0-40%) to afford 619 mg (15%) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate. To the mixture thus obtained The mixture was stirred at room temperature overnight after addition To the reaction mixture stirred in an external ice-bath After addition the mixture was stirred at room temperature for 4 h filtered to remove the solid The phases were separated The aqueous phase was extracted with EtOAc The combined organic phase was washed with brine dried over anhydrous Na2SO4 concentrated to give the residue which was purified by CombiFlash (40 g silica gel column, EtOAc/Hexane: 0-40%)

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

Procedure: 0.58 g (8.36 mmol) of hydroxylamine hydrochloride and 1.15 g (8.36 mmol) of potassium carbonate are added to a solution of 1.00 g (4.18 mmol) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (U.S. Pat. No. 6,498,159) in 60 mL of ethanol, and the mixture is then left stirring at room temperature for 12 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and water, the aqueous phase is separated out and extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia. 0.831 g of pure product is thus obtained in the form of a white powder. After evaporating off the solvent under reduced pressure water, the aqueous phase is separated out extracted twice with dichloromethane the combined organic phases are dried over sodium sulfate After evaporating off the solvent the residue obtained is purified by chromatography on silica gel eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia

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

Procedure: 0.58 g (8.36 mmol) of hydroxylamine hydrochloride and 1.15 g (8.36 mmol) of potassium carbonate are added to a solution of 1.00 g (4.18 mmol) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (U.S. Pat. No. 6,498,159) in 60 mL of ethanol, and the mixture is then left stirring at room temperature for 12 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and water, the aqueous phase is separated out and extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia. 0.831 g of pure product is thus obtained in the form of a white powder. After evaporating off the solvent under reduced pressure water, the aqueous phase is separated out extracted twice with dichloromethane the combined organic phases are dried over sodium sulfate After evaporating off the solvent the residue obtained is purified by chromatography on silica gel eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia

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

Procedure: 567 ml solution of 37.8 g tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate in methanol was cooled on ice water, and 43 g of 30% aqueous hydrogen peroxide was added dropwise thereinto. 63 ml of 1 N aqueous sodium hydroxide was added dropwise thereto, and the mixture was stirred at room temperature for 2 hr. 1000 ml ethyl acetate, 600 ml water and 100 ml saturated aqueous sodium thiosulfate pentahydrate were added thereto, and the organic layer was recovered. The extracted solution was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated to give 28.4 g of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. was added dropwise the organic layer was recovered The extracted solution was washed with brine dried over anhydrous magnesium sulfate filtered The filtrate was evaporated

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

Procedure: 300 ml ethanol was ice-cooled, and 6.13 g of sodium borohydride was dissolved therein. 100 ml solution of 38.9 g of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate in ethanol was added dropwise thereinto over 25 min. The reaction solution was treated with saturated aqueous ammonium chloride and evaporated. The resulting residue was partitioned into ethyl acetate and water, and the ethyl acetate layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 36.6 g of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate. cooled evaporated The resulting residue was partitioned into ethyl acetate and water the ethyl acetate layer was washed with brine dried over magnesium sulfate After filtration the solvent was evaporated the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

Procedure: 106.1 g zinc dust was added to a mixture of 62.5 g tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate and 500 ml saturated ammonium chloride in methanol. The mixture was stirred for 1 hr and 20 min at room temperature and filtered through Celite. The filtrate was evaporated, 1 N hydrochloric acid/ethyl acetate was added thereto, and the organic layer was recovered. The extract was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 38.9 g of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate. filtered through Celite The filtrate was evaporated 1 N hydrochloric acid/ethyl acetate was added the organic layer was recovered The extract was washed with water, saturated sodium bicarbonate and brine dried over anhydrous magnesium sulfate filtered The filtrate was evaporated