9-Azabicyclo[3.3.1]nonan-3-one, 9-(phenylmethyl)-

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:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

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 two-liter, 2-neck flask, an overhead stirrer and an addition funnel were used. Glutaraldehyde (100 mL, 50% aq. solution) was placed in the flask. Water (63 mL) was added. 36.5 grams of 1,3-acetonedicarboxylic acid were added. Some bubbling was observed. NaOAc (14.25 g) was added and the mixture was stirred vigorously. A solution of benzylamine hydrochloride (35.6 g) in 112 mL of water was placed in the addition funnel. Alternatively it may be advantageous to dissolve the benzylamine hydrochloride in 80 mL of water and 30 mL of 0.12 N aqueous HCl, instead of 112 mL of H2O. The amine solution was added to the reaction mixture portionwise. Foaming and bubbling was observed. A dark yellow, sticky solid formed. The reaction mixture was allowed to stir overnight. Methylene chloride (500 mL) was added, followed by K2CO3 which was added until the pH˜8. The layers were separated and the aqueous layer was extracted with CH2Cl2 (500 mL). The combined organic layers were passed through 300 mL of basic alumina and dried over MgSO4. The solution was then passed through 1.2 L of silica gel. The silica gel was washed with 300 mL of CH2Cl2 after which the silica gel was eluted with 2000 mL of 5% MeOH in CH2Cl2. The combined organic layers were concentrated by rotary evaporation to afford 26.9 g (47% yield) of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one as a pale yellow solid. The pale yellow solid was dissolved in THF and 4 N HCl in dioxane was added to obtain the hydrochloride salt as a white precipitate. NB. This is a modification of a procedure found in: G. Gonzalez Trigo, Anales de Quimica, 1979, 782-783. Foaming and bubbling A dark yellow, sticky solid formed to stir overnight was added until the pH˜8 The layers were separated the aqueous layer was extracted with CH2Cl2 (500 mL) dried over MgSO4 The silica gel was washed with 300 mL of CH2Cl2 after which the silica gel was eluted with 2000 mL of 5% MeOH in CH2Cl2 The combined organic layers were concentrated by rotary evaporation

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

実験手順: To a solution in water (400 ml) of pentandial (84.5 g) and benzylamine hydrochloride (36.3 g), cooled at 0° C. 30.8 g of 1,3-acetonedicarboxylic acid are added. 70 ml of an aqueous solution of sodium acetate at 10% are then added. The obtained mixture is kept under stirring at room temperature for one hour and then heated for 4 hours to 50° C. The mixture is then acidified at pH 2 with a 10% w. HCl aqueous solution and then washed with diethyl ether. The pH is then brought to 6 with sodium bicarbonate and the aqueous phase extracted with dichloromethane. The organic extracts are anhydrified on sodium sulphate and the solvent evaporated to obtain 38.5 g of the compound 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (6a) as a light coloured solid. heated for 4 hours to 50° C HCl aqueous solution and then washed with diethyl ether the aqueous phase extracted with dichloromethane the solvent evaporated

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

実験手順: To a 1 L round-bottomed flask equipped with a condenser and nitrogen inlet were added 80 g (0.2 mol) of a 25% aqueous solution of glutaraldehyde, 29.2 g (0.2 mol) 1,3-acetonedicarboxylic acid, and 11.4 g (0.2 mol) benzylamine. After the initial reaction had subsided, the pH was adjusted to 5 and maintained for 14 hours. The reaction was then taken up in 6N HCl, washed with ethyl acetate, and basified with 6N sodium hydroxide solution. The aqueous layer was extracted with methylene chloride, and the organic layer filtered through diatomaceous earth (Celite [trademark]) and evaporated. The residue was chromatographed on silica gel with ethyl acetate/methylene chloride as eluent to afford 15.034 g (33%) of a pale orange solid, mp 70-73C. To a 1 L round-bottomed flask equipped with a condenser and nitrogen inlet After the initial reaction maintained for 14 hours washed with ethyl acetate The aqueous layer was extracted with methylene chloride the organic layer filtered through diatomaceous earth (Celite [trademark]) evaporated The residue was chromatographed on silica gel with ethyl acetate/methylene chloride as eluent

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

実験手順: To a solution of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (0.5 g) in chloroform (4.4 ml), cooled down to −5° C., 1 ml of conc. H2SO4 is dropwise added while maintaining the temperature below 15° C. Then NaN3 (0.28 g) is slowly added, at small portions so to avoid temperatures in the reaction mixture higher than 35° C. The mixture is then heated at reflux for 2 hours. The reaction mixture is poured into a vessel containing about 200 ml of ice. Solid K2CO3 is added up to a strongly alkaline pH. An emulsion is formed, that is added of 25 ml of a 60% KOH aqueous solution. Stirring is effected for 10 minutes. At the end the formed inorganic salts are filtered and the reaction mixture extracted with chloroform. The organic phase is dehydrated with sodium sulphate and the solvent evaporated. 0.50 g of 10-benzyl-3,10-diazabicyclo[4.3.1]decan-4-one (1py1) are obtained as a light solid. while maintaining the temperature below 15° C higher than 35° C The mixture is then heated at reflux for 2 hours The reaction mixture is poured into a vessel An emulsion is formed At the end the formed inorganic salts are filtered the reaction mixture extracted with chloroform the solvent evaporated

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

実験手順: A two-liter, 2-neck flask, an overhead stirrer and an addition funnel were used. Glutaraldehyde (100 mL, 50% aq. solution) was placed in the flask. Water (63 mL) was added. 36.5 grams of 1,3-acetonedicarboxylic acid were added. Some bubbling was observed. NaOAc (14.25 g) was added and the mixture was stirred vigorously. A solution of benzylamine hydrochloride (35.6 g) in 112 mL of water was placed in the addition funnel. Alternatively it may be advantageous to dissolve the benzylamine hydrochloride in 80 mL of water and 30 mL of 0.12 N aqueous HCl, instead of 112 mL of H2O. The amine solution was added to the reaction mixture portionwise. Foaming and bubbling was observed. A dark yellow, sticky solid formed. The reaction mixture was allowed to stir overnight. Methylene chloride (500 mL) was added, followed by K2CO3 which was added until the pH ˜8. The layers were separated and the aqueous layer was extracted with CH2Cl2 (500 mL). The combined organic layers were passed through 300 mL of basic alumina and dried over MgSO4. The solution was then passed through 1.2 L of silica gel. The silica gel was washed with 300 mL of CH2Cl2 after which the silica gel was eluted with 2000 mL of 5% MeOH in CH2Cl2. The combined organic layers were concentrated by rotary evaporation to afford 26.9 g (47% yield) of 9-benzyl-9-azabicyclo[3.3.1-]nonan-3-one as a pale yellow solid. The pale yellow solid was dissolved in THF and 4 N HCl in dioxane was added to obtain the hydrochloride salt as a white precipitate. NB. This is a modification of a procedure found in: G. Gonzalez Trigo, Anales de Quimica, 1979, 782-783. Foaming and bubbling A dark yellow, sticky solid formed to stir overnight was added until the pH ˜8 The layers were separated the aqueous layer was extracted with CH2Cl2 (500 mL) dried over MgSO4 The silica gel was washed with 300 mL of CH2Cl2 after which the silica gel was eluted with 2000 mL of 5% MeOH in CH2Cl2 The combined organic layers were concentrated by rotary evaporation

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1