(3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methanamine

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

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

Procedure: The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml) and treated with acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium cyanoborohydride (341 mg, 5.4 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours; it was then diluted with water and methylene chloride and acidified to pH 1 with 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer was 10; the mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (eluant: 89:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide a colorless oil (390 mg, 2:1 mixture of 3-benzyl-1-ethylaminomethyl-3-azabicyclo[3.1.0]hexane and 1-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane). This material was dissolved in dioxane (18 ml) and water (2 ml) and treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol); the reaction mixture was allowed to stir for 18 hours at room temperature. The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer as extracted three times with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). 1H NMR (CDCl3): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J=7 Hz, 3H), 0.46 (bs, 1H). The compound of Preparation A.4 the mixture was extracted three times with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to provide to stir for 18 hours at room temperature The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate The aqueous layer as extracted three times with methylene chloride the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide)

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

Procedure: Lithium aluminum hydride (70 ml of a 1M solution in diethyl ether, 70 mmol) was added to a solution of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml). After 18 hours at room temperature, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml of a 15% aqueous solution), and water (7.8 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title product as a viscous, slightly yellow oil (3.47 g, 100% yield), which was used without purification. 1H NMR (CDCl ): 7.20 (m, 5H), 3.54 (AB quartet, J=12 Hz, 2H), 2.92 (d, J=8 Hz, 1H), 2.87 (d, J=9 Hz, 1H), 2.81 (d, J=13 Hz, 1H), 2.59 (d, J=13 Hz, 1 H), 2.33 (dd, J=8, 4 Hz, 1H), 2.25 (d, J=7 Hz, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.30 (dd, J=8, 5 Hz, 1H). The mixture was filtered the filtrate was concentrated under reduced pressure

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

Procedure: The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml) and treated with acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium cyanoborohydride (341 mg, 5.4 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours; it was then diluted with water and methylene chloride and acidified to pH 1 with 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer was 10; the mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (eluant: 89:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide a colorless oil (390 mg, 2:1 mixture of 3-benzyl-1-ethylaminomethyl-3-azabicyclo[3.1.0]hexane and 1-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane). This material was dissolved in dioxane (18 ml) and water (2 ml and treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol); the reaction mixture was allowed to stir for 18 hours at room temperature. The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). 1H NMR (CDCl3): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J=7 Hz, 3H), 0.46 (bs, 1H). The compound of Preparation A.4 the mixture was extracted three times with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to provide to stir for 18 hours at room temperature The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate The aqueous layer was extracted three times with methylene chloride the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide)

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

Procedure: The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml) and treated with acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium cyanoborohydride (341 mg, 5.4 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours; it was then diluted with water and methylene chloride and acidified to pH 1 with 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer was 10; the mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (eluant: 89:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide a colorless oil (390 mg, 2:1 mixture of 3-benzyl-1-ethylaminomethyl-3-azabicyclo[3.1.0]hexane and 1-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane). This material was dissolved in dioxane (18 ml) and water (2 ml and treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol); the reaction mixture was allowed to stir for 18 hours at room temperature. The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). 1H NMR (CDCl3): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J=7 Hz, 3H), 0.46 (bs, 1H). The compound of Preparation A.4 the mixture was extracted three times with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to provide to stir for 18 hours at room temperature The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate The aqueous layer was extracted three times with methylene chloride the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide)

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

Procedure: Lithium aluminum hydride (70 ml of a 1M solution in diethyl ether, 70 mmol) was added to a solution of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml). After 18 hours at room temperature, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml of a 15% aqueous solution), and water (7.8 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title product as a viscous, slightly yellow oil (3.47 g, 100% yield), which was used without purification. 1H NMR (CDCl3): 7.20 (m, 5H), 3.54 (AB quartet, J=12 Hz, 2H), 2.92 (d, J=8 Hz, 1H), 2.87 (d, J=9 Hz, 1H), 2.81 (d, J=13 Hz, 1H), 2.59 (d, J=13 Hz, 1H), 2.33 (dd, J=8, 4 Hz, 1H), 2.25 (d, J=7 Hz, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.30 (dd, J=8, 5 Hz, 1H). The mixture was filtered the filtrate was concentrated under reduced pressure

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

Procedure: Lithium aluminum hydride (70 ml of a 1M solution in diethyl ether, 70 mmol) was added to a solution of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml). After 18 hours at room temperature, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml of a 15% aqueous solution), and water (7.8 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title product as a viscous, slightly yellow oil (3.47 g, 100% yield), which was used without purification. 1H NMR (CDCl3): 7.20 (m, 5H), 3.54 (AB quartet, J=12 Hz, 2H), 2.92 (d, J=8 Hz, 1H), 2.87 (d, J=9 Hz, 1H), 2.81 (d, J=13 Hz, 1H), 2.59 (d, J=13 Hz, 1H), 2.33 (dd, J=8, 4 Hz, 1H), 2.25 (d, J=7 Hz, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.30 (dd, J=8, 5 Hz, 1H). The mixture was filtered the filtrate was concentrated under reduced pressure

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

Procedure: The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml) and treated with acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium cyanoborohydride (341 mg, 5.4 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours; it was then diluted with water and methylene chloride and acidified to pH 1 with 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer was 10; the mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (eluant: 89:10:1 chloroform: methanol: concentrated ammonium hydroxide) to provide a colorless oil (390 mg, 2:1 mixture of 3-benzyl-1-ethylaminomethyl-3-azabicyclo[3.1.0]hexane and 1-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane). This material was dissolved in dioxane (18 ml) and water (2 ml) and treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol); the reaction mixture was allowed to stir for 18 hours at room temperature. The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform: methanol: concentrated ammonium hydroxide) to provide the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). 1H NMR (CDCl3): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J=7 Hz, 3H), 0.46 (bs, 1H). The compound of Preparation A.4 the mixture was extracted three times with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to provide to stir for 18 hours at room temperature The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate The aqueous layer was extracted three times with methylene chloride the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform: methanol: concentrated ammonium hydroxide)

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

Procedure: The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml) and treated with acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium cyanoborohydride (341 mg, 5.4 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours; it was then diluted with water and methylene chloride and acidified to pH 1 with 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer was 10; the mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (eluant: 89:10:1 chloroform: methanol: concentrated ammonium hydroxide) to provide a colorless oil (390 mg, 2:1 mixture of 3-benzyl-1-ethylaminomethyl-3-azabicyclo[3.1.0]hexane and 1-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane). This material was dissolved in dioxane (18 ml) and water (2 ml) and treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol); the reaction mixture was allowed to stir for 18 hours at room temperature. The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform: methanol: concentrated ammonium hydroxide) to provide the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). 1H NMR (CDCl3): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J=7 Hz, 3H), 0.46 (bs, 1H). The compound of Preparation A.4 the mixture was extracted three times with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to provide to stir for 18 hours at room temperature The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate The aqueous layer was extracted three times with methylene chloride the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform: methanol: concentrated ammonium hydroxide)

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

Procedure: Lithium aluminum hydride (70 ml of a 1M solution in diethyl ether, 70 mmol) was added to a solution of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml). After 18 hours at room temperature, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml of a 15% aqueous solution), and water (7.8 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title product as a viscous, slightly yellow oil (3.47 g, 100% yield), which was used without purification. 1H NMR (CDCl3): 7.20 (m, 5H), 3.54 (AB quartet, J=12 Hz, 2H), 2.92 (d, J=8 Hz, 1H), 2.87 (d, J=9 Hz, 1H), 2.81 (d, J=13 Hz, 1H), 2.59 (d, J=13 Hz, 1H), 2.33 (dd, J=8, 4 Hz, 1H), 2.25 (d, J=7 Hz, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.30 (dd, J=8, 5 Hz, 1H). The mixture was filtered the filtrate was concentrated under reduced pressure

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

Procedure: Lithium aluminum hydride (70 ml of a 1M solution in diethyl ether, 70 mmol) was added to a solution of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml). After 18 hours at room temperature, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml of a 15% aqueous solution), and water (7.8 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title product as a viscous, slightly yellow oil (3.47 g, 100% yield), which was used without purification. 1H NMR (CDCl3): 7.20 (m, 5H), 3.54 (AB quartet, J=12 Hz, 2H), 2.92 (d, J=8 Hz, 1H), 2.87 (d, J=9 Hz, 1H), 2.81 (d, J=13 Hz, 1H), 2.59 (d, J=13 Hz, 1H), 2.33 (dd, J=8, 4 Hz, 1H), 2.25 (d, J=7 Hz, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.30 (dd, J=8, 5 Hz, 1H). The mixture was filtered the filtrate was concentrated under reduced pressure

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

Procedure: The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml) and treated with acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium cyanoborohydride (341 mg, 5.4 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours; it was then diluted with water and methylene chloride and acidified to pH 1 with 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer was 10; the mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (eluant: 89:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide a colorless oil (390 mg, 2:1 mixture of 3-benzyl-1-ethylaminomethyl-3-azabicyclo[3.1.0]hexane and 1-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane). This material was dissolved in dioxane (18 ml) and water (2 ml) and treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol); the reaction mixture was allowed to stir for 18 hours at room temperature. The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with methylene chloride and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). 1H NMR (CDCl3): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J=7 Hz, 3H), 0.46 (bs, 1H). The compound of Preparation A.4 the mixture was extracted three times with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to provide to stir for 18 hours at room temperature The solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate The aqueous layer was extracted three times with methylene chloride the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The resulting colorless oil was subjected to purification on a Chromatotron (trademark) (eluant: 400:10:1 chloroform:methanol:concentrated ammonium hydroxide)