4-hydroxypiperidine-1-carbonitrile

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: In a variation of the method described by Yarovenko et al, (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl2 (1 N in ether, 120 mL, 120 mmol) was added in a dropwise fashion over 15 min to a magnetically stirred solution of N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and 4-hydroxy-piperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl acetate (500 mL). Precipitate formed immediately upon addition, and at a point the stirring bar became immobilized in the matrix, requiring the reaction to be manually shaken for the remainder of addition. After standing for 15 min, the supernatant was decanted and filtered, and the residue was rinsed twice with ether, furnishing a hard white precipitate which was collected by filtration. This material was taken up in conc. HCl (50 mL), diluted to 4 N with EtOH (100 mL), and refluxed for 1 h. Upon cooling, a white precipitate was removed by filtration, then the filtrate was reduced to 50 mL and diluted with 100 mL water. Solid Na2CO3 was added until the mixture was basic, CH2Cl2 was added, and the resulting mixture was filtered, rinsing with CH2Cl2. The organic extract was separated, dried over MgSO4, and the solvent was removed to afford a viscous, amber oil as 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71% yield): 1H NMR (CDCl3) δ 3.95 (m, 3 H), 3.37 (m, 2 H), 2.88 (m, 1 H), 2.34 (br s, 1 H), 1.93 (m, 2 H), 1.63 (m, 2 H), 1.28 (d, 6 H, J=7.1 Hz), MS m/z 212.3 (M+). Precipitate formed immediately upon addition the reaction the supernatant was decanted filtered the residue was rinsed twice with ether furnishing a hard white precipitate which was collected by filtration diluted to 4 N with EtOH (100 mL) refluxed for 1 h Upon cooling a white precipitate was removed by filtration diluted with 100 mL water Solid Na2CO3 was added until the mixture CH2Cl2 was added the resulting mixture was filtered rinsing with CH2Cl2 The organic extract was separated dried over MgSO4 the solvent was removed

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

実験手順: In a variation of the method described by Yarovenko et al, (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl2 (1 N in ether, 120 mL, 120 mmol) was added in a dropwise fashion over 15 min to a magnetically stirred solution of N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and 4-hydroxy-piperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl acetate (500 mL). Precipitate formed immediately upon addition, and at a point the stirring bar became immobilized in the matrix, requiring the reaction to be manually shaken for the remainder of addition. After standing for 15 min, the supernatant was decanted and filtered, and the residue was rinsed twice with ether, furnishing a hard white precipitate which was collected by filtration. This material was taken up in conc. HCl (50 mL), diluted to 4 N with EtOH (100 mL), and refluxed for 1 h. Upon cooling, a white precipitate was removed by filtration, then the filtrate was reduced to 50 mL and diluted with 100 mL water. Solid Na2CO3 was added until the mixture was basic, CH2Cl2 was added, and the resulting mixture was filtered, rinsing with CH2Cl2. The organic extract was separated, dried over MgSO4, and the solvent was removed to afford a viscous, amber oil as 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71% yield): 1H NMR (CDCl3) δ 3.95 (m, 3 H), 3.37 (m, 2 H), 2.88 (m, 1 H), 2.34 (br s, 1 H), 1.93 (m, 2 H), 1.63 (m, 2 H), 1.28 (d, 6 H, J=7.1 Hz), MS m/z 212.3 (M+). Precipitate formed immediately upon addition the reaction the supernatant was decanted filtered the residue was rinsed twice with ether furnishing a hard white precipitate which was collected by filtration diluted to 4 N with EtOH (100 mL) refluxed for 1 h Upon cooling a white precipitate was removed by filtration diluted with 100 mL water Solid Na2CO3 was added until the mixture CH2Cl2 was added the resulting mixture was filtered rinsing with CH2Cl2 The organic extract was separated dried over MgSO4 the solvent was removed

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

実験手順: A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05 (m, 2 H), 1.87 (m, 2 H), 1.70 (br s, 1 H), 1.62 (m, 2 H), MS m/z 212.1 (M+). A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel while vigorously stirring to form a thick, uniform slurry The flask was then placed in an ice bath the contents were vigorously mixed while cooling stirring The ice bath was removed the mechanical stirrer was replaced by a magnetic stirrer the reaction mixture was stirred for 16 h was added in order MgSO4 (500 g) was added vigorous stirring was continued for 15 min The resulting suspension was filtered rinsing with CH2Cl2 (2.0 L) A light amber, viscous oil was obtained upon solvent removal

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

実験手順: In a variation of the method described by Yarovenko et al, (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl2, (1 N in ether, 120 mL, 120 mmol) was added in a dropwise fashion over 15 min to a magnetically stirred solution of N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and 4-hydroxypiperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl acetate (500 mL). Precipitate formed immediately upon addition, and at a point the stirring bar became immobilized in the matrix, requiring the reaction to be manually shaken for the remainder of addition. After standing for 15 min, the supernatant was decanted and filtered, and the residue was rinsed twice with ether, furnishing a hard white precipitate which was collected by filtration. This material was taken up in conc. HCl (50 mL), diluted to 4 N with EtOH (100 mL), and refluxed for 1 h. Upon cooling, a white precipitate was removed by filtration, then the filtrate was reduced to 50 mL and diluted with 100 mL water. Solid Na2CO3 was added until the mixture was basic, CH2Cl2 was added, and the resulting mixture was filtered, rinsing with CH2Cl2. The organic extract was separated, dried over MgSO4, and the solvent was removed to afford a viscous, amber oil as 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71% yield): 1H NMR (CDCl3) δ 3.95 (m, 3H), 3.37 (m, 2H), 2.88 (m, 1H), 2.34 (br s, 1H), 1.93 (m, 2H), 1.63 (m, 2H), 1.28 (d, 6H, J=7.1 Hz); MS m/z 212.3 (M+). Precipitate formed immediately upon addition the reaction the supernatant was decanted filtered the residue was rinsed twice with ether furnishing a hard white precipitate which was collected by filtration diluted to 4 N with EtOH (100 mL) refluxed for 1 h Upon cooling a white precipitate was removed by filtration diluted with 100 mL water Solid Na2CO3 was added until the mixture CH2Cl2 was added the resulting mixture was filtered rinsing with CH2Cl2 The organic extract was separated dried over MgSO4 the solvent was removed

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

実験手順: A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300–400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1H), 3.39 (m, 2H), 3.05 (m, 2H), 1.87 (m, 2H), 1.70 (br s, 1H), 1.62 (m, 2H); MS m/z 212.1 (M+). A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel while vigorously stirring to form a thick, uniform slurry The flask was then placed in an ice bath the contents were vigorously mixed while cooling stirring The ice bath was removed the mechanical stirrer was replaced by a magnetic stirrer the reaction mixture was stirred for 16 h was added in order MgSO4 (500 g) was added vigorous stirring was continued for 15 min The resulting suspension was filtered rinsing with CH2Cl2 (2.0 L) A light amber, viscous oil was obtained upon solvent removal

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium bicarbonate was dissolved in water, and a solution of 4-hydroxypiperidine in dichloromethane and BrCN were added thereto at 0° C. The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted twice with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound. at 0° C further stirred at room temperature for 2 hours After completion of the reaction the reaction mixture was extracted twice with dichloromethane The organic layer thus obtained was dried over anhydrous sodium sulfate concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium bicarbonate was dissolved in water, and a solution of 4-hydroxypiperidine in dichloromethane and BrCN were added thereto at 0° C. The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted twice with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound. at 0° C further stirred at room temperature for 2 hours After completion of the reaction the reaction mixture was extracted twice with dichloromethane The organic layer thus obtained was dried over anhydrous sodium sulfate concentrated under reduced pressure

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: In a variation of the method described by Yarovenko et al, (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl2 (1 N in ether, 120 mL, 120 mmol) was added in a dropwise fashion over 15 min to a magnetically stirred solution of N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and 4-hydroxy-piperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl acetate (500 mL). Precipitate formed immediately upon addition, and at a point the stirring bar became immobilized in the matrix, requiring the reaction to be manually shaken for the remainder of addition. After standing for 15 min, the supernatant was decanted and filtered, and the residue was rinsed twice with ether, furnishing a hard white precipitate which was collected by filtration. This material was taken up in conc. HCl (50 mL), diluted to 4 N with EtOH (100 mL), and refluxed for 1 h. Upon cooling, a white precipitate was removed by filtration, then the filtrate was reduced to 50 mL and diluted with 100 mL water. Solid Na2CO3 was added until the mixture was basic, CH2Cl2 was added, and the resulting mixture was filtered, rinsing with CH2Cl2. The organic extract was separated, dried over MgSO4, and the solvent was removed to afford a viscous, amber oil as 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71% yield): 1H NMR (CDCl3) δ 3.95 (m, 3 H), 3.37 (m, 2 H), 2.88 (m, 1 H), 2.34 (br s, 1 H), 1.93 (m, 2 H), 1.63 (m, 2 H), 1.28 (d, 6 H, J=7.1 Hz), MS m/z 212.3 (M+). Precipitate formed immediately upon addition the reaction the supernatant was decanted filtered the residue was rinsed twice with ether furnishing a hard white precipitate which was collected by filtration diluted to 4 N with EtOH (100 mL) refluxed for 1 h Upon cooling a white precipitate was removed by filtration diluted with 100 mL water Solid Na2CO3 was added until the mixture CH2Cl2 was added the resulting mixture was filtered rinsing with CH2Cl2 The organic extract was separated dried over MgSO4 the solvent was removed

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

実験手順: A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05 (m, 2 H), 1.87 (m, 2 H), 1.70 (br s, 1 H), 1.62 (m, 2 H), MS m/z 212.1 (M+). A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel while vigorously stirring to form a thick, uniform slurry The flask was then placed in an ice bath the contents were vigorously mixed while cooling stirring The ice bath was removed the mechanical stirrer was replaced by a magnetic stirrer the reaction mixture was stirred for 16 h was added in order MgSO4 (500 g) was added vigorous stirring was continued for 15 min The resulting suspension was filtered rinsing with CH2Cl2 (2.0 L) A light amber, viscous oil was obtained upon solvent removal

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

実験手順: A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05 (m, 2 H), 1.87 (m, 2 H), 1.70 (br s, 1 H), 1.62 (m, 2 H), MS m/z 212.1 (M+). A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel while vigorously stirring to form a thick, uniform slurry The flask was then placed in an ice bath the contents were vigorously mixed while cooling stirring The ice bath was removed the mechanical stirrer was replaced by a magnetic stirrer the reaction mixture was stirred for 16 h was added in order MgSO4 (500 g) was added vigorous stirring was continued for 15 min The resulting suspension was filtered rinsing with CH2Cl2 (2.0 L) A light amber, viscous oil was obtained upon solvent removal