1-propylsulfonylpiperidin-4-one

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

実験手順: To a flask in an ice-bath was added 1-(propylsulfonyl)piperidin-4-one (5.0 g, 24.4 mmol), trimethylsilylcyanide (3.25 mL, 24.2 mmol) and diethyl ether (3 mL) followed by addition of zinc iodide (0.005 g). This gave a yellow suspension which turned to an orange solution after 20 min stirring at room temperature. To the solution was added a solution of tert-butyl piperazine-1-carboxylate (4.54 g, 24.4 mmol) in methanol (35 mL). The solution was then refluxed overnight. The reaction was cooled and more trimethylsilylcyanide (0.5 eq) and zinc iodide (0.005 g) were added. The reaction was heated at reflux overnight and no starting material remained by TLC. The reaction mixture was evaporated to dryness and the product crystallised from ethyl acetate/iso-hexane to give tert-butyl 4-[4-cyano-1-(propylsulfonyl)piperidin-4-yl]piperazine-1-carboxylate as an off-white crystalline solid. 1H NMR (360 MHz, CDCl3): δ 3.80 (d, J=13.5 Hz, 2 H); 3.48 (t, J=4.9 Hz, 4 H); 3.15-3.09 (m, 2 H); 2.93-2.89 (m, 2 H); 2.60 (t, J=4.9 Hz, 4 H); 2.22 (d, J=13.4 Hz, 2 H); 1.91-1.81 (m, 4 H); 1.47 (s, 9 H); 1.07 (t, J=7.4 Hz, 3 H). This gave a yellow suspension which The solution was then refluxed overnight The reaction was cooled The reaction was heated at reflux overnight The reaction mixture was evaporated to dryness the product crystallised from ethyl acetate/iso-hexane

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

実験手順: To a flask in an ice-bath was added 1-(propylsulfonyl)piperidin-4-one (5.0 g, 24.4 mmol), trimethylsilylcyanide (3.25 mL, 24.2 mmol) and diethyl ether (3 mL) followed by addition of zinc iodide (0.005 g). This gave a yellow suspension which turned to an orange solution after 20 min stirring at room temperature. To the solution was added a solution of tert-butyl piperazine-1-carboxylate (4.54 g, 24.4 mmol) in methanol (35 mL). The solution was then refluxed overnight. The reaction was cooled and more trimethylsilylcyanide (0.5 eq) and zinc iodide (0.005 g) were added. The reaction was heated at reflux overnight and no starting material remained by TLC. The reaction mixture was evaporated to dryness and the product crystallised from ethyl acetate/iso-hexane to give tert-butyl 4-[4-cyano-1-(propylsulfonyl)piperidin-4-yl]piperazine-1-carboxylate as an off-white crystalline solid. 1H NMR (360 MHz, CDCl3): δ 3.80 (d, J=13.5 Hz, 2 H); 3.48 (t, J=4.9 Hz, 4 H); 3.15-3.09 (m, 2 H); 2.93-2.89 (m, 2 H); 2.60 (t, J=4.9 Hz, 4 H); 2.22 (d, J=13.4 Hz, 2 H); 1.91-1.81 (m, 4 H); 1.47 (s, 9 H); 1.07 (t, J=7.4 Hz, 3 H). This gave a yellow suspension which The solution was then refluxed overnight The reaction was cooled The reaction was heated at reflux overnight The reaction mixture was evaporated to dryness the product crystallised from ethyl acetate/iso-hexane

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

実験手順: Sodium cyanide (0.98 g, 20.0 mmol) was added to a solution of piperidine (1.98 ml, 20.0 mmol) in 1 N hydrochloric acid (20 mL). A solution of 1-(propylsulfonyl)piperidin-4-one (4.11 g, 20.0 mmol) in methanol (40 mL) was added dropwise to the mixture over 30 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The precipitate was filtered and washed with water (10 mL) and dried under high vacuum at 60° C. which gave a white solid. The volume of the filtrate was reduced to approx 20 mL and the pH of the aqueous residue was adjusted to 7 by the addition of 4 N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give 1′-(propylsulfonyl)-1,4′-bipiperidine-4′-carbonitrile as a colourless oil. 1H NMR (400 MHz, CDCl3): δ 3.70-3.64 (m, 2 H); 3.09-3.03 (m, 2 H); 2.85-2.81 (m, 2 H); 2.51 (t, J=5.0 Hz, 4 H); 2.15 (d, J=13.6 Hz, 2 H); 1.83-1.75 (m, 4 H); 1.58-1.54 (m, 4 H); 1.45-1.39 (m, 2 H); 1.00 (t, J=7.5 Hz, 3 H). On complete addition the mixture The precipitate was filtered washed with water (10 mL) dried under high vacuum at 60° C. which gave a white solid The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL) The combined organics were dried over anhydrous sodium sulfate filtered evaporated

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

実験手順: Sodium cyanide (0.98 g, 20.0 mmol) was added to a solution of piperidine (1.98 ml, 20.0 mmol) in 1 N hydrochloric acid (20 mL). A solution of 1-(propylsulfonyl)piperidin-4-one (4.11 g, 20.0 mmol) in methanol (40 mL) was added dropwise to the mixture over 30 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The precipitate was filtered and washed with water (10 mL) and dried under high vacuum at 60° C. which gave a white solid. The volume of the filtrate was reduced to approx 20 mL and the pH of the aqueous residue was adjusted to 7 by the addition of 4 N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give 1′-(propylsulfonyl)-1,4′-bipiperidine-4′-carbonitrile as a colourless oil. 1H NMR (400 MHz, CDCl3): δ 3.70-3.64 (m, 2 H); 3.09-3.03 (m, 2 H); 2.85-2.81 (m, 2 H); 2.51 (t, J=5.0 Hz, 4 H); 2.15 (d, J=13.6 Hz, 2 H); 1.83-1.75 (m, 4 H); 1.58-1.54 (m, 4 H); 1.45-1.39 (m, 2 H); 1.00 (t, J=7.5 Hz, 3 H). On complete addition the mixture The precipitate was filtered washed with water (10 mL) dried under high vacuum at 60° C. which gave a white solid The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL) The combined organics were dried over anhydrous sodium sulfate filtered evaporated

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

実験手順: To a flask in an ice-bath was added 1-(propylsulfonyl)piperidin-4-one (5.0 g, 24.4 mmol), trimethylsilylcyanide (3.25 mL, 24.2 mmol) and diethyl ether (3 mL) followed by addition of zinc iodide (0.005 g). This gave a yellow suspension which turned to an orange solution after 20 min stirring at room temperature. To the solution was added a solution of tert-butyl piperazine-1-carboxylate (4.54 g, 24.4 mmol) in methanol (35 mL). The solution was then refluxed overnight. The reaction was cooled and more trimethylsilylcyanide (0.5 eq) and zinc iodide (0.005 g) were added. The reaction was heated at reflux overnight and no starting material remained by TLC. The reaction mixture was evaporated to dryness and the product crystallised from ethyl acetate/iso-hexane to give tert-butyl 4-[4-cyano-1-(propylsulfonyl)piperidin-4-yl]piperazine-1-carboxylate as an off-white crystalline solid. 1H NMR (360 MHz, CDCl3): δ 3.80 (d, J=13.5 Hz, 2 H); 3.48 (t, J=4.9 Hz, 4 H); 3.15-3.09 (m, 2 H); 2.93-2.89 (m, 2 H); 2.60 (t, J=4.9 Hz, 4 H); 2.22 (d, J=13.4 Hz, 2 H); 1.91-1.81 (m, 4 H); 1.47 (s, 9 H); 1.07 (t, J=7.4 Hz, 3 H). This gave a yellow suspension which The solution was then refluxed overnight The reaction was cooled The reaction was heated at reflux overnight The reaction mixture was evaporated to dryness the product crystallised from ethyl acetate/iso-hexane

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

実験手順: Sodium cyanide (0.98 g, 20.0 mmol) was added to a solution of piperidine (1.98 ml, 20.0 mmol) in 1 N hydrochloric acid (20 mL). A solution of 1-(propylsulfonyl)piperidin-4-one (4.11 g, 20.0 mmol) in methanol (40 mL) was added dropwise to the mixture over 30 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The precipitate was filtered and washed with water (10 mL) and dried under high vacuum at 60° C. which gave a white solid. The volume of the filtrate was reduced to approx 20 mL and the pH of the aqueous residue was adjusted to 7 by the addition of 4 N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give 1′-(propylsulfonyl)-1,4′-bipiperidine-4′-carbonitrile as a colourless oil. 1H NMR (400 MHz, CDCl3): δ 3.70-3.64 (m, 2 H); 3.09-3.03 (m, 2 H); 2.85-2.81 (m, 2 H); 2.51 (t, J=5.0 Hz, 4 H); 2.15 (d, J=13.6 Hz, 2 H); 1.83-1.75 (m, 4 H); 1.58-1.54 (m, 4 H); 1.45-1.39 (m, 2 H); 1.00 (t, J=7.5 Hz, 3 H). On complete addition the mixture The precipitate was filtered washed with water (10 mL) dried under high vacuum at 60° C. which gave a white solid The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL) The combined organics were dried over anhydrous sodium sulfate filtered evaporated