3-piperidin-4-ylpropan-1-ol;hydrochloride

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solution of 50.0 g of 3-(4-cyanophenoxy)propyl methanesulfonate in 250 mL of N,N-dimethylformamide, 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride were added at room temperature, which was then stirred at 70° C. for 7 hours. To the reaction mixture, after being cooled down to room temperature, 250 mL of water and 150 mL of toluene were added, and then hydrochloric acid was added to adjust the pH to 1.0. The aqueous layer was separated, adjusted to pH 10.0 with a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 min and under cooling on ice for 30 min. The solid matter was collected by filtration and washed twice with 50 mL of water and twice with 50 mL of toluene to obtain 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile monohydrate as a white solid. To the reaction mixture, after being cooled down to room temperature The aqueous layer was separated stirred at room temperature for 15 min under cooling on ice for 30 min The solid matter was collected by filtration washed twice with 50 mL of water and twice with 50 mL of toluene

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

Procedure: Prepared similarly to Intermediate 20 from 3-(4-piperidinyl)-1-propanol hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.2 Hz, 3H) 1.01-1.23 (m, 5H) 1.36-1.45 (m, 2H) 1.56-1.63 (m, 2H) 1.72-1.81 (m, 2H) 2.22-2.29 (m, 2H) 2.73 (s, 17H residual DMF) 2.81 (d, J=11.54 Hz, 2H) 2.86-2.92 (m, 18H residual DMF) 3.30-3.39 (m, 3H) 4.30-4.36 (m, 1H) 7.95 (s, 8H residual DMF)

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

Procedure: 1.00 g (7.29 mmol) of 4-pyridinepropanol was dissolved in 3N aqueous hydrochloric acid solution and 206 mg of platinum oxide was added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere at an ordinary pressure for 12 hours. The reaction mixture was filtered with Celite and the filtrate was distilled off under reduced pressure. The thus obtained residue was reprecipitated from methanol-ether to obtain 1.31 g (yield: quantitative) of the title compound as a white solid. The reaction mixture was filtered with Celite the filtrate was distilled off under reduced pressure The thus obtained residue was reprecipitated from methanol-ether

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an N,N-dimethylformamide (250 mL) solution of 50.0 g of 3-(4-cyanophenoxy)propyl=methanesulfonate were added 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate, and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride at room temperature, which was then stirred at 70° C. for 6 hours and 50 minutes. The reaction mixture was cooled down to room temperature, to which water and toluene were then added, followed by adjustment to pH 1.0 using hydrochloric acid. The aqueous layer was separated, adjusted to pH 10.0 using a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 minutes and then under cooling with ice for 30 minutes. The precipitate was collected by filtration and washed with water and toluene to provide 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile as white solid form. were then added The aqueous layer was separated stirred at room temperature for 15 minutes under cooling with ice for 30 minutes The precipitate was collected by filtration washed with water and toluene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an N,N-dimethylformamide (250 mL) solution of 50.0 g of 3-(4-cyanophenoxy)propyl=methanesulfonate were added 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate, and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride at room temperature, which was then stirred at 70° C. for 6 hours and 50 minutes. The reaction mixture was cooled down to room temperature, to which water and toluene were then added, followed by adjustment to pH 1.0 using hydrochloric acid. The aqueous layer was separated, adjusted to pH 10.0 using a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 minutes and then under cooling with ice for 30 minutes. The precipitate was collected by filtration and washed with water and toluene to provide 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile as white solid form. were then added The aqueous layer was separated stirred at room temperature for 15 minutes under cooling with ice for 30 minutes The precipitate was collected by filtration washed with water and toluene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solution of 50.0 g of 3-(4-cyanophenoxy)propyl methanesulfonate in 250 mL of N,N-dimethylformamide, 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride were added at room temperature, which was then stirred at 70° C. for 7 hours. To the reaction mixture, after being cooled down to room temperature, 250 mL of water and 150 mL of toluene were added, and then hydrochloric acid was added to adjust the pH to 1.0. The aqueous layer was separated, adjusted to pH 10.0 with a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 min and under cooling on ice for 30 min. The solid matter was collected by filtration and washed twice with 50 mL of water and twice with 50 mL of toluene to obtain 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile monohydrate as a white solid. To the reaction mixture, after being cooled down to room temperature The aqueous layer was separated stirred at room temperature for 15 min under cooling on ice for 30 min The solid matter was collected by filtration washed twice with 50 mL of water and twice with 50 mL of toluene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solution of 50.0 g of 3-(4-cyanophenoxy)propyl methanesulfonate in 250 mL of N,N-dimethylformamide, 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride were added at room temperature, which was then stirred at 70° C. for 7 hours. To the reaction mixture, after being cooled down to room temperature, 250 mL of water and 150 mL of toluene were added, and then hydrochloric acid was added to adjust the pH to 1.0. The aqueous layer was separated, adjusted to pH 10.0 with a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 min and under cooling on ice for 30 min. The solid matter was collected by filtration and washed twice with 50 mL of water and twice with 50 mL of toluene to obtain 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile monohydrate as a white solid. To the reaction mixture, after being cooled down to room temperature The aqueous layer was separated stirred at room temperature for 15 min under cooling on ice for 30 min The solid matter was collected by filtration washed twice with 50 mL of water and twice with 50 mL of toluene

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

Procedure: Prepared similarly to Intermediate 20 from 3-(4-piperidinyl)-1-propanol hydrochloride.

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

Procedure: 20 g (111 mmol) 3-piperidin-4-yl-propan-1-ol hydrochloride are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 0.5 g pyridinium tosylate. The mixture is stirred for two days at RT. After addition of 1 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[3-tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved in 90 ml acetonitrile without further purification and added to 35 g (135 mmol) diphenyl bromomethane (95%) and 29 g (210 mmol) potassium carbonate and stirred for four days at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-diphenylmethyl-4-[3-(tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved without further purification in 130 ml methanol and added to 25 ml conc. hydrochloric acid, and the mixture is stirred at RT overnight. Subsequently, the solvent is removed under vacuum and the residue is taken up with 300 ml water and extracted with 300 ml acetic acid ethyl ester. The organic phase is discarded and the aqueous phase is made alkaline with 17 g sodium hydroxide and extracted with 300 g acetic acid ethyl ester. After washing the organic phase with 40 ml water, this is dried over sodium sulfate and the solvent is removed under vacuum: The oil is dried under high-vacuum and processed further without purification. Yield: 22.4 g (65%). this is concentrated under vacuum to dryness The resulting 4-[3-tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved in 90 ml acetonitrile without further purification stirred for four days at RT The mixture is filtered the solvent is removed under vacuum The resulting 1-diphenylmethyl-4-[3-(tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved without further purification in 130 ml methanol added to 25 ml conc. hydrochloric acid the mixture is stirred at RT overnight Subsequently, the solvent is removed under vacuum extracted with 300 ml acetic acid ethyl ester extracted with 300 g acetic acid ethyl ester After washing the organic phase with 40 ml water this is dried over sodium sulfate the solvent is removed under vacuum The oil is dried under high-vacuum processed further without purification

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

Procedure: Prepared similarly to Intermediate 20 from 3-(4-piperidinyl)-1-propanol hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.2 Hz, 3H) 1.01-1.23 (m, 5H) 1.36-1.45 (m, 2H) 1.56-1.63 (m, 2H) 1.72-1.81 (m, 2H) 2.22-2.29 (m, 2H) 2.73 (s, 17H residual DMF) 2.81 (d, J=11.54 Hz, 2H) 2.86-2.92 (m, 18H residual DMF) 3.30-3.39 (m, 3H) 4.30-4.36 (m, 1H) 7.95 (s, 8H residual DMF)

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

Procedure: 1.00 g (7.29 mmol) of 4-pyridinepropanol was dissolved in 3N aqueous hydrochloric acid solution and 206 mg of platinum oxide was added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere at an ordinary pressure for 12 hours. The reaction mixture was filtered with Celite and the filtrate was distilled off under reduced pressure. The thus obtained residue was reprecipitated from methanol-ether to obtain 1.31 g (yield: quantitative) of the title compound as a white solid. The reaction mixture was filtered with Celite the filtrate was distilled off under reduced pressure The thus obtained residue was reprecipitated from methanol-ether

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an N,N-dimethylformamide (250 mL) solution of 50.0 g of 3-(4-cyanophenoxy)propyl=methanesulfonate were added 32.5 g of potassium iodide, 32.9 g of sodium bicarbonate, and 37.0 g of 3-(4-piperidinyl)-1-propanol hydrochloride at room temperature, which was then stirred at 70° C. for 6 hours and 50 minutes. The reaction mixture was cooled down to room temperature, to which water and toluene were then added, followed by adjustment to pH 1.0 using hydrochloric acid. The aqueous layer was separated, adjusted to pH 10.0 using a 20% sodium hydroxide aqueous solution, and stirred at room temperature for 15 minutes and then under cooling with ice for 30 minutes. The precipitate was collected by filtration and washed with water and toluene to provide 52.3 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile as white solid form. were then added The aqueous layer was separated stirred at room temperature for 15 minutes under cooling with ice for 30 minutes The precipitate was collected by filtration washed with water and toluene