1-benzyl-4-(hydroxymethyl)piperidin-4-ol

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

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

Procedure: 60% sodium hydride (0.30 g) was added to a solution of the compound (1.66 g) obtained in Step 2 in anhydrous dimethylformamide (8 mL) under cooling with ice-water, and stirred at room temperature for thirty minutes under nitrogen atmosphere. 4-fluorobenzonitrile (0.91 g) was added to the mixture and stirred at room temperature for two days. The resulting mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; ethyl acetate:hexane=1:1) to obtain the titled compound (2.2 g). stirred at room temperature for two days extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; ethyl acetate:hexane=1:1)

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

Procedure: 60% sodium hydride (0.30 g) was added to a solution of the compound (1.66 g) obtained in Step 2 in anhydrous dimethylformamide (8 mL) under cooling with ice-water, and stirred at room temperature for thirty minutes under nitrogen atmosphere. 4-fluorobenzonitrile (0.91 g) was added to the mixture and stirred at room temperature for two days. The resulting mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; ethyl acetate:hexane=1:1) to obtain the titled compound (2.2 g). stirred at room temperature for two days extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; ethyl acetate:hexane=1:1)

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

Procedure: 85% potassium hydroxide (40.6 g) was dissolved in water (615 mL) and mixed with dioxane (103 mL). A dioxane solution (103 mL) of the compound (25.0 g) obtained in Step 1 was added dropwise to the mixture at 90° C. over 60 minutes under nitrogen atmosphere and stirred at the same temperature for 20 minutes. With cooling the reaction solution with ice-water, the pH of the solution was adjusted to 9 with concentrated hydrochloric acid, the mixture was saturated with salt, and extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from hexane:ether and collected by filtration to obtain the titled compound (24.6 g) as crystals. extracted with ethyl acetate dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The residue was crystallized from hexane ether and collected by filtration

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

Procedure: A suspension of 26.0 g (117 mmol) 1-benzyl-4-hydroxymethyl-piperidin-4-ol and 5.0 g 10% Pd/C in 500 mL MeOH was hydrogenated at 50° C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (4 h). The catalyst was filtered off and washed with MeOH. After the solvent had been eliminated the residue was reacted further without purification. was hydrogenated at 50° C. (4 h) The catalyst was filtered off washed with MeOH was reacted further without purification

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

Procedure: A suspension of 26.0 g (117 mmol) 1-benzyl-4-hydroxymethyl-piperidin-4-ol and 5.0 g 10% Pd/C in 500 mL MeOH was hydrogenated at 50° C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (4 h). The catalyst was filtered off and washed with MeOH. After the solvent had been eliminated the residue was reacted further without purification. was hydrogenated at 50° C. (4 h) The catalyst was filtered off washed with MeOH was reacted further without purification

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

Procedure: 100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol. cooled to 7, and then the mixture was evaporated Ethyl acetate was added to the residue the insoluble mattters were removed by filtration The filtrate was evaporated purified by silica gel column chromatography

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

Procedure: 100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol. cooled to 7, and then the mixture was evaporated Ethyl acetate was added to the residue the insoluble mattters were removed by filtration The filtrate was evaporated purified by silica gel column chromatography

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

Procedure: 100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol. cooled to 7, and then the mixture was evaporated Ethyl acetate was added to the residue the insoluble mattters were removed by filtration The filtrate was evaporated purified by silica gel column chromatography

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

Procedure: 100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol. cooled to 7, and then the mixture was evaporated Ethyl acetate was added to the residue the insoluble mattters were removed by filtration The filtrate was evaporated purified by silica gel column chromatography

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

Procedure: 100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol. cooled to 7, and then the mixture was evaporated Ethyl acetate was added to the residue the insoluble mattters were removed by filtration The filtrate was evaporated purified by silica gel column chromatography

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

Procedure: 500 mg of 1-benzyl-4-(hydroxymethyl)piperidin-4-ol (synthesized according to the method described in J. Med. Chem., 1988, 486-491) was dissolved in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added thereto, and the mixture was subjected to hydrogenation at room temperature overnight. The reaction mixture was filtrated to remove precipitates, the precipitates were washed with ethanol and water, and the filtrate was concentrated under reduced pressure. The obtained residue was turned into powder by adding diethylether to obtain 374 mg of the objective compound as a white powder. The reaction mixture was filtrated to remove precipitates the precipitates were washed with ethanol and water the filtrate was concentrated under reduced pressure by adding diethylether