(4-amino-1-benzylpiperidin-4-yl)methanol

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L 4-neck round bottom flask was added (4-amino-1-benzylpiperidin-4-yl)methanol (21.86 g, 99 mmol) and diisopropyl amine (23.0 g, 249 mmol) in dry toluene (300 ml). The reaction mixture was cooled to 0° C. and a solution of triphosgene (35.57 g, 119 mmol) in toluene (100 ml) was added. The reaction mixture was heated to 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water (200 ml), basified with aqueous NH4OH, and extracted with ethyl acetate (3×200 ml). The organic layers were combined and washed with two 200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was stirred in hexanes for 1.5 hours and filtered again to afford the title compound. The reaction mixture was heated to 60° C. for 1.5 h After cooling to room temperature extracted with ethyl acetate (3×200 ml) washed with two 200 ml portions of water and 200 ml of brine dried over anhydrous sodium sulfate filtered concentrated filtered again

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L 4-neck round bottom flask was added LAH (9.42 g, 248 mmol) in dry THF (1000 mL) and the reaction mixture was cooled to 0° C. A solution of methyl 4-amino-1-benzylpiperidine-4-carboxylate (47.0 g, 165 mmol) in dry THF (250 ml) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and quenched with water and filtered. The solid was washed with 50 ml of ethyl acetate. The organic layer of the filtrate was separated, washed with 2×200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. to warm to room temperature The reaction mixture was cooled to 0° C. quenched with water filtered The solid was washed with 50 ml of ethyl acetate The organic layer of the filtrate was separated washed with 2×200 ml portions of water and 200 ml of brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

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

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

Procedure: 1.04 g (4.72 mmol) of 4-amino-1-benzyl-4-hydroxymethylpiperidine (for preparation see: Eur. J. Med. Chim. Ther. (1974) 9, 424-433) are suspended in 16 ml of dichloromethane and 842 mg (5.2 mmol) of carbonyldiimidazole are added. As the reaction progresses, a solution forms, which following complete reaction is diluted with dichloromethane and washed first with water, then with a 5 percent sodium bicarbonate solution and once again with water. The organic phase is dried over sodium sulfate and freed from the solvent on a rotary evaporator. 1.04 g of the title compound are obtained as a crude product, which is reacted further as it is. As the reaction progresses reaction washed first with water The organic phase is dried over sodium sulfate freed from the solvent on a rotary evaporator

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

Procedure: A. mixture of 4-amino-1-(phenylmethyl)-4-piperidinemethanol (0.0182 mol) and 2-propenenitrile (0.0304 mol) in ethanol (80 ml) was stirred and refluxed over the weekend. 2-Propenenitrile (2 ml) was added. The mixture was stirred and refluxed for 5 hours. 2-Propenenitrile (2 ml) was added again. The mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 3-[[4-(hydroxymethyl)-1(phenylmethyl)-4-piperidinyl]amino]-propanenitrile (interm. 10). refluxed over the weekend The mixture was stirred refluxed for 5 hours The mixture was stirred refluxed overnight The solvent was evaporated The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5) The desired fractions were collected the solvent was evaporated

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (2 mL 14 mmol) was added to a DCM (50 mL) solution containing chloroacetyl chloride (1 mL, 14 mmol) and compound 391 (3 g, 14 mmol). The resulting mixture was stirred 2 h at 23° C. The solvent was stripped and THF was added followed by potassium tert-butoxide (5 g, 41 mmol). The resulting solution was stirred overnight at room temperature. The reaction was then concentrated to dryness and the resulting residue was washed with 200 mL of absolute ethanol. The ethanolic solution was then concentrated to give 3.16 g of 9-(phenylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecan-2-one. The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 261, Calculated 261. The resulting solution was stirred overnight at room temperature The reaction was then concentrated to dryness the resulting residue was washed with 200 mL of absolute ethanol The ethanolic solution was then concentrated

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

Procedure: Lithium aluminum hydride (1.94 g, 51.2 mmol) was added to a THF (100 mL) solution of 4-amino-1-benzylpiperidine-4-carboxylic acid [Albert, J. S. et al. J. Med. Chem. 2002, 45, (18), 3972-3983] (390) (3.00 g, 12.8 mmol). The resulting mixture was stirred for 1.5 h at reflux. The reaction was cooled to room temperature and the following additions were made slowly: 2 mL of water followed by 2 mL of 1 N NaOH, and finally 4 mL of water. The mixture was then filtered and concentrated to give compound 391 as a thick clear oil (2.22 g, 79% yield). The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 221, Calculated 221. at reflux The mixture was then filtered concentrated

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

Procedure: Lithium aluminum hydride (1.94 g, 51.2 mmol) was added to a THF (100 mL) solution of 4-amino-1-benzylpiperidine-4-carboxylic acid [Albert, J. S. et al. J. Med. Chem. 2002, 45, (18), 3972-3983] (390) (3.00 g, 12.8 mmol). The resulting mixture was stirred for 1.5 h at reflux. The reaction was cooled to room temperature and the following additions were made slowly: 2 mL of water followed by 2 mL of 1 N NaOH, and finally 4 mL of water. The mixture was then filtered and concentrated to give compound 391 as a thick clear oil (2.22 g, 79% yield). The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 221, Calculated 221. at reflux The mixture was then filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L 4-neck round bottom flask was added (4-amino-1-benzylpiperidin-4-yl)methanol (21.86 g, 99 mmol) and diisopropyl amine (23.0 g, 249 mmol) in dry toluene (300 ml). The reaction mixture was cooled to 0° C. and a solution of triphosgene (35.57 g, 119 mmol) in toluene (100 ml) was added. The reaction mixture was heated to 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water (200 ml), basified with aqueous NH4OH, and extracted with ethyl acetate (3×200 ml). The organic layers were combined and washed with two 200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was stirred in hexanes for 1.5 hours and filtered again to afford the title compound. The reaction mixture was heated to 60° C. for 1.5 h After cooling to room temperature extracted with ethyl acetate (3×200 ml) washed with two 200 ml portions of water and 200 ml of brine dried over anhydrous sodium sulfate filtered concentrated filtered again

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L 4-neck round bottom flask was added (4-amino-1-benzylpiperidin-4-yl)methanol (21.86 g, 99 mmol) and diisopropyl amine (23.0 g, 249 mmol) in dry toluene (300 ml). The reaction mixture was cooled to 0° C. and a solution of triphosgene (35.57 g, 119 mmol) in toluene (100 ml) was added. The reaction mixture was heated to 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water (200 ml), basified with aqueous NH4OH, and extracted with ethyl acetate (3×200 ml). The organic layers were combined and washed with two 200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was stirred in hexanes for 1.5 hours and filtered again to afford the title compound. The reaction mixture was heated to 60° C. for 1.5 h After cooling to room temperature extracted with ethyl acetate (3×200 ml) washed with two 200 ml portions of water and 200 ml of brine dried over anhydrous sodium sulfate filtered concentrated filtered again