methyl 1-benzyl-4-oxopiperidine-3-carboxylate

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

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

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

Procedure: A solution of 1-benzyl-3-carbomethoxy-4-piperidone (1.0 g, 4.0 mmol) in THF (10 mL) was treated with 0.5M potassium bis(trimethylsilyl)amide in toluene (9.6 mL, 4.8 mmol) for 15 min, followed by the addition of benzyl bromide (1.2 g, 4.8 mmol). After 2 h, the reaction mixture was quenched with sat. NH4Cl and extracted with ether. The combined organic layers were washed with brine, dried with MgSO4 and concentrated. The product was purified by silica gel chromatography eluting with 4:1 hexane-EtOAc to give 3-carbomethoxy-1,3-dibenzyl-4-piperidone (0.61 g) as a light yellow oil. the reaction mixture was quenched with sat. NH4Cl extracted with ether The combined organic layers were washed with brine dried with MgSO4 concentrated The product was purified by silica gel chromatography eluting with 4:1 hexane-EtOAc

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

Procedure: To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H). to stir for 14 h while warming to room temperature The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution the organic layer was removed the aqueous layer was washed four times with EtOAc The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum Purification by silica gel chromatography

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

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

Procedure: To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H). to stir for 14 h while warming to room temperature The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution the organic layer was removed the aqueous layer was washed four times with EtOAc The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum Purification by silica gel chromatography

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

Procedure: To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H). to stir for 14 h while warming to room temperature The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution the organic layer was removed the aqueous layer was washed four times with EtOAc The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum Purification by silica gel chromatography

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

Procedure: Methyl-1-benzyl-4-oxo-3-piperidine carboxylate (5.68 g., 20 mmoles) and guanidine hydrochloride (2.0 g., 21 mmoles) were suspended and stirred in dry DMF (45 mls) before potassium carbonate (5.68 g., 41 mmoles) was added portionwise over 15 minutes. The reaction mixture was poured onto cold water (750 mls) to release a white/beige solid which was rapidly stirred for 30 minutes. The solid was filtered washed with water (100 mls) and dried in a vacuum desiccator. The product was then slurried in ether (150 mls), filtered and dried in vacuo overnight, to leave an off-white solid (4.46 g., 87% yield). Single spot by tlc (MeOH, Rf 0.66), LC-MS (retention 2.20 mins., mass 257 M+H). was added portionwise over 15 minutes The solid was filtered washed with water (100 mls) dried in a vacuum desiccator filtered dried in vacuo overnight to leave an off-white solid (4.46 g., 87% yield)

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

Procedure: To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcI MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H). to stir for 14 h while warming to room temperature The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution the organic layer was removed the aqueous layer was washed four times with EtOAc The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum Purification by silica gel chromatography

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

Procedure: A solution of 1-benzyl-3-carbomethoxy-4-piperidone (1.0 g, 4.0 mmol) in THF (10 mL) was treated with 0.5M potassium bis(trimethylsilyl)amide in toluene (9.6 mL, 4.8 mmol) for 15 min, followed by the addition of benzyl bromide (1.2 g, 4.8 mmol). After 2 h, the reaction mixture was quenched with sat. NH4Cl and extracted with ether. The combined organic layers were washed with brine, dried with MgSO4 and concentrated. The product was purified by silica gel chromatography eluting with 4:1 hexane-EtOAc to give 3-carbomethoxy-1,3-dibenzyl-4-piperidone (0.61 g) as a light yellow oil. the reaction mixture was quenched with sat. NH4Cl extracted with ether The combined organic layers were washed with brine dried with MgSO4 concentrated The product was purified by silica gel chromatography eluting with 4:1 hexane-EtOAc

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

Procedure: To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H). to stir for 14 h while warming to room temperature The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution the organic layer was removed the aqueous layer was washed four times with EtOAc The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum Purification by silica gel chromatography

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

Procedure: To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H). to stir for 14 h while warming to room temperature The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution the organic layer was removed the aqueous layer was washed four times with EtOAc The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum Purification by silica gel chromatography