1-BENZYL-2-PIPERIDONE 98+%

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: To a suspension of sodium hydride (80%, 3.3 g, 0.11 mol) in dry toluene (250 ml) under argon, was added dropwise a solution of δ-valerolactam (9.9 g, 0.10 mol) in toluene (50 ml). When the addition was complete, the mixture was heated under reflux for 1 h, then cooled to ambient temperature. A solution of benzyl bromide (13 ml, 18.8 g, 0.11 mol) in toluene (50 ml) containing dimethyl formamide (1 ml) was then added dropwise over 15 minutes. The resulting mixture was heated under reflux for 4 h. On cooling, the mixture was filtered and the filtrate was dried (Na2SO4) and evaporated in vacuo to give an oil. Bulb-to-bulb distillation gave the title compound (D26) as a yellow oil (8.0 g). When the addition the mixture was heated under reflux for 1 h was then added dropwise over 15 minutes The resulting mixture was heated under reflux for 4 h On cooling the mixture was filtered the filtrate was dried (Na2SO4) evaporated in vacuo to give an oil Bulb-to-bulb distillation

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

Procedure: To a suspension of sodium hydride (80%, 3.3 g, 0.11 mol) in dry toluene (250 ml) under argon, was added dropwise a solution of δ-valerolactam (9.9 g, 0.10 mol) in toluene (50 ml). When the addition was complete, the mixture was heated under reflux for 1 h, then cooled to ambient temperature. A solution of benzyl bromide (13 ml, 18.8 g, 0.11 mol) in toluene (50 ml) containing dimethyl formamide (1 ml) was then added dropwise over 15 minutes. The resulting mixture was heated under reflux for 4 h. On cooling, the mixture was filtered and the filtrate was dried (Na2SO4) and evaporated in vacuo to give an oil. Bulb-to-bulb distillation gave the title compound (D26) as a yellow oil (8.0 g). When the addition the mixture was heated under reflux for 1 h was then added dropwise over 15 minutes The resulting mixture was heated under reflux for 4 h On cooling the mixture was filtered the filtrate was dried (Na2SO4) evaporated in vacuo to give an oil Bulb-to-bulb distillation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Phenylmethyl-2-piperidinone (See: Yamaguchi M, Hirao 1 (1985) "A direct synthesis of [(tert-butoxycarbonyl)methylidene]-azacycloalkanes from N-alkyllactams" J. Org. Chem., 50, 1975-1977) (3.40 g, 18 mmol) was reacted with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5 M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 7. After the addition of benzyl bromide, the reaction mixture was stirred for 2 h at -78° C., and then quenched with saturated NH4Cl (50 mL). The reaction mixture was extracted with ether (3×40 mL) and the combined ether extract washed with brine (40 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue (8.40 g) thus obtained, was chromatographed over silica gel (hexanes-CHCl3 -EtOAC, 15:4:1 and then 7:2:1) to give the product lactam (3.14 g, 63%) as a colorless solid: mp 94-95° C. (CH2Cl2 -hexanes). as described above in the preparation of Example 7 quenched with saturated NH4Cl (50 mL) The reaction mixture was extracted with ether (3×40 mL) the combined ether extract washed with brine (40 mL) dried over MgSO4 The solvent was removed in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Benzyl-4-hydroxy-4-(4-methylphenyl)piperidine may be prepared in the following manner: several drops of p-bromotoluene and a crystal of iodine are added to magnesium turnings (1.7 g) in diethyl ether (25 cc), under a current of argon. The mixture in heated to boiling, then a solution of p-bromotoluene (12.1 g) in diethyl ether (70 cc) is poured in in such a manner as to maintain the reflux. The reaction medium is stirred for 30 minutes at the boiling point of the solvent, then cooled to a temperature of about 20° C. A solution of 1-benzylpiperidone (6.7 g) in diethyl ether (60 cc) is added, and stirring is maintained for 15 hours at the same temperature. A saturated solution of ammonium chloride (150 cc) is added to the mixture; the aqueous phase is decanted and the organic phase is extracted with diethyl ether (2×150 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant. 1-Benzyl-4-hydroxy-4- ((4-methylphenyl)piperidone (5 g) is obtained in the form of an oil, which is used in the crude state in the subsequent syntheses. The mixture in heated to maintain the reflux stirring is maintained for 15 hours at the same temperature the aqueous phase is decanted the organic phase is extracted with diethyl ether (2×150 cc) dried over anhydrous magnesium sulphate filtered concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa) The residue obtained is purified by flash-chromatography on a silica column under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant

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

Procedure: To a solution of hydroxylamine hydrochloride (3.67 g, 52.8 mmol) in water (10 mL) and ethyl alcohol (80 mL) was added 1-benzyl piperidone (10.0 g, 52.8 mmol) at room temperature. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The resulting white solid was filtered, washed with ether and dried (8.4 g, 80%). It was added in small portions to a suspension of lithium aluminum hydride (2.3 g, 60.0 mmol) in diethyl ether (150 mL) at room temperature and the suspension was heated to reflux for 8 h. The reaction mixture was cooled to 0° C. and quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL). The white suspension was filtered and the filtrate was dried over MgSO4. The solvent was removed in vacuo after filtration. 4-Amino-1-benzyl-piperidine was obtained as a colorless oil (6.0 g). It was used in the next step without purification. The reaction mixture was heated to reflux for 4 h The resulting white solid was filtered washed with ether dried (8.4 g, 80%) the suspension was heated to reflux for 8 h The reaction mixture was cooled to 0° C. quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL) The white suspension was filtered the filtrate was dried over MgSO4 The solvent was removed in vacuo after filtration

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

Procedure: To a solution of hydroxylamine hydrochloride (3.67 g, 52.8 mmol) in water (10 mL) and ethyl alcohol (80 mL) was added 1-benzyl piperidone (10.0 g, 52.8 mmol) at room temperature. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The resulting white solid was filtered, washed with ether and dried (8.4 g, 80%). It was added in small portions to a suspension of lithium aluminum hydride (2.3 g, 60.0 mmol) in diethyl ether (150 mL) at room temperature and the suspension was heated to reflux for 8 h. The reaction mixture was cooled to 0° C. and quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL). The white suspension was filtered and the filtrate was dried over MgSO4. The solvent was removed in vacuo after filtration. 4-Amino-1-benzyl-piperidine was obtained as a colorless oil (6.0 g). It was used in the next step without purification. The reaction mixture was heated to reflux for 4 h The resulting white solid was filtered washed with ether dried (8.4 g, 80%) the suspension was heated to reflux for 8 h The reaction mixture was cooled to 0° C. quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL) The white suspension was filtered the filtrate was dried over MgSO4 The solvent was removed in vacuo after filtration

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

Procedure: A solution containing N-benzyl piperidone 1 (5 g, 26.4 mmol) and pyrrolidine 2 (2.82 g, 39.6 mmol) in toluene (60 mL) was heated to reflux with azeotropic removal of water. The reaction mixture was then cooled and concentrated under reduced pressure. The resulting oil was dissolved in ether, dried over magnesium sulfate, and concentrated under reduced pressure. The crude enamine 3 was used in the next step. was heated The reaction mixture was then cooled concentrated under reduced pressure The resulting oil was dissolved in ether dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: 30 mL (0.162 Mol) 1-benzylpiperidone (L) and 16.1 mL (0.185 Mol) morpholine (M) are dissolved in 407 mL tetrahydrofuran at ambient temperature. While cooling, 1.0 g (5 mmol) of p-toluenesulphonic acid and 14.6 mL glacial acetic acid are added, whereupon a jelly-like precipitate is formed. 52.19 g (0.246 Mol) sodium triacetoxyborohydride are added while cooling with ice, during which time the reaction temperature rises to 30° C. After 4 hours at 20° C., 90 mL water are added dropwise. After another 30 minutes, 280 mL of 17% potassium carbonate solution are added. The mixture is stirred intensively, while gas is observed to be given off. After separation of the phases the organic phase is dried and evaporated down. While cooling is formed while cooling with ice, during which time the reaction temperature rises to 30° C After another 30 minutes After separation of the phases the organic phase is dried evaporated down

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

Procedure: To a stirred solution of 2-bromopyridine (10 mmol) in THF (120 mL) at −78° C. under argon, 2.5 M n-butyl lithium solution in hexane (4.5 mL, 11.25 mmol) was injected over 5 min. After 25 min, 1-benzylpiperidone (10 mmol) was added neat. After 30 min, the mixture was quenched by addition of aqueous NH4Cl solution (50 mL). The mixture diluted with ethyl acetate (200 mL), washed with brine (150 mL), dried (Na2SO4). Solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc/Hexane from 20% to 60%) to give the desired product(1.78 g, 66.41% ). 1H-NMR was consistent with the structure. After 30 min the mixture was quenched by addition of aqueous NH4Cl solution (50 mL) The mixture diluted with ethyl acetate (200 mL) washed with brine (150 mL) dried (Na2SO4) Solvent was evaporated the residue was purified by column chromatography (silica gel, EtOAc/Hexane from 20% to 60%)

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

Procedure: To a stirred solution of 2-bromopyridine (10 mmol) in THF (120 mL) at −78° C. under argon, 2.5 M n-butyl lithium solution in hexane (4.5 mL, 11.25 mmol) was injected over 5 min. After 25 min, 1-benzylpiperidone (10 mmol) was added neat. After 30 min, the mixture was quenched by addition of aqueous NH4Cl solution (50 mL). The mixture diluted with ethyl acetate (200 mL), washed with brine (150 mL), dried (Na2SO4). Solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc/Hexane from 20% to 60%) to give the desired product(1.78 g, 66.41% ). 1H-NMR was consistent with the structure. After 30 min the mixture was quenched by addition of aqueous NH4Cl solution (50 mL) The mixture diluted with ethyl acetate (200 mL) washed with brine (150 mL) dried (Na2SO4) Solvent was evaporated the residue was purified by column chromatography (silica gel, EtOAc/Hexane from 20% to 60%)