1-benzyl-3-ethylpiperidin-4-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Benzyl-3-ethyl-piperidin-4-one (33 g, 152.0 mmole) was added to the stirred suspension of sodium hydride (9.5 g, 200.0 mmole) in tetrahydrofuran (300 ml) at 32° C. and stirring was continued for 1 hr. Methyl iodide (30 ml, 490.0 mmole) in dry tetrahydrofuran (100 ml) was added it at 0-5° C. The resulting mixture stirred at room temperature for 4 hr, water (100 ml) and ethyl acetate (800 ml) were added respectively. Organic layer was separated, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3,5-dimethyl-3-ethylpiperidin-4-one. Yield 22.0 g (59%), C16H23NO, m/z 246 (M+1). The resulting mixture stirred at room temperature for 4 hr Organic layer was separated dried (Na2SO4) concentrated to give crude product, which was purified through column chromatography Elute from 10% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Benzyl-3-ethylpiperidin-4-one (2 g, 9.2 mmole) was added to the stirred suspension of potassium tert.-butoxide (1.5 g, 13.3 mmole) in tetrahydrofuran (25 ml) at 0° C. The reaction mixture was stirred for 15 min, methyl iodide (2 g, 14.1 mmole) was added over a period of 10 min at 0° C. and stirring continued for 1 hr. The resulting mixture was stirred for 16 hr at ambient temperature, water (25 ml) was added and extracted with ethyl acetate (100 ml). Ethyl acetate layer on concentrated furnished 1-benzyl-3-ethyl-3-methylpiperid-4-one as oil, which was used as such in the next step. Yield 1.5 g (71%), C15H2NO, m/z 232 (M+1). stirring continued for 1 hr The resulting mixture was stirred for 16 hr at ambient temperature extracted with ethyl acetate (100 ml) Ethyl acetate layer on concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium borohydride (0.456 g, 12.0 mmole) was added to the stirred solution of 1-benzyl-3-ethyl piperidin-4-one (5.4 g, 24.0 mmole) in methanol (25 ml) at 0-5° C. over a period of 15 min, and stirring was continued for 30 min at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (25 ml) and extracted with ethyl acetate (2×100 ml). The extract was dried (sodium sulphate) and concentrated to dryness to furnish 1-benzyl-3-ethyl-4-hydroxypiperidine product as oil, which was used as such in the next step. Yield 5.2 g (96%), C14H21NO, m/z 220 (M+1). The reaction mixture was concentrated to dryness triturated with water (25 ml) extracted with ethyl acetate (2×100 ml) The extract was dried (sodium sulphate) concentrated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl chloroformate (37.49 g, 346 mmol) was added to a stirred solution of 1-benzyl-3-ethyl-4-piperidone (24.0 g, 110 mmol) in benzene (200 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 16 hr and concentrated to dryness to give 1-carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96%), C10H17NO3, m/z 200 (M+1). The obtained reaction mixture was refluxed concentrated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl chloroformate (37.49 g, 346 mmol) was added to a stirred solution of 1-benzyl-3-ethyl-4-piperidone (24.0 g, 110 mmol) in benzene (200 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 16 hr and concentrated to dryness to give 1-carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96%), C10H17NO3, m/z 200 (M+1). The obtained reaction mixture was refluxed concentrated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl chloroformate (37.49 g, 346 mmol) was added to a stirred solution of 1-benzyl-3-ethyl-4-piperidone (24.0 g, 110 mmol) in benzene (200 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 16 hr and concentrated to dryness to give 1-carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96%), C10H17NO3, m/z 200 (M+1). The obtained reaction mixture was refluxed concentrated to dryness

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a −78° C. solution of 1-benzyl-piperidin-4-one (3.79 g, 20 mmol) in anhydrous THF (20 mL) was added lithium hexamethyldisilazide (21 mL, 21 mmol of a 1.0 M solution in THF). After being stirred at −78° C. for 30 min, a solution of iodoethane (1.7 mL, 21 mmol) in THF (5 mL) was added to the reaction mixture. The resultant solution was stirred at 25° C. for 2 h and quenched with water. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (hexane/EtOAc) to provide 0.51 g (11.5% yield) of 1-benzyl-3-ethyl-piperidin-4-one, which was converted into 1-benzyl-3-ethyl-piperidin-4-ylamine (3) using the same procedure as in Scheme 1-1. ((±)-cis:(±)-trans=1:1) LCMS m/z: 219 (M+H)+. This material was used without further purification. quenched with water The aqueous layer was extracted with CH2Cl2 washed with brine dried over MgSO4 The solution was filtered concentrated in vacuo to give the crude product The crude material was purified by flash column chromatography (hexane/EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Benzyl-3-ethyl-piperidin-4-one (33 g, 152.0 mmole) was added to the stirred suspension of sodium hydride (9.5 g, 200.0 mmole) in tetrahydrofuran (300 ml) at 32° C. and stirring was continued for 1 hr. Methyl iodide (30 ml, 490.0 mmole) in dry tetrahydrofuran (100 ml) was added it at 0-5° C. The resulting mixture stirred at room temperature for 4 hr, water (100 ml) and ethyl acetate (800 ml) were added respectively. Organic layer was separated, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3,5-dimethyl-3-ethylpiperidin-4-one. Yield 22.0 g (59%), C16H23NO, m/z 246 (M+1). The resulting mixture stirred at room temperature for 4 hr Organic layer was separated dried (Na2SO4) concentrated to give crude product, which was purified through column chromatography Elute from 10% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Benzyl-3-ethyl-piperidin-4-one (33 g, 152.0 mmole) was added to the stirred suspension of sodium hydride (9.5 g, 200.0 mmole) in tetrahydrofuran (300 ml) at 32° C. and stirring was continued for 1 hr. Methyl iodide (30 ml, 490.0 mmole) in dry tetrahydrofuran (100 ml) was added it at 0-5° C. The resulting mixture stirred at room temperature for 4 hr, water (100 ml) and ethyl acetate (800 ml) were added respectively. Organic layer was separated, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3,5-dimethyl-3-ethylpiperidin-4-one. Yield 22.0 g (59%), C16H23NO, m/z 246 (M+1). The resulting mixture stirred at room temperature for 4 hr Organic layer was separated dried (Na2SO4) concentrated to give crude product, which was purified through column chromatography Elute from 10% ethyl acetate in hexane