tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate

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: To a solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (Wityak J., et al., J. Med. Chem., 40, p. 50 (1997): 27.6 g) in diethyl ether was added dibromobarbituric acid (17.0 g), and the mixture was mixed for 12 hours. The insolubles were filtered off, and the filtrate was diluted with diethyl ether, sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (31.8 g) as a pale yellow viscous oily matter. the mixture was mixed for 12 hours The insolubles were filtered off the filtrate was diluted with diethyl ether sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine dried over anhydrous sodium sulfate The solvent was distilled off

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of N-(6-fluoro-2-pyridinyl)-2,2-dimethylpropanamide (Turner, James A., J. Org. Chem., 1983, 48, 3401–3408, 1.15 g, 5.87 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of n-butyllitium (8.1 ml, 12.9 mmol) at −78° C. over 10 min., and the mixture was stirred at 0° C. for 1 h. After cooling to −78° C., a solution of 1,1-dimethylethyl 4-(3-oxopropyl)-1-piperidinecarboxylate (Keenan, Richard M. et. al, J. Med. Chem., 1999, 42, 545–559, 1.70 g, 7.04 mmol) in tetrahydrofuran (5 ml) was added to the mixture. After stirring for 0.5 h, the mixture was allowed to warm up to room temperature and stirred for further 2 h. The mixture was quenched with water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 0.86 g (34%) of the title compound as a pale yellow amorphous solid. After cooling to −78° C. After stirring for 0.5 h to warm up to room temperature stirred for further 2 h The mixture was quenched with water (20 ml) extracted with ethyl acetate (100 ml) The organic layer was washed with brine (50 ml) dried over magnesium sulfate Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of N-(6-fluoro-2-pyridinyl)-2,2-dimethylpropanamide (Turner, James A., J. Org. Chem., 1983, 48, 3401–3408, 1.15 g, 5.87 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of n-butyllitium (8.1 ml, 12.9 mmol) at −78° C. over 10 min., and the mixture was stirred at 0° C. for 1 h. After cooling to −78° C., a solution of 1,1-dimethylethyl 4-(3-oxopropyl)-1-piperidinecarboxylate (Keenan, Richard M. et. al, J. Med. Chem., 1999, 42, 545–559, 1.70 g, 7.04 mmol) in tetrahydrofuran (5 ml) was added to the mixture. After stirring for 0.5 h, the mixture was allowed to warm up to room temperature and stirred for further 2 h. The mixture was quenched with water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 0.86 g (34%) of the title compound as a pale yellow amorphous solid. After cooling to −78° C. After stirring for 0.5 h to warm up to room temperature stirred for further 2 h The mixture was quenched with water (20 ml) extracted with ethyl acetate (100 ml) The organic layer was washed with brine (50 ml) dried over magnesium sulfate Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1)

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

実験手順: To a stirred solution of oxalyl chloride (2 mL, 22 mmol) in dry dichloromethane (50 mL) at −78° C. under argon, was added dropwise a solution of dimethylsulfoxide (3.4 mL, 44 mmol) in dichloromethane (10 mL). After 2 min, a solution of 3-[N-(t-butoxycarbonyl)piperidin-4-yl]propanol (4.86 g, 20 mmol) in dichloromethane (10 mL) was added dropwise over 5 min. After stirring an additional 15 min at −78° C., triethylamine (14 mL) was added dropwise. After 5 min, the reaction became a thick white slurry and was allowed to warm to RT and stirred for 16 h. The reaction mixture was washed with cold 1N hydrochloric acid and with brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate/hexane) to yield the title compound (4.18 g, 87%). TLC Rf 0.40 (30% ethyl acetate/hexane); 1H NMR (CDCl3) δ0.95-1.80 (7H, m), 1.48 (9H, s), 2.40-2.90 (4H, m), 4.14 (2H, br dt), 9.88 (1H, t). After 5 min to warm to RT stirred for 16 h The reaction mixture was washed with cold 1N hydrochloric acid and with brine dried (magnesium sulfate) concentrated The residue was purified by flash chromatography (silica gel, 30% ethyl acetate/hexane)

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

実験手順: A solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (0.874 g, 3.62 mmol) in methanol (15 mL) was added with potassium carbonate (1.00 g, 7.24 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with dimethyl (1-diazo-2-oxopropyl)phosphonate (0.692 g, 3.62 mmol), and the mixture was stirred at room temperature for additional 3 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(but-3-ynyl)piperidine-1-carboxylate (0.670 g, 78%). the mixture was stirred at room temperature for additional 3 hours The reaction mixture was concentrated added with water the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

実験手順: A solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (1.00 g, 4.11 mmol) in methylene chloride (20 mL) was cooled to 0° C., and added with the Dess-Martin reagent (2.27 g, 5.34 mmol), and then the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate, and then further washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (0.874 g, 88%). The reaction mixture was filtered the filtrate was washed with saturated aqueous sodium hydrogencarbonate further washed with saturated brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

実験手順: To a suspension of PCC (11.52 g, 53.44 mmol) and sodium acetate (4.38 g, 53.4 mmol) in DCM (60 mL) was added a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanol (10.00 g, 41.09 mmol) in DCM (20 mL). After 4 hours at room temperature, the mixture was diluted with ether and passed though a short column of fluorisil® using ether as an eluent. The eluate was concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 8.32 g (84%) of the desired aldehyde as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 9.76 (t, J=1.5 Hz, 1H), 4.05 (bs, 2H), 2.64 (bt, J=11.7 Hz, 2H), 2.45 (dt, J=7.3, 1.5 Hz, 2H), 1.60 (m, 3H), 1.43 (s, 9H, overlapped with m, 2H), 1.08 (dq, J=12.1, 4.0 Hz, 2H). The eluate was concentrated in vacuo

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

実験手順: To a solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (Wityak J., et al., J. Med. Chem., 40, p. 50 (1997): 27.6 g) in diethyl ether was added dibromobarbituric acid (17.0 g), and the mixture was mixed for 12 hours. The insolubles were filtered off, and the filtrate was diluted with diethyl ether, sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (31.8 g) as a pale yellow viscous oily matter. the mixture was mixed for 12 hours The insolubles were filtered off the filtrate was diluted with diethyl ether sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine dried over anhydrous sodium sulfate The solvent was distilled off

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of N-(6-fluoro-2-pyridinyl)-2,2-dimethylpropanamide (Turner, James A., J. Org. Chem., 1983, 48, 3401–3408, 1.15 g, 5.87 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of n-butyllitium (8.1 ml, 12.9 mmol) at −78° C. over 10 min., and the mixture was stirred at 0° C. for 1 h. After cooling to −78° C., a solution of 1,1-dimethylethyl 4-(3-oxopropyl)-1-piperidinecarboxylate (Keenan, Richard M. et. al, J. Med. Chem., 1999, 42, 545–559, 1.70 g, 7.04 mmol) in tetrahydrofuran (5 ml) was added to the mixture. After stirring for 0.5 h, the mixture was allowed to warm up to room temperature and stirred for further 2 h. The mixture was quenched with water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 0.86 g (34%) of the title compound as a pale yellow amorphous solid. After cooling to −78° C. After stirring for 0.5 h to warm up to room temperature stirred for further 2 h The mixture was quenched with water (20 ml) extracted with ethyl acetate (100 ml) The organic layer was washed with brine (50 ml) dried over magnesium sulfate Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1)