1-benzyl-2-methylpiperidin-4-one

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

実験手順: 6.97 g of 4-methoxy-2-methylpyridine was dissolved in 200 ml of acetone and 13.5 g of benzyl bromide was added thereto. Then the resulting mixture was heated under reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The precipitate was taken up by filtration and the solid matter was dissolved in 60 ml of water. Next, 5.35 g of sodium borohydride was added thereto in portions. After stirring for 15 minutes, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. To the obtained residue was added 5 N hydrochloric acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was made basic by adding potassium carbonate, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 6.84 g of the title compound as a colorless oily substance. Then the resulting mixture was heated under reflux for 2 hours and 30 minutes The precipitate was taken up by filtration the solid matter was dissolved in 60 ml of water Next, 5.35 g of sodium borohydride was added the reaction mixture was concentrated under reduced pressure diluted with ethyl acetate washed successively with water a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure To the obtained residue was added 5 N hydrochloric acid the resulting mixture was stirred at room temperature overnight by adding potassium carbonate extracted with ethyl acetate washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (eluted with n-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 solution of the product of step B (3.8 g, 18.7 mmol) in acetic acid (20 mL) was added Pd/C 10% (380 mg) cautiously. The resulting mixture was hydrogenated at 50 psi H2 for 3 h. The reaction mixture was filtered through celite and washed with acetic acid (20 mL). The filtrate was concentrated in vacuo to yield 2-methylpiperidin-4-one acetate as a brown oil (2.98 g, >99%) which was sufficiently pure for the next step: 1H NMR (CD3OD, 400 MHz) δ 3.24-3.19 (m, 1H), 2.86-2.81 (m, 1H), 2.74-2.67 (m, 1H), 2.51-2.49 (m, 2H), 2.37-2.28 (m, 2H), 2.22-2.18 (m, 1H), 2.12-2.02 (m, 2H), 1.08 (d, J=6.4 Hz, 3H). The reaction mixture was filtered through celite washed with acetic acid (20 mL) The filtrate was concentrated in vacuo

反応条件: temp:16.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of benzylamine (5.2 mL, 47 mmol) in acetonitrile (30 mL) was added aqueous NaHCO3 solution (20 mL, 1.8 M, 36 mmol). After cooling to 16° C., the crude product obtained in step A (3.46 g, 32.9 mmol) dissolved in acetonitrile (30 mL) was added slowly over 40 minutes. After addition, the solution was heated to reflux for 1 h. The solvent was evaporated in vacuo to approximate 25 mL volume and ethyl acetate (60 mL) added. The resulting solution was stirred for 15 minutes. The organic layer was separated, washed with water (60 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 8:1 to 7:3 hexanes/ethyl acetate) to give 1-benzyl-2-methylpiperidin-4-one (3.9 g, 54%) as a brown oil: 1H NMR (CDCl3, 300 MHz) δ 7.39-7.26 (m, 5H), 3.96 (d, J=13.5 Hz, 1H), 3.45 (d, J=13.2 Hz, 1H), 3.03-2.95 (m, 2H), 2.56-2.51 (m, 2H), 2.39-2.31 (m, 2H), 2.28-2.24 (m, 1H), 1.17 (d, J=6.3 Hz, 3H). was added slowly over 40 minutes After addition the solution was heated to reflux for 1 h The solvent was evaporated in vacuo to approximate 25 mL volume and ethyl acetate (60 mL) added The organic layer was separated washed with water (60 mL) dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue purified by flash column chromatography (SiO2, 8:1 to 7:3 hexanes/ethyl acetate)

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

実験手順: 6.97 g of 4-methoxy-2-methylpyridine was dissolved in 200 ml of acetone and 13.5 g of benzyl bromide was added thereto. Then the resulting mixture was heated under reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The precipitate was taken up by filtration and the solid matter was dissolved in 60 ml of water. Next, 5.35 g of sodium borohydride was added thereto in portions. After stirring for 15 minutes, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. To the obtained residue was added 5 N hydrochloric acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was made basic by adding potassium carbonate, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 6.84 g of the title compound as a colorless oily substance. Then the resulting mixture was heated under reflux for 2 hours and 30 minutes The precipitate was taken up by filtration the solid matter was dissolved in 60 ml of water Next, 5.35 g of sodium borohydride was added the reaction mixture was concentrated under reduced pressure diluted with ethyl acetate washed successively with water a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure To the obtained residue was added 5 N hydrochloric acid the resulting mixture was stirred at room temperature overnight by adding potassium carbonate extracted with ethyl acetate washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate)