1-(恶烷-4-基)乙酮

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask was charged with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (11.7 g, 67.5 mmol) and THF (350 mL). The resulting mixture was immersed in a cooling bath at −60° C., and methylmagnesium bromide (3.0 M in ether, 33.8 mL, 101.4 mmol) was added via syringe over ˜8 min. The temperature of the bath was allowed to rise to 0° C. over 6 h. At that time, the reaction was diluted with water and EtOAc and stirred vigorously for 10 min. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120 g silica, 80 mL/min, 0% to 100% EtOAc/hexanes) to give 4-acetyltetrahydro-4H-pyran 3 (7.05 g, 55.0 mmol, 81%). 1H NMR (400 MHz, CDCl3) for 3: δ 3.95 (ddd, J=11.6, 4.4, 2.8 Hz, 2 H), 3.38 (dt, Jd=2.8 Hz, Jt=11.6 Hz, 2 H), 2.50 (m, 1 H), 2.12 (s, 3 H), 1.75 (m, 2 H), 1.65 (m, 2 H). LCMS for 3 (conditions D): tR=0.83 min, m/e=129.4 (M+H, base). The resulting mixture was immersed in a cooling bath at −60° C. The phases were separated the aqueous layer was extracted with EtOAc washed with brine dried over MgSO4 filtered concentrated

反应条件: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (130 mg, 0.4 mmol), 1-(tetrahydro-2H-pyran-4-yl)ethanone (52 mg, 0.4 mmol) and AcOH (0.1 mL) in MeOH (10 mL). The mixture was stirred at 22° C. for 1 h, then NaBH3CN (76 mg, 1.2 mmol) was added. The mixture was stirred at 22° C. for 4 h. The reaction mixture was concentrated and quenched with water. The mixture solution was extracted with DCM, the combined organic layers were concentrated and the residue was purified by prep-TLC to give the desired compound (14.0 mg, Yield 8%). 1H NMR (CD3OD, 400 MHz): δ 6.90-7.07 (m, 6H), 6.81 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.03 Hz, 1H), 3.98-4.04 (m, 1H), 3.87 (d, J=11.3 Hz, 2H), 3.70 (s, 2H), 3.28-3.45 (m, 5H), 2.82 (brs, 4H), 2.56-2.65 (m, 2H), 1.70 (d, J=13.8 Hz, 1H), 1.57 (brs, 1H), 1.17-1.37 (m, 3H), 1.04 (d, J=6.3 Hz, 3H). LCMS (m/z): 438.3 (M+1). The mixture was stirred at 22° C. for 4 h The reaction mixture was concentrated quenched with water The mixture solution was extracted with DCM the combined organic layers were concentrated the residue was purified by prep-TLC

反应条件: temp:7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a flask made of glass having an inner volume of 500 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 35.0 g (273 mmol) of 4-acetyltetrahydropyran synthesized in the same manner as in Reference example 2, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., and to the reaction mixture were added 175 ml of toluene, 55 ml (330 mmol) of 6 mol/l hydrochloric acid and 35 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 70 ml of toluene. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Fluent; hexane/ethyl acetate=1/1 (volume ratio)) to give 40.9 g (Isolation yield: 76%) of methyl 3-(4-tetrahydropyranyl)-3-oxopropanoate with a purity of 93.9% (analytical value by differential diffractometry) as a colorless liquid. In a flask made of glass equipped with a stirring device the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off After completion of the reaction After the organic layer was separated the aqueous layer was extracted twice with 70 ml of toluene The organic layer was concentrated under reduced pressure the concentrate was purified by silica gel column chromatography (Fluent; hexane/ethyl acetate=1/1 (volume ratio))

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 202 g (1.0 mol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 95% and synthesized in the same manner as in Reference example 1 and 720 ml of methanol, and the temperature of the mixture was raised to 35° C. with stirring. Then, to the mixture was gently added dropwise a mixed solution comprising 201 g (2.0 mol) of 35% by weight aqueous hydrogen peroxide solution and 91 ml (0.73 mol) of 8 mol/l aqueous sodium hydroxide solution, and the mixture was reacted at 40° C. for 5 hours with stirring. After completion of the reaction, to the resulting reaction mixture was added a saturated aqueous sodium sulfate solution to decompose the remaining hydrogen peroxide, then, the mixture was concentrated under reduced pressure, and the concentrate was extracted three times with 500 ml of ethyl acetate. The organic layer was distilled under reduced pressure (90 to 92° C., 2.0 kPa) to give 113 g (Isolation yield: 85%) of 4-acetyltetrahydropyran with a purity of 99% (areal percentage by gas chromatography) as a colorless liquid. In a flask made of glass equipped with a stirring device the mixture was reacted at 40° C. for 5 hours with stirring After completion of the reaction to the resulting reaction mixture the mixture was concentrated under reduced pressure the concentrate was extracted three times with 500 ml of ethyl acetate The organic layer was distilled under reduced pressure (90 to 92° C., 2.0 kPa)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesized in the same manner as in Reference example 1 and 1.70 g (10 mmol) of 47% hydrobromic acid, and the mixture was reacted at 120° C. for 1 hour with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.17 g (Reaction yield: 65%) of 4-acetyltetrahydropyran was found to be formed. In a flask made of glass equipped with a stirring device the mixture was reacted at 120° C. for 1 hour After completion of the reaction, when the reaction mixture

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a flask made of glass having an inner volume of and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesized in the same manner as in Reference example 1 and 2.52 ml (10 mmol) of 4 mol/l hydrochloric acid, and the mixture was reacted at 120° C. for 4 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.23 g (Reaction yield: 90%) of 4-acetyltetrahydropyran was found to be formed. In a flask made of glass equipped with a stirring device the mixture was reacted at 120° C. for 4 hours After completion of the reaction, when the reaction mixture

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesized in the same manner as in Reference example 1 and 1.08 ml (10 mmol) of 9 mol/l sulfuric acid, and the mixture was reacted at 120° C. for 1.5 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.25 g (Reaction yield: 96%) of 4-acetyltetrahydropyran was found to be formed. In a flask made of glass equipped with a stirring device the mixture was reacted at 120° C. for 1.5 hours After completion of the reaction, when the reaction mixture