| 50% |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 8h; |
1 [EXAMPLES]
[EXAMPLES] Next, the present invention is explained more specifically by referring to Examples, but the scope of the present invention is not limited by these. Reference example 1 (Synthesis of 4-acetyl-4-methoxycarbonyltetrahydropyran) In a flask made of glass having an inner volume of 1000 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 143 g (1.0 mol) of 2,2'-dichloroethyl ether, 276 g (2.0 mol) of anhydrous potassium carbonate, 10 g (0.06 mol) of potassium iodide and 600 ml of N,N-dimethylformamide, and the temperature of the mixture was raised to up to 80°C with stirring. Then, 139 g (1.2 mol) of methyl 3-oxobutanoate was gently added dropwise to the mixture, and the mixture was reacted at the same temperature for 8 hours. After completion of the reaction, 1000 ml of water was added to the reaction mixture, and the resulting mixture was extracted three times with 600 ml of ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure (125 to 127°C, 1.3 kPa) to give 95 g (Isolation yield: 50%) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 98% (areal percentage by gas chromatography) as a pale yellow liquid. The physical properties of the 4-acetyl-4-methoxycarbonyltetrahydropyran were as follows. CI-MS (m/e); 187 (M+1) 1H-NMR (CDCl3, δ (ppm)); 1.95 to 2.01 (2H, m), 2.13 to 2.18 (5H, m), 3.55 to 3.61 (2H, m), 3.73 to 3.79 (5H, m) |
|
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; |
25
Add butanoic acid, 3-oxo-, methyl ester (18.60 mL, 172.20 mmol), bis(2- chloroethyl)ether (20.20 mL, 1.0 eq), potassium carbonate (52.42 g, 2.2 eq), and sodium iodide (25.88 g, 1.0 eq) in dimethylformamide (861 mL). Heat the reaction mixture at 80°C overnight. Cool to room temperature. Add additional potassium carbonate (23.78 g) and sodium iodide (25.88 g). Heat the reaction mixture at 80°C for two hours, then allow the mixture to cool to room temperature. Filter through Celite and wash with ethyl acetate. Wash the filtrate with water and brine. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give methyl 4-acetyltetrahydro-2H- pyran-4-carboxylate (23.06 g).Combine methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (23.06 g, 123.84 mmol) with isopropyl alcohol (124 mL) and water (124 mL). Add sulfuric acid (33.00 mL, 5.0 eq). Heat the reaction mixture to 100°C over two nights. Cool and add the reaction mixture slowly to a mixture of sodium bicarbonate (136 g) in water (1 L).Extract with dichloromethane. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 25% ethyl acetate in hexanes to 50% ethyl acetate in hexanes, to give the title compound (7.39 g, 34%). ¾ NMR (400 MHz, DMSO-d6) δ 3.79 (m, 2H), 3.27 (m, 2H), 2.54 (m, 1H), 2.05 (s, 3H), 1.66 (m, 2H), 1.38 (m, 2H). |
| 26.600 g |
Stage #1: acetoacetic acid methyl ester; 3-oxa-1,5-dichloropentane With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 18h;
Stage #2: With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 2h; |
Intermediate P20: 1 -(Tetrahydro-2H-pyran-4-yl)ethanone
The mixture of methyl acetylacetate (24.770 g, 211.18 mmol), bis(2-chloroethyl) ether (30.506 g, 211.18 mmol), potassium carbonate (64.861 g, 464.59 mmol) and sodium iodide (31.974 g, 211.18 mmol) in N,N-dimethylformamide (1065 ml) was heated at 80°C for 18 hours. The mixture was cooled to room temperature, further portions of potassium carbonate (29.430 g, 210.80 mmol) and sodium iodide (31.974 g, 211.18 mmol) were added and the whole was heated at 80°C for further 2 hours. The reaction mixture was filtered over celite, washed with ethyl acetate (500 ml), then organic layer was washed with water (300 ml), brine (150 ml) and dried over sodium sulphate. Drying agent and solvent were removed to obtain 26.600 g of the intermediate compound methyl 4-acetyl- tetrahydro-2H-pyran-4-carboxylate. To the obtained compound (26.600 g, 112.47 mmol) isopropanol (125 ml), water (125 ml) and concentrated sulphuric acid (55.151 g, 562.37 mmol) were added and the whole was heated at reflux for 48 hours. The mixture was alkalized with sodium hydroxide solution (45.5 g NaOH in 500 ml of water). Aqueous layer was extracted with chloroform (3 x 100 ml). Extracts were dried over sodium sulphate. Crude product obtained after removing drying agent and solvent in the form of a brown liquid was distilled under reduced pressure using Vigreux column and collecting fraction boiling at 75-83°C/20 mm Hg. 10.874 g of the title product were obtained (yield 36.4%) in the form of a colorless liquid. |
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