| 73% |
iron; In pyridine; at 110 - 120℃; for 1.0h;Product distribution / selectivity; |
Example 40 (Synthesis of tetrahydropyran-4-carboxylic acid) In a flask made of glass equipped with a stirring device, a thermometer and a reflux condenser and having an inner volume of 50 ml were charged, under nitrogen atmosphere, 1.0 g (5.74 mmol) of <strong>[5337-04-2]tetrahydropyran-4,4-dicarboxylic acid</strong>, 32 mg (0.57 mmol) of iron and 3.0 ml of pyridine, and the mixture was reacted at 110 to 120C for 1 hour under stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, and 5 ml of water, 5 ml (60 mmol) of conc. hydrochloric acid and 10 ml of ethyl acetate were successively added in this order to the reaction mixture. The aqueous layer and the organic layer (the ethyl acetate layer) were separated, and the aqueous layer was washed three times with each 10 ml of ethyl acetate. Then, the organic layer and the ethyl acetate extracts were combined and concentrated under reduced pressure to give 548 mg (Isolation yield: 73%) of tetrahydropyran-4-carboxylic acid with purity of 100% (analytical value by differential refractometry) as white crystals. |
| 72% |
copper(I) oxide; In pyridine; at 110 - 120℃; for 1.0h;Product distribution / selectivity; |
Example 39 (Synthesis of tetrahydropyran-4-carboxylic acid) In a flask made of glass equipped with a stirring device, a thermometer and a reflux condenser and having an inner volume of 50 ml were charged 1.0 g (5.74 mmol) of <strong>[5337-04-2]tetrahydropyran-4,4-dicarboxylic acid</strong> with purity of 100%, 21 mg (0.14 mmol) of copper(I) oxide and 3.0 ml of pyridine under nitrogen atmosphere, and the mixture was reacted at 110 to 120C for 1 hour under stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 5 ml of water, 5 ml (60 mmol) of conc. hydrochloric acid and 10 ml of ethyl acetate were successively added in this order to the reaction mixture. The aqueous layer and the organic layer (the ethyl acetate layer) were separated, the aqueous layer was extracted three times with each 10 ml of ethyl acetate, then, the organic layer and the ethyl acetate extracts were combined and the mixture was concentrated under reduced pressure to give 534 mg (Isolation yield: 72%) of tetrahydropyran-4-carboxylic acid with purity of 100% (analytical value by differential refractometry) as white crystals. Physical properties of the tetrahydropyran-4-carboxylic acid are as follows. Melting point; 83 to 84C CI-MS (m/e); 131 (M+1) 1H-NMR (DMSO-d6, delta (ppm)); 1.45 to 1.60 (2H, m), 1.68 to 1.76 (2H, m), 2.40 to 2.52 (1H, m), 3.28 to 3.37 (2H, m), 3.77 to 3.83 (2H, m), 12.19 (1H, brs) Example 42 (Synthesis of tetrahydropyran-4-carboxylic acid) In a flask made of glass equipped with a stirring device, a thermometer and a dropping funnel and having an inner volume of 200 ml were charged, under nitrogen atmosphere, 115.6 ml of N,N-dimethylformamide and 13.51 g (0.25 mol) of sodium methoxide, an inner temperature was cooled to 5C, then 33.02 g (0.25 mol) of dimethyl malonate was gradually added dropwise thereto under stirring. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours to prepare a solution containing a sodium salt of dimethyl malonate. In a flask made of glass equipped with a stirring device, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 200 ml was charged 14.45 g (0.10 mol) of bis(2-chloroethyl)ether with purity of 99%, and after raising a temperature of the mixture to 80C, the above-mentioned solution containing the sodium salt of dimethyl malonate was gradually added dropwise thereto. After completion of the dropwise addition, the mixture was subjected to cyclization under nitrogen atmosphere at 85C for 20 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrated material was washed with 30 ml of N,N-dimethylformamide. The filtrate and the washed solution were combined, the temperature of the mixture was cooled to 5C, and 36.0 g (0.45 mol) of a 50% sodium hydroxide aqueous solution was gradually added dropwise thereto. After completion of the dropwise addition, 52 ml of water was added to the mixture, and the resulting mixture was subjected to hydrolysis at room temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to 5C, 44 ml (0.45 mol) of 35% hydrochloric acid was gradually added dropwise thereto. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and then, the reaction mixture was concentrated under reduced pressure. To the concentrate were added 200 ml of ethyl acetate and 100 ml of water and the resulting mixture was separated, then, the obtained organic layer was washed with 20 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. To the obtained concentrate was added 30 ml of methyl isobutyl ketone, and the mixture was filtered to give crystals of <strong>[5337-04-2]tetrahydropyran-4,4-dicarboxylic acid</strong>. In a flask made of glass equipped with a stirring device, a thermometer and a dropping funnel and having an inner volume of 50 ml were charged the above-mentioned <strong>[5337-04-2]tetrahydropyran-4,4-dicarboxylic acid</strong>, 17.6 ml of pyridine and 123.1 mg (0.86 mmol) of copper(I) oxide, and the mixture was subjected to decarboxylation under nitrogen atmosphere at 110 to 120C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, 30 ml of water, 30 ml (360 mmol) of conc. hydrochloric acid and 60 ml of ethyl acetate were successively added in this order, and the aqueous layer and the organic layer were separated. After the aqueous layer was washed three times with each 60 ml of ethyl acetate, these extracts and the organic layer were combined and concentrated under reduced pressure to give 3.15 (Isolation yield: 24.2%) of tetrahydropyran-4-carboxylic acid with purity of 100% (analytical value by differential refractometry) as white crystals. |
| 64% |
at 185℃; for 1.0h;Neat (no solvent); |
Tetrahydro-4H-pyran-4,4-dicarboxylic acid (1.01 g, 5.80 mmol) is stirred at 185C for one hour. The resulting residue is crystallized from toluene (5 mL) to give tetrahydro-2H-pyran-4-carboxylic acid (480.6 mg, 3.69 mmol, 64 %). 1H-NMR (DMSO-d6) delta: 1.48-1.58 (2H, m), 1.70-1.74 (2H, m), 2.42-2.48 (1H, m), 3.29-3.36.(2H,m), 3.78-3.83 (2H, m), 12.22 (1H; s). |
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