| 73% |
With sulfuric acid; In toluene; at 95℃; for 72.0h;Heating / reflux; |
To 3-hydroxypyridine-2-carboxylic acid (25 g, 179.5 mmol) in a 1 L dried flask was added 400 mL ethanol and 100 mL toluene followed by the addition of 10 mL sulfuric acid. The mixture was heated at reflux (95 C.) for 3 days. After cooling to rt, the mixture was concentrated to ¼ of its volume, and diluted with 600 mL ethyl acetate and 200 mL water. The aqueous layer was extracted with 200 mL ethyl acetate, and the combined organic layers were washed with sat NaHCO3 (3×200 mL), brine, and dried over Na2SO4. The solid was filtered off and the solvent was concentrated under reduced pressure to give 21.9 g of ethyl 3-hydroxypyridine-2-carboxylate (73%), which was used in the next step without purification. This ester (21.9 g, 131 mmol) was dissolved in pyridine and cooled to -40 C., followed by addition of trifluoromethanesulfonic anhydride (48 g, 170 mmol). The reaction mixture was then warmed to 0 C. for 30 min, and then warmed to rt for another 30 min. Water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×200 mL), and the combined organic layers were washed with sat sodium bicarbonate (200 mL), water (200 mL), brine (200 mL), and dried over sodium sulfate. The solid was filtered off, and the solvent was removed under reduced pressure to give 39 g (99%) of desired product, which was used in the next step without further purification. 1H NMR (300 MHz, CD2Cl2) delta 8.73 (dd, 1H), 7.72 (dd, 1H), 7.62 (dd, 1H), 4.46 (q, 2H), 1.42 (t, 3H). |
| 70% |
With sulfuric acid; In toluene; at 78℃; for 60.0h;Dean-Stark; |
A solution of 3-hydroxypicolinic acid (2.50 g, 18.0 mmol) in EtCH (60 mL) and toluene (20 mL) was treated with conc. H2S04 (1 mL) and stirred under reflux for 60 h withazeotropic removal of water via Dean-Stark trap. The solvent was evaporated, the residue was dissolved in water (50 mL) and carefully basified with a sat. NaHCO3 solution, upon which a white precipitate appeared. The mixture was diluted with EtOAc (30 mL) and the aqueous layer was extracted three times with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Mg504, filtered and evaporated to giveethyl 3-hydroxypicolinate (2.10 g, 70%) as a colorless liquid.1H NMR (400 MHz, Chloroform-o) 6 = 10.78 (s, 1H, OH), 8.30 (dd, J= 4.2, 1.5 Hz, 1H,H-Ar), 7.47 - 7.34 (m, 2H, H-Ar), 4.54 (q, J= 7.1 Hz, 2H, O-CH2CH3), 1.49 (t, J= 7.1Hz, 3H, O-CH2CH3) ppm.MS (ESl+, H20/MeCN) mlz(%): 168.0 (100, [M + H]j. |
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3-Hydroxy-picolinic acid (15.6 g, 42.1 mmol), ethanol (360 mL), benzene (100 mL) and 98% sulfuric acid (6 mL) were heated under reflux for 40 h. After evaporation of the ethanol and benzene, the residue was dissolved in water, neutralized with sodium bicarbonate, and extracted with chloroform. The organic layer was dried (MgS04), filtered, and then the solvent was evaporated to give ethyl 3-hydroxy-picolinate as a brown oily residue (11.0 g).A mixture of ethyl 3-hydroxy-picolinate (11.0 g, 65.8 mmol), ethyl bromoacetate (12.1 g, 72.4 mmol) and anhydrous potassium carbonate (11.8 g, 85.5 mmol) in acetone (120 mL) was heated under reflux for 15 h. After cooling, the inorganic material separated by filtration. The filtrate was dissolved in chloroform, washed with water, then brine and dried (MgSO4), filtered, and the solvent was evaporated to give a brown oily residue. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give ethyl 2- (2-ethoxycarbonyl-3-pyridyloxy) acetate (13.7 g) as a yellow oil (13.7 g). Ethyl 2- (2-ethoxycarbonyl-3-pyridyloxy) acetate (13.6 g, 54.0 mmol) and sodium ethoxide (8. 08 g, 118.8 mmol) in toluene (200 mL) were heated under reflux for 18 h. After cooling, a precipitate was collected by filtration, dissolved in the minimum amount of hot water (about 300 mL), and acidified with acetic acid (6 mL). The resulting precipitate was filtered, and dried in vacuo to give ethyl 3-hydroxyfuro [3,2-b] pyridine-2-carboxylate as a solid (7.0 g). Ethyl 3-hydroxyfuro [3,2-b] pyridine-2-carboxylate (6.90 g, 25.8 mmol) was dissolved in 10% hydrochloric acid (50 mL), and heated under reflux for 3 h. Evaporation of the hydrochloric acid solution gave furo [3,2-b] pyridin-3 (2H)-one hydrochloride (9.0 g). A portion of the furo [3,2-b] pyridin-3 (2H) -one hydrochloride was converted to its free base by treatment with saturated sodium bicarbonate and extraction with chloroform in preparation for the following step. N, N-Diisopropylethylamine (1.08 g, 8.34 mmol) was added slowly to a solution of furo [3,2-b] pyridin-3 (2H) -one (1.40 g, 7.25 mmol) in dry dichloromethane (60 mL) under nitrogen at-10°r; C. Then trifluromethanesulfonic anhydride (2.45 g, 8.70 mmol) was added slowly. The mixture was warmed to RT, and stirred overnight. The reaction was quenched with water. The organic layer was washed with water and brine, dried (MgS04), and then the solvent was evaporated to give a brown oily residue, which was purified by flash chromatography using chloroform to give the sub-title compound (980 mg) as a light-brown oil. |
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