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Sulfuric acid (1 ml_) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 ml_). The clear solution is stirred at 700C for 18 h. The mixutre is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3x250 ml_). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give 2-chloro-6-methoxy- isonicotinic acid ethyl ester (4.32 g) as a white solid; LC-MS: tR = 1.00 min, [M+1]+ = 215.89.
a) Sulfuric acid (1 mL) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 70 C. for 18 h. The mixture is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3*250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> ethyl ester (4.32 g) as a white solid; LC-MS: tR=1.00 min, [M+1]+=215.89.
With sulfuric acid; at 70℃; for 18h;
a) Sulfuric acid (1 mL) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 70 C. for 18 h. The mixture is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3*250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> ethyl ester (4.32 g) as a white solid; LC-MS: tR=1.00 min, [M+1]+=215.89.
3.205 g
With thionyl chloride; In toluene; at 0 - 20℃; for 24h;
Step 1 : Ethyl 2-chloro-6-methoxyisonicotinate To a previously sonicated suspension of <strong>[15855-06-8]2-chloro-6-methoxyisonicotinic acid</strong> (4.0g, 21 mmol) in ethanol (50 ml.) was added thionyl chloride (4.64 ml_, 64.0 mmol) at 0C. The reaction mixture was stirred at 0C for 2 h and then at room temperature for 18h. Thionyl chloride (4.64 ml_, 64.0 mmol) was slowly added and the mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by slowly pouring into a saturated aqueous solution of sodium bicarbonate (200 ml_). Ice was added to the mixture to lower the temperature. The mixture was extracted with diethyl ether (150 ml_ x2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear syrup as crude product. The crude product was dried for 2 h under high vacuum while heating to 80C. The resulting residue was concentrated from toluene (500 ml.) to afford ethyl 2-chloro-6- methoxyisonicotinate as an off white solid (3.205 g). 1H NMR (400 MHz, CDCI3) delta 1.40 (s, 3H), 3.98 (s, 3H), 4.39 (s, 2H), 7.22 (s, 1 H), 7.44 (s, 1 H).
Sulfuric acid (1 mL) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 700C for 18 h. The mixutre is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3x250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> ethyl ester (4.32 g) as a white solid; LC-MS: tR = 1.00 min, [M+1]+ = 215.89.
With hydrogen; triethylamine;palladium 10% on activated carbon; In methanol; at 20℃; under 155.149 Torr;
To a suspension of the title compound of Preparation 22 (1.94 g, 6.49 mmol) in acetonitrile (150 mL), sodium iodide (4.90 g, 32.69 mmol) and trimethylsilyl chloride (4.10 mL, 32.42 mmol) were added. The resulting suspension was stirred under nitrogen atmosphere at 400C for 3 days. The mixture was cooled to O0C and the solid was filtered off, washed with acetonitrile and dried to yield 1.66 g (90%) of the title compound.LRMS: m/z 285(M+1 )+ Retention time: 2.86min (method B)
Freshly prepared sodium methoxide (from 1.5 g sodium in 15 mL dry methanol) was added dropwise to a solution of Example 16 (5.0 g, 26 mmol) in dry methanol (25 mL). The reaction mixture was refluxed for 24 h, allowed to cool to RT and poured in aqueous HCl (10%, 100 mL). A pinkish solid separated and was collected on a filter, washed with water and air-dried (4.0 g, 82%). IH NMR (400 MHz, DMSO-d6) 5 3.89 (s, 3H) 7.17 (s, 1H) 7.39 (s, 1H) 13.96 (br s, OH).
81%
In methanol; for 24h;Reflux;
200 mL of a25% solution of sodium methoxide in methanol was added on a solution of 10.3 g (53.6 mmol) of 2,6-dichloropyridine-4-carboxylic acid (1) in100 mL of methanol and refluxed for 24 h. The mixture was cooled toroom temperature, filtered off and evaporated. The solid was dissolvedin water, acidified with 2 N HCl and extracted with ethyl acetate. Theorganic phase was dried over anhydrous Na2SO4, filtered andevaporated, to obtain 8.1 g (43.2 mmol, 81%) of 2-chloro-6-methoxypyridine-4-carboxylic acid (2) as a brown amorphous solid.1H NMR (200 MHz, CD3OD): 3.87 (3H, s), 7.15 (1H, s), 7.36 (1H, s). 13CNMR (50 MHz, CD3OD): 54.5 (CH3), 109.4 (CH), 115.5 (CH), 144.3 (C),148.1 (C), 164.1 (C), 164.6 (C).
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