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Step 1: Ethyl 2-chloro-6-methylisonicotinate (97). To a stirred solution of 96 (7.0 g, 40.79 mmol) in ethanol (70 mL) was added conc H2SO4 (2 mL) at 0 C. dropwise followed by heating at 80 C. for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and washed with water, sodium bicarbonate solution and sat. NaCl. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford 97 (7 g, 86%) as a white solid.
a) A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 equivalent) in EtOH (200 ml.) and a few drops of concentrated sulfuric acid is stirred at 75C for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 ml.) and washed with a solution of sat. aq. NaHCO3 (70 ml.) and water (2x70 ml_). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR = 0.92 min, [M+1]+ = 200.17.
A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 eq.) in ethanol (200 mL) and a few drops of concentrated sulfuric acid is stirred at 75C for24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 mL) and washed with a solution of sat. aq. NaHCO3 (70 mL) and water (2x70 mL). <n="40"/>The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6- methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR = 0.92 min, [M+1]+ = 200.17; A solution of 2-chloro-6-methyl-isonicotinic acid (15.5 g, 90.3 mmol) in ethanol (200 mL) and H2SO4 (0.5 mL) is stirred at 75C for 24 h. The solvent is evaporated and the residue is dissolved in EA (200 mL). The solution is washed with sat. aq. NaHCO3-solution (70 mL) and water (70 mL), dried over MgSO4, filtered, concentrated and dried under HV to give 2-chloro-6-methyl-isonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR = 0.92 min; [M+1]+ = 200.17.
A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 equivalent) in EtOH (200 mL) and a few drops of concentrated sulfuric acid is stirred at 75 C. for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 mL) and washed with a solution of sat. aq. NaHCO3 (70 mL) and water (2×70 mL). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR=0.92 min, [M+1]+=200.17.
a) To a solution of 2-chloro-6-methylisonicotinic acid (50 g, 291.4 mmol) in ethanol (750 mL), a few drops of concentrated sulfuric acid are added and the mixture is stirred at 75 C. for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (300 mL) and washed with a solution of sat. aq. NaHCO3 (100 mL) followed with brine (2*70 mL). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (54.9 g) as a white solid after recrystallization from heptane; LC-MS: tR=0.92 min, [M+1]+=200.17.
a) Concentrated H2SO4 (1.16 mL, 21.6 mmol) is added dropwise to a suspension of 2-chloro-6-methylpyridine-4-carboxylic acid (11.58 g, 67.49 mmol) in ethanol (100 mL). The reaction mixture is then stirred at 70 C. for 24 h. Sat. NaHCO3 is added slowly to reach pH 8 and the aq. solution is extracted with EA three times. The org. extracts are collected, dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylpyridine-4-carboxylic acid ethyl ester (11.81 g) as an off white solid; LC-MS: tR=0.91 min, [M+H]+=199.93.
With sulfuric acid; In ethanol; at 75℃; for 24h;Product distribution / selectivity;
a) A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 eq.) in ethanol (200 mL) and a few drops of concentrated sulfuric acid is stirred at 75 C. for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 mL) and washed with a solution of sat. aq. NaHCO3 (70 mL) and water (2*70 mL). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR=0.92 min, [M+1]+=200.17.
To a solution of 2-chloro-6-methylisonicotinic acid (50 g, 291.4 mmol) in ethanol (750 ml_), a few drops of concentrated sulfuric acid are added and the mixture is stirred at 75C for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (300 ml.) and washed with a solution of sat. aq. NaHCO3 (100 ml.) followed with brine (2x70 ml_). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6- methylisonicotinic acid ethyl ester (54.9 g) as a white solid after recrystallization from heptane; LC-MS: tR = 0.92 min, [M+1]+ = 200.17.
The starting material was prepared as follows: A solution of 2-chloro-6-methyl-4-pyridinecarboxylic acid (2 g, 12 mmol) in ethanol (100 ml) and concentrated sulphuric acid (10 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methylene chloride. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (1/9) to give ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (2 g, 86%). 1 H NMR Spectrum: (CDCl3) 1.41(t, 3H); 2.6(s, 3H); 4.40(q, 2H); 7.63(s, 1H); 7.69(s, 1H) MS - ESI: 200 [MH]+ Elemental Analysis: Found C 54.4 H 5.3 N 7.0 C9 H10 NO2 Cl Requires C 54.1 H 5.0 N 7.0%
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