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Phosphorus oxychloride (2 mL) was slowly added to a stirred 3-Methylisonicotinamide (25, 300 mg, 2.2 mmol). The resulting solutionwas heated to reflux for 24 h, then reaction mixture was cooled to roomtemperature, and the excess phosphorus oxychloride was removedunder reduced pressure. Crushed ice was slowly added to the oily residue,and the solution was neutralized with saturated aqueous sodiumcarbonate solution. The crude product was extracted with EtOAc(3×25 mL), and combined organic extracts were washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. Resulting residue was purified by flash columnchromatography on silica gel (EtOAc/Petroleum ether 1:4) to yield thewhite solid (65%). 1H NMR (400 MHz, CDCl3) delta 8.67 (s, 1H), 8.59 (d,J=5.0 Hz, 1H), 7.46 (d, J=5.0 Hz, 1H), 2.54 (s, 3H).
12 g
With trichlorophosphate; for 24h;Reflux;
3-Methyl-4-cyanopyridine (123) Phosphorus oxychloride (100 mL, 1.1 mol) was slowly added to the crude amide 122 (15 g, 0.11 mol) while cooling the mixture in an ice bath. The resulting solution was heated at reflux for 24 h. The reaction mixture was cooled to room temperature and the excess phosphorus oxychloride was removed under reduced pressure. Crushed ice (150 g) was slowly added to the oily residue, and the solution was neutralized with saturated ammonium hydroxide. The crude product was extracted with chloroform (3*100 mL). The combined extracts were filtered through a layer of silica gel, washing with extra portions of chloroform. The filtrates were evaporated to dryness to yield 123 as colorless crystals (12 g, 90%): mp 45-47 C. (lit. (J. Med. Chem. 2000, 43, 3168-3185) mp 50 C.). 1H NMR (300 MHz, CDCl3) delta 8.66 (s, 1H), 8.59 (d, J=5.0 Hz, 1H), 7.45 (d, J=5.0 Hz, 1H), 2.54 (s, 3H).
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