Methyl 2-chloro-6-methylpyridine-4-carboxylate

Uses

Methyl 2-Chloro-6-methylisonicotinate is used in the synthesis of pyridine derivatives as antitubercular agents

Synthesis

General procedure: 2-chloro-6-methylpyridine-4-carboxylic acid (2.37 g, 15.5 mmol) was added to a stirred solution of phosphorus oxychloride (POCl3, 10 mL, 107 mmol) and heated to reflux for 18 hours. Upon completion of the reaction, excess POCl3 was removed by distillation under reduced pressure and the residue was cooled to -5°C. Methanol (20 mL) was slowly added dropwise and stirred for 24 h at room temperature. Subsequently, methanol was removed by complete distillation and the reaction mixture was neutralized with solid sodium bicarbonate (NaHCO3) and partitioned between water (30 mL) and ethyl acetate (EtOAc, 30 mL). The aqueous layer was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by rapid chromatography on silica gel (eluent: dichloromethane, CH2Cl2) to afford methyl 2-chloro-6-methyl-isonicotinate (2 g, 10.8 mmol, 69% yield) as a white solid. Thin layer chromatography (TLC, silica gel plate, dichloromethane as unfolding agent) Rf value was 0.66. Nuclear magnetic resonance hydrogen spectrum (1H NMR, 300 MHz, CDCl3) δ 2.59 (s, 3H), 3.94 (s, 3H), 7.61 (s, 1H), 7.67 (s, 1H); nuclear magnetic resonance carbon spectrum (13C NMR, 75 MHz, CDCl3) δ 24.2, 52.9, 120.8, 121.2, 140.3, 151.4, 160.5, 164.6; mass spectrum (MS, EI, 70 eV): m/z (relative abundance) [M+H]+ 186 (100).

References

[1] Tetrahedron Letters, 2007, vol. 48, # 6, p. 999 - 1002
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4629 - 4635
[3] Chemistry - A European Journal, 2015, vol. 21, # 33, p. 11745 - 11756