Carbon Dioxide → Methyl 2-aminopyridine-4-carboxylate

Participants

Reaction Conditions

Reaction Steps

A mixture of acetic anhydride (16.8 g, 0.164 mol), triethylamine (33.1 g, 0.327 mol) and acetonitrile (107.4 g, 2.61 mol) was heated to 45° C. before adding 2,4-pyridinedicarboxylic acid N-oxide (22.0 g, 0.12 mol) as a single portion. Once the evolution of carbon dioxide had subsided the resulting dark mixture was left to stir for 1 hour at 45° C. The solvent was evaporated, the residue dissolved in 10% potassium hydroxide solution (200 ml) and then heated at reflux for 16 h. The mixture was cooled to 0° C., neutralised with concentrated hydrochloric acid and the aqueous slurry evaporated to dryness. The residue was suspended in methanol (200 ml), hydrogen chloride gas was bubbled through this suspension for 5 minutes and the mixture was then heated at reflux for 16 h. The reaction was cooled, the solids removed by filtration and the filtrate concentrated to give a black oil. The residue was mixed with water (600 ml) and carefully made basic with solid sodium hydrogencarbonate. The aqueous was extracted with ethyl acetate (2×500 ml), the organics combined, washed with brine, dried over sodium sulphate containing 3 g decolourising charcoal, filtered and evaporated to give 2-aminopyridin-4-ylcarboxylic acid methyl ester (13.0 g) as a tan powder contaminated with ca. 20% 2-hydroxypyridin-4-ylcarboxylic acid methyl ester. Used without further purification. A small sample was purified by silica gel chromatography eluting with dichloromethane/methanol/conc. ammonia (95:4.5:0.5) giving the aminopyridine as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δH 2.50 (3H, s), 8.49 (1H, dd, J 3 and 7), 8.65 (1H, d, J 3), 8.80 (1H, d, J 7).

Provenance & Evidence