Synthesis
The general procedure for the synthesis of methyl 2-aminoisonicotinate from methanol and 2-aminoisonicotinic acid was as follows: 2-aminoisonicotinic acid (207 g, 1.5 mol) was dissolved in methanol (1.8 L) to prepare a solution. The solution was slowly added dropwise to thionyl chloride (238 g, 2 mol) at 50 °C. After the dropwise addition was completed, the reaction temperature was maintained at 50 °C and the reaction mixture continued to be stirred for 5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue, saturated aqueous sodium carbonate solution was added and the pH was adjusted to 9-10 to make the reaction mixture basic. Subsequently, the mixed solution was extracted with dichloromethane (300 ml each time for 3 times). The organic layers were combined and dried with anhydrous sodium sulfate. Finally, the solvent was removed by concentration to give methyl 2-aminoisonicotinate (189 g, 83% yield) as a yellow solid. The structure of the product was confirmed by 1H-NMR (d6-DMSO, 300 MHz): δ 3.96 (s, 3H); 7.14 (d, 1H); 7.49 (br, 1H); 8.07 (d, 1H); 8.18 (br, 2H, NH).
References
[1] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
[2] Journal of the American Chemical Society, 2018, vol. 140, # 9, p. 3322 - 3330
[3] Chemistry - A European Journal, 2012, vol. 18, # 27, p. 8498 - 8507
[4] Patent: EP3018125, 2016, A1. Location in patent: Paragraph 0515-0518
[5] Russian Journal of Organic Chemistry, 2015, vol. 51, # 5, p. 744 - 745
