General procedure for the synthesis of ethyl 2-methyl-5-nitronicotinate from nitromalonaldehyde and ethyl 3-aminocrotonate: nitromalonaldehyde (416 g, 3.6 mol) and ethyl 3-aminocrotonate (339 g, 2.6 mol) were added to a solvent mixture consisting of ethanol (1.9 L), water (1.9 L) and glacial acetic acid (240 mL). The reaction mixture was stirred and reacted at 50 °C overnight. Upon completion of the reaction, the reaction solution was concentrated by distillation under reduced pressure. The concentrated residue was dissolved in dichloromethane (5.0 L) and filtered to remove insoluble matter. The filtrate was concentrated and purified by column chromatography (eluent ratio: ethyl acetate:petroleum ether = 1:10) to afford the target product ethyl 2-methyl-5-nitronicotinate (165 g, 30% yield) as a white solid. The product was characterized by 1H NMR (CDCl3, 300 MHz): δ= 1.23-1.26 (t, 3H), 2.25 (s, 3H), 4.14-4.21 (q, 2H), 8.91-8.92 (t, 1H), 9.37-9.38 (d, 1H).LC-MS analysis showed that the [M + 1]+ peak was located at 210.2.
