The general procedure for the synthesis of 3-(2-fluoro-4-iodophenylamino)-4-carboxylic acid pyridine from 3-fluoroisonicotinic acid is as follows:
Intermediate 1: Synthesis of 3-(2-fluoro-4-iodophenylamino)-isonicotinic acid:
4-Iodo-2-fluoroaniline (20.0 g, 84.38 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL) under inert atmosphere and cooled to -65 °C. Subsequently, 1.0 M bis(trimethylsilyl)aminolithium tetrahydrofuran solution (255 mL, 255 mmol) was slowly added, keeping the reaction temperature below -55 °C. After addition, the reaction mixture was stirred for 30 min, then 3-fluoroisonicotinic acid (8.0 g, 56.69 mmol) was added. The reaction mixture was stirred at room temperature for 4 days. After the reaction was completed, the mixture was poured into 2.0 N aqueous sodium hydroxide solution (1000 mL) and ethyl acetate (250 mL). The organic and aqueous layers were separated and the aqueous layer was further extracted from the organic phase with aqueous sodium hydroxide solution (2 x 1000 mL). The aqueous phase was combined and the pH was adjusted to 2 with concentrated hydrochloric acid to precipitate the target product. The solid was collected by filtration, washed with water (300 mL) and dried under high vacuum at 40 °C for 18 h to afford the yellow solid product 3-(2-fluoro-4-iodophenylamino)-isonicotinic acid (19.05 g, 53.19 mmol, 94% yield).
Mass spectrum (MS): [M+1] 359.
1H NMR (400 MHz, DMSO-D6): δ 7.3565 (t, J = 8.8 Hz, 1H), 7.5509 (d, J = 8.4 Hz, 1H), 7.7521 (m, 2H), 8.1175 (d, J = 4.7 Hz, 1H), 8.4472 (s, 1H), 9.2184 (s, 1H).
