The general procedure for the synthesis of 4,6-dichloroindole-2-carboxylic acid from ethyl 4,6-dichloroindole-2-carboxylate was as follows: first, the intermediate 4,6-dichloro-1H-indole-2-carboxylic acid (I-id) was prepared. This was done as follows: ethyl 4,6-dichloro-1H-indole-2-carboxylate (1c) (50 g, 193.72 mmol) was dissolved in a mixed solvent consisting of THF and water (1:1, 900 mL), followed by the addition of LiOH-H2O (24.41 g, 581.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. Upon completion of the reaction, THF was removed by distillation, the residue was diluted with water (400 mL) and acidified with aqueous 2N HCl to pH 6.0. The acidified solution was extracted with ethyl acetate (4×150 mL), and the combined organic layers were washed with brine (350 mL), dried over anhydrous Na2SO4, and finally concentrated under reduced pressure to afford 4,6-dichloro-1H-indole-2 -carboxylic acid (1d) 39 g in 87.5% yield as a light brown solid. The product was characterized by 1H NMR (400 MHz, DMSO-d6) and ESI MS: 1H NMR δ 12.25 (s, 1H), 7.43 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H); ESI MS m/z 227.7 (M-H).
