Synthesis
General procedure for the synthesis of 5-trifluoromethylindole-2-carboxylic acid from pyruvic acid and 4-amino-3-iodobenzotrifluoride: A mixture of 2.28 g of 2-iodo-4-trifluoromethylaniline, 2.10 g of pyruvic acid, 2.67 g of DAI3CO, 89 mg of palladium(II) acetate, and 25 mL of DMF was stirred for 24 hr at 100°C, and the reaction was carried out in a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 25 mL of ethyl acetate and 50 mL of 5M hydrochloric acid were added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed sequentially with water and saturated saline, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The residue was washed with chloroform to give 1.15 g of 5-trifluoromethylindole-2-carboxylic acid (hereinafter referred to as "Compound 7").1H-NMR (DMSO-d6) δ: 13.24 (br s, 1H), 12.20 (br s, 1H), 8.08 (s, 1H), 7.60 (d, 1H, J = 8.8), 7.60 (d, 1H, J = 8.8). 1H, J = 8.8 Hz), 7.51 (dd, 1H, J = 8.8, 1.6 Hz), 7.24 (d, 1H, J = 1.6 Hz).
References
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2722 - 2725
[2] Patent: WO2015/49616, 2015, A1. Location in patent: Page/Page column 66; 67
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4385 - 4388
[4] Patent: US2007/88071, 2007, A1. Location in patent: Page/Page column 16
[5] Patent: US2015/289512, 2015, A1. Location in patent: Paragraph 1210; 1211
