Synthesis
3) Synthesis of 2-iodo-4-(trifluoromethyl)benzoic acid (Compound 211-3)
[0356] 2-Amino-4-(trifluoromethyl)benzoic acid (25.0 g) was dissolved in a dilute sulfuric acid solution prepared from concentrated sulfuric acid (60 ml dropwise at 0°C) and water (600 ml). Subsequently, an aqueous sodium nitrite solution prepared from sodium nitrite (12.4 g) and water (60 ml) was added for the diazotization reaction. An aqueous solution of potassium iodide prepared from potassium iodide (30.0 g) and water (60 ml) was added dropwise to the reaction system, and then the mixture was gradually heated to 80 °C and stirred at that temperature for 1 hour. After completion of the reaction, the reaction mixture was cooled and 2% aqueous sodium thiosulfate solution was added to quench the reaction and stirred for some time. The precipitated solid was collected by filtration to give the crude product (30.5 g). The above steps were repeated to obtain crude product (22.0 g) from another batch of 2-amino-4-(trifluoromethyl)benzoic acid (25.0 g). The solid products obtained from the two combinations were purified by silica gel column chromatography to give the final compound 211-3 (39.5 g) as a light yellow solid. The product was characterized by 1H-NMR (DMSO-d6) with the following chemical shift δ (ppm): 7.82-7.90 (2H, m), 8.27 (1H, s), 13.8 (1H, brs).
References
[1] RSC Advances, 2013, vol. 3, # 38, p. 17271 - 17280
[2] Patent: EP2842937, 2015, A1. Location in patent: Paragraph 0356-0357
[3] Journal of Organic Chemistry, 2017, vol. 82, # 4, p. 2263 - 2268
[4] Organic Letters, 2017, vol. 19, # 7, p. 1578 - 1581
