446-18-4

The general procedure for the synthesis of 2-methyl-4-fluoro-5-nitroaniline from 4-fluoro-2-methylaniline is as follows: 1. fuming nitric acid (3.35 mL, 84 mmol) was slowly added dropwise to a solution of 4-fluoro-2-methylaniline (10.5 g, 84 mmol) dissolved in 90 mL of concentrated sulfuric acid at -5 °C. 2. The reaction mixture was stirred continuously at 0 °C for 2 hours. 3. The reaction mixture was diluted by adding cold water (300 mL) to the reaction mixture. 4. Adjust the pH to 10 by slowly adding cold NaOH solution (10N). 5. The precipitate precipitated was collected by filtration to afford Intermediate IV-e as a yellow solid (12.7 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) data of intermediate IV-e: δ 7.30 (d, J=6.8 Hz, 1H), 7.17 (d, J=12.3 Hz, 1H), 5.39 (s, 2H), 2.14 (s, 3H).

[1] Patent: WO2014/202763, 2014, A1. Location in patent: Page/Page column 51
[2] Patent: WO2015/193846, A1. Location in patent: Page/Page column 57; 58
[2] Patent: , 2015, . Location in patent: Page/Page column 57; 58
[4] Patent: WO2008/33999, 2008, A2. Location in patent: Page/Page column 91-92
[5] Patent: US5645610, 1997, A