Yield: 96%

Reaction Conditions:

with sulfuric acid;nitric acid at -10; for 3 h;Cooling with ice;

Steps:

3 2-fluoro-4-methyl-5-nitroaniline (10)
To H2SO4 (250 mL) was slowly added 2-fluoro-4-methylaniline (25.03 g, 200 mmol) while cooling the mixture on ice to prevent excessive warming, and the resulting mixture was stirred until all precipitated solids dissolved to give a transparent brown solution. This aniline solution was then cooled to -10 °C. A second solution was prepared by careful addition of 68-70% m/m HNO₃ (20.0 g, 14.1 mL, -220 mmol) to H₂S0 (28 mL) while cooling the mixture on ice to maintain the temperature at room temperature or below. The HNO₃/H2SO4 solution was then added to the cooled aniline solution dropwise over 3 h, taking care not to allow the internal temperature to rise above -5 °C. At the end of the addition, the reaction mixture was carefully poured into ice water (1.5 L) and the resulting mixture was carefully basified by slow addition of an NaOH solution (-450 g dissolved in 600 mL water) , cooling the mixture in an ice bath to maintain the internal temperature below 60 °C at all times. The resulting precipitate was collected by filtration, washed thoroughly with water (4x), and dried to provide the pure product 10 as a yellow solid (32.65 g, 96%). *H NMR (500 MHz, CDCla) δ 7.49 (d, J= 8.2 Hz, 1H) , 6.92 (d, J= 11.2 Hz, 1H) , 3.89 (br s, 2H) , 2.48 (s, 3H); ¹³C NMR (126 MHz, CDCI3) δ 154.5 and 152.5, 145.0, 133.5 and 133.3, 125.1 and 125.0, 119.0 and 118.8, 113.2 and 113.1, 20.21.

References:

THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK;KRUEGEL, Andrew;SAMES, Dalibor;JAVITCH, Jonathan A. WO2018/170275, 2018, A1 Location in patent:Page/Page column 114; 118-119