Synthesis
The general procedure for the synthesis of 2-amino-5-methoxybenzotrifluoride from 3-trifluoromethyl-4-nitroanisole was as follows:(b) Preparation of 4-methoxy-2-(trifluoromethyl)aniline by amination of 4-methoxy-2-(trifluoromethyl)nitrobenzene: In a 300 mL stainless steel autoclave, 25.0 g (0.11 mol) of 4-methoxy-2-(trifluoromethyl) nitrobenzene was dissolved in 150 mL of 95% ethanol. After purging the reactor with nitrogen, 1.1 g of 5% palladium-carbon catalyst was added and the autoclave was sealed. After purging with nitrogen again, the reactor was charged with 60 psi (413 kPa) hydrogen and stirring was started. During the reaction, the temperature was maintained between 25°C and 30°C by intermittent ice bath cooling. After approximately 90 minutes, hydrogen absorption was stopped. The pressure in the autoclave is released, flushed with nitrogen and opened. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 22 g (100% yield) of a light yellow oily product identified as 4-methoxy-2-(trifluoromethyl)aniline.1H NMR analysis gave the following results: (δ, CDCl3) 7.82 (dd, J = 2 and 9 Hz, 1H), 7.00 (d, J = 2 Hz, 1H), 6.48 (d, J = 9 Hz, 1H ), 3.87 (br s, 2H) and 3.60 (s, 3H). Mass spectral analysis showed (m/e) 191 (M+), 176, 156, 128 and 52. The product was used directly in subsequent steps without further purification.
References
[1] Patent: US4879398, 1989, A
[2] Patent: CN107793413, 2018, A. Location in patent: Paragraph 0150; 0151; 0154; 0155
[3] Tetrahedron Letters, 2004, vol. 45, # 26, p. 5131 - 5133
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 7, p. 2109 - 2118
[5] Patent: WO2005/47273, 2005, A1. Location in patent: Page/Page column 44
