Synthesis
Step 3: Synthesis of 4-nitropyridine-2-amino intermediate-22
N-(4-methoxybenzyl)-4-nitropyridin-2-amine (Int-21, 27.8 g, 0.11 mol) and anisole (13 mL, 0.12 mol) were dissolved in trifluoroacetic acid (112 mL) and the reaction was heated at 80 °C for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was ground with EtOAc and hexane to give a pale yellow solid, which was separated by filtration. The filtrate was allowed to stand overnight to precipitate a second batch of crystals. The two solid batches were combined, dissolved in 1N NaOH solution (250 mL) and extracted with EtOAc (2 x 250 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give 4-nitropyridin-2-amine as an orange solid (10.2 g, 67% yield).
LCMS (FA) ES+: m/z 140.
1H NMR (400 MHz, CD3OD) δ ppm: 8.15 (dd, J = 5.7, 0.6 Hz, 1H), 7.23 (dd, J = 2.0, 0.6 Hz, 1H), 7.20 (dd, J = 5.7, 2.0 Hz, 1H).
References
[1] Patent: WO2011/146591, 2011, A1. Location in patent: Page/Page column 72-73
[2] Patent: US2012/15942, 2012, A1. Location in patent: Page/Page column 51
[3] Patent: EP3305788, 2018, A1. Location in patent: Paragraph 0059; 0062
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1836 - 1846
