Synthesis
Step b: Synthesis of 5-bromo-2-fluoro-4-methylaniline
To a stirred solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g, 0.230 mol) in ethanol (300 mL) was added SnCl2-2H2O (51.8 g, 0.230 mol). The reaction mixture was heated to reflux and maintained for 3 hours. Upon completion of the reaction, the solvent was removed by evaporation under reduced pressure to give the crude product. The crude product was dissolved in ice water and the pH was adjusted to 7 with saturated aqueous NaHCO3. The precipitated solid was collected by filtration and the filtrate was extracted with dichloromethane (200 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc = 10/1) to afford 5-bromo-2-fluoro-4-methylaniline (5.0 g, two-step yield 30%).
1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 11.6 Hz, 1H), 3.64 (br, 2H), 2.26 (s, 3H).
MS (ESI) m/z (M + H+) 204.0.
References
[1] Patent: WO2013/134298, 2013, A1. Location in patent: Page/Page column 42
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[3] Patent: WO2013/134243, 2013, A1. Location in patent: Page/Page column 9-11
[4] Patent: US2008/9524, 2008, A1. Location in patent: Page/Page column 407
[5] Patent: US2015/231142, 2015, A1. Location in patent: Paragraph 1251
