Synthesis
General method: Preparation of 4-bromo-2-ethoxy-1-nitrobenzene. To a tetrahydrofuran (5 mL) solution of ethanol (0.07 mL, 1.193 mmol) cooled to 0°C was slowly added sodium hydride (60% suspended in mineral oil, 68 mg, 1.705 mmol). The reaction mixture was stirred at 0 °C for 15 min under nitrogen protection. Subsequently, 2-fluoro-4-bromonitrobenzene (250 mg, 1.136 mmol) was added and the reaction mixture was continued to be stirred for 18 hours, during which time it was slowly warmed to room temperature. Upon completion of the reaction, the mixture was concentrated in vacuum. It was diluted by adding ether (20 mL) and 0.5 M hydrochloric acid (20 mL). The aqueous layer was alkalized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuum to afford the target product 4-bromo-2-ethoxy-1-nitrobenzene (270 mg, 97% yield).1H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 ( dd, J = 8.5, 2.0 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H).
References
[1] Patent: WO2014/37750, 2014, A1. Location in patent: Paragraph 00265; 00266
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 8, p. 3671 - 3688
