Synthesis
General procedure: To a stirred solution of 4-bromo-3-fluoroaniline (50.0 g, 0.263 mol, 1 eq.) in acetone (660 ml) was added sodium bicarbonate (27.63 g, 0.329 mol, 1.25 eq.) and saturated sodium bicarbonate solution (333 ml). The reaction mixture was cooled to 15 °C and benzyl chloroformate (39 ml, 0.276 mol, 1.05 eq.) was added slowly and the reaction temperature was controlled not to exceed 22 °C. After addition, the reaction was stirred at room temperature for 90 minutes. After completion of the reaction, acetone was removed by distillation under reduced pressure. The aqueous phase was extracted with ethyl acetate (3 x 150 ml), the organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the organic phase was concentrated under reduced pressure, n-hexane was added and stirred at room temperature for 30 min, and the first solid products were collected by filtration. The filtrate was concentrated, and the residual solid was mixed with heptane and stirred at 0 °C for 30 min, and filtered to obtain the second batch of solid product. The two batches of solids were combined to afford the target compound N-(4-bromo-3-fluorophenyl)formic acid phenylmethyl ester (85.3 g, quantitative yield).
References
[1] Patent: US9133213, 2015, B2. Location in patent: Page/Page column 28
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5310 - 5321
[3] Patent: WO2015/66413, 2015, A1. Location in patent: Page/Page column 141; 142
[4] Patent: WO2010/42887, 2010, A2. Location in patent: Page/Page column 16-17
[5] Patent: EP2692727, 2014, A2. Location in patent: Paragraph 0158-0159
