Synthesis
Step 1: 3,5-difluorobenzoic acid (80 g, 506 mmol) was stirred with concentrated sulfuric acid (250 mL) for 1 hour at room temperature. Subsequently, concentrated nitric acid (90 mL) was added slowly and dropwise while the reaction temperature was controlled below 45 °C by a water bath. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by slowly pouring the reaction solution into crushed ice, the precipitated solid was collected by filtration and washed thoroughly with cold water to afford 3,5-difluoro-2-nitrobenzoic acid (compound 273) as a white solid (93.0 g, 91% yield). The product could be used directly in the subsequent reaction without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.01 (ddd, J = 10.9, 8.5, 2.8 Hz, 1H), 7.71 (dt, J = 8.4, 2.2 Hz, 1H).
References
[1] Patent: WO2013/132376, 2013, A1. Location in patent: Page/Page column 234
[2] Patent: EP1214299, 2004, B1. Location in patent: Page 18
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 7, p. 2733 - 2743
