实验操作A 10 L double-jacketed glass reactor was charged with ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (6) (200 g, 0.844 mol, 1.0 equiv), 2,4-difluorophenylboronic acid (160 g, 1.01 mol, 1.2 equiv), Pd(OAc)2 (1.89 g, 8.44 mmol, 1.0 mol %), and Xantphos (4.88 g, 8.44 mmol, 1.0 mol %). A solution of NMM (204 mL, 1.86 mol, 2.2 equiv) in toluene (1.6 L, 8.0 vol) was added at IT = 20−25 °C, followed by the addition of H2O (0.8 L, 4.0 vol). The reaction mixture was strongly stirred (300 rpm) at IT = 20−25 °C for 7 h. Then, iPrOAc (0.6 L, 3.0 vol) was added and the phases were separated. The aqueous phase was extracted once with iPrOAc (1.0 L, 5.0 vol). The combined organic phases were recharged to the reactor, a slight vacuum was applied and the organic phase concentrated at ET = 80 °C until a minimal stirring volume was reached. Then, iPrOH (total amount used for solvent switch: 4 L) was continuously added and the distillation continued. Final iPrOH content in the reactor after distillation: ca. 1.2 L (6.0 vol). The mixture was kept at IT = 65−75 °C and then slowly cooled to IT = 20−25 °C over 2 h. The resulting suspension was aged for an additional hour at IT = 20−25 °C. The solid was collected by filtration, washed with iPrOH (2 × 0.4 L), and dried at 65 °C under a vacuum for 3 h to give 1 (193 g, 0.714 mol, 85% yield) as light-yellow crystalline needles. LC/ MS purity: 99% a/a. 参考文献Org. Process Res. Dev. 2020, 24, 228−234
