6.3 Preparation of Isoxazole-3-carbonitrile: To a dry 10L three-necked flask fitted with a thermometer, mechanical stirrer and dropping funnel under nitrogen protection were added 52000 g (18.6 mL) of dichloromethane and 289.8 g (1.04 mol, purity determined to be 64.5 wt%) of 5-ethoxy-4,5-dihydroisoxazole-3-carbonitrile. The reaction mixture was cooled to 0-5 °C and then 173.8 g (0.6 mol) diazabicyclo[5.4.0]undecene was slowly added dropwise at the same temperature for a controlled time of 20-30 min. After the dropwise addition, the reaction mixture was continued to be stirred at 0-5 °C for 2-3 hours until HPLC showed that the reaction was complete. Subsequently, the reaction mixture was neutralized with 1000.0 g (3.45 L) of 0.1 N hydrochloric acid to pH 6.5-7.0 at 0-5 °C. The neutralized mixture was extracted twice with 1170 g (4.0 L) of methyl tert-butyl ether. After separation of the organic layers, the organic phases were combined and dried over 116 g (0.44 mol) of anhydrous sodium sulfate, filtered and concentrated in vacuum to give the crude isoxazole-3-carbonitrile (544.6 g, purity determined to be 21.99 wt%, the actual product 119.8 g, yield 62%). The crude product was purified by reduced pressure distillation (40 ℃/5mmHg) to give 97.3g of colorless oil (99% purity, 50% yield). The structure of the product was analyzed by 1H NMR (CDCl3, 400 MHz) δ 8.64 (d, J=1.6 Hz, 1H), 6.70 (d, J=1.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 160.92, 139.19, 109.95, 107.40; Elemental analysis results: measured value: C, 50.02; N, 27.74; H Calculated value (C4H2N2O): C, 51.07; N, 29.78; H, 2.14.
