After complete addition, the suspension was stirred for 15 min and cooled to 30 °C. Water (17.5 kg) was added, and the contents of the reactor were transferred to a 180 L reactor for further processing. The remaining 52.5 kg of water was added, and the batch was cooled to 10−15 °C. After stirring at this temperature for 1 h, the suspension was filtered on a Nütsche filter. The crystals were washed with water (3 × 22.4 kg) and dried under nitrogen. The material was isolated as a white solid (8.24 kg, 99.7% yield, 99.6% pure, mp = 56 °C)
引入二氟甲基，采用二氟一氯甲烷，有毒气体，来源受限 采用SCDA，二氟一氯乙酸钠，烷基化脱羧路径 没有什么捷径，就是筛选不同的碱和溶剂，一系列筛选结束，选择了碱性偏强的磷酸钾搭配NMP为溶剂，最后尝试降低物料用量（entry 20）
案例三
实验操作
An inerted reactor was charged with MeCN (42 L, 6 L/kg), followed by 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate 3 (7 kg, 1 equiv) and CuI (0.54 kg, 0.1 equiv) at 20−25 °C.
The reactor was inerted with nitrogen three more times, and the stirred mixture was warmed up to 50 °C. A solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.33 kg, 1.05 equiv) in MeCN (42 L, 6 L/kg) was then added slowly to the hot mixture at a rate that maintained the internal temperature in the 50 ± 5 °C range.
After reaction completion, the mixture was cooled down to 10 °C. Triethylamine (10.11 kg, 3.5 equiv) was slowly charged to the mixture followed by water (35 L, 5 L/kg) while maintaining the temperature below 10 °C. Once both additions were completed, the mixture was warmed up to 25 °C and layers were separated.
参考文献
https://doi.org/10.1021/acs.oprd.3c00493
