A scalable process has been developed for the synthesis of trans-2-methylcyclopropanecarboxylic acid via the stereoselective cyclopropanation of ethyl crotonate with dimethylsulfoxonium methylide (Corey’s ylide). This well-known reaction is generally low yielding and very challenging to scale up as it involves highly reactive reagents. A design of experiment (DoE) allowed us to quickly define the optimal ranges for the reaction parameters. A very significant increase of the yield was obtained by adding the ylide to ethyl crotonate in DMSO at 80 °C in anhydrous conditions. In view of a scale-up at a multikilogram scale, several experiments were then performed combining Process Analytical Technologies (PAT) and Calorimetry (Dynamic DSC, Adiabatic Reaction Calorimetry and Vent Sizing Package). For safety reasons at high temperatures on large scale the reaction was also evaluated in a continuous flow reactor. Thanks to these studies, we were able to develop an efficient process avoiding the hazardous accumulation of the thermally unstable dimethylsulfoxonium methylide.

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开发可逆的合成反式-2-甲基环丙烷羧酸的方法

已经开发了可扩展的方法来合成反式通过丁烯酸乙酯与甲基二甲基亚砜鎓（Corey's ylide）的巴豆酸乙酯的立体选择性环丙烷化，生成-2-甲基环丙烷羧酸。这种众所周知的反应通常收率低，并且由于涉及高反应性试剂，因此很难扩大规模。实验设计（DoE）使我们能够快速定义反应参数的最佳范围。通过在无水条件下于80°C在DMSO中将叶立德加入巴豆酸乙酯中，可以显着提高收率。考虑到以千克为单位进行放大，然后结合过程分析技术（PAT）和量热法（动态DSC，绝热反应量热法和通风口定型包装）进行了一些实验。出于安全原因，在高温下大规模进行反应也在连续流反应器中进行了评估。