Development of a Scalable Process for the Synthesis of trans-2-Methylcyclopropanecarboxylic Acid

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 degrees 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 How reactor. Thanks to these studies, we were able to develop an efficient process avoiding the hazardous accumulation of the thermally unstable dimethylsulfoxonium methylide.