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

Abstract

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.

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

“…For safe operations in a cyclopropanation using dimethylsulfoxonium methylide at high temperatures, continuous operation was found more suitable for safe scale-up by carrying out the reaction at or below room temperature [19] (Scheme 1).…”

“…The synthesis of trans-2-methylcyclopropanecarboxylic acid was set up through stereoselective cyclopropanation of ethyl crotonate with Corey's Ylide [19]. After the screening and optimisation of reaction conditions, reaction calorimetry and dynamic differential scanning calorimetry (DSC) allowed to assess the safety issues of the reaction, especially aiming at scale-up in flow reactors.…”

Design of Experiments (DoE) and Process Optimization. A Review of Recent Publications

“…Lilly researchers used DoE to optimize the cyclopropanation of olefin 225 with dimethylsulfoxonium methylide (Corey's ylide, 224; Scheme 19). 104 Five factors were examined: temperature (60, 80 °C), cation (Na + or K + ), anion (t-BuO − , HO − ), addition type (base or preformed 224), and addition time (40, 80 min). A total of 16 experiments were run (2 5−1 , no center points).…”

Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development

“…Common tools that are routinely used in manufacturing include thermocouples and pressure sensors. Spectroscopic tools (e.g., near-infrared, − mid-infrared, − Raman, − UV − and NMR) − are utilized for increased analytical specificity (ability to monitor for the presence or disappearance of functional groups during the synthesis). By monitoring these specific functional groups, qualitative trending or quantitative assessment of the reaction component(s) levels is achieved.…”