(610f) Safer Process Design through Continuous Processing – Enantioselective Di-Rhodium Catalyzed Cyclopropanation through a Reactive Aryldiazoacetate Intermediate

Adoption of continuous processes in the pharmaceutical sector remains sporadic despite wide adoption of such processes throughout the petroleum, commodity, and specialty chemicals industry; however, the unique advantages of flow processes to provide dramatically improved heat and mass transfer, to enable differentiated reaction chemistries, and to unlock routes to safer scale-up combine to offer compelling advantages for employing such production strategies. In this presentation, we will discuss the development of a continuous-flow process for the safe formation of a reactive aryldiazoacetate intermediate, extraction of reaction byproducts, drying of the aryldiazoacetate, and its direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction, particularly through the lens of process design and safety.

The process was developed with safety as a primary consideration. In order to enable this scale-up, first the thermal onset temperatures of both the arylsulfonyl hydrazone starting materials and reaction solutions were measured. An appropriate arylsulfonyl hydrazone starting material and organic soluble base was screened to facilitate a Bamford−Stevens diazo-generating flow process at temperatures well below the thermal onset temperature. Reaction conditions were selected that could still facilitate rapid kinetics to minimize aryldiazoacetate accumulation while avoiding conditions prone to thermal runaway. To prevent deactivation of the catalyst in the subsequent cyclopropanation reaction, the Bamford−Stevens reaction byproducts must be efficiently removed. This was achieved via a continuous aqueous extraction using an in-line liquid−liquid membrane separator. Due to the negative impacts of water on the subsequent cyclopropanation, water levels below 100 ppm in the final aryldiazoacetate solution were maintained by adsorption. Finally, the kinetics of the cyclopropanation reaction were then measured at small scale in an Omnical SuperCRC calorimeter and used to predict potential accumulation of the diazoacetate intermediate during fed-batch operation. Performance vs. this model was assessed using Process Analytical Technology, specifically IR, which was also used to monitor reactive intermediate accumulation online during operation.

The complete process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale in the future within AbbVie. The optimized reaction conditions led to a significant safety advantage in conducting the process in flow, reducing the aryldiazoacetate inventory during operation and increasing temperature control and heat transfer. In conclusion, the study demonstrates a safe, scalable, and efficient process for the formation, extraction, and drying of an aryldiazoacetate and its direct use in a sensitive cyclopropanation reaction. The results provide valuable insights for the design of future flow processes involving sensitive diazo compounds and water-sensitive reactions.