Thermal Risk Assessment: A Powerful Tool for Route Selection for Scale-Up Applied to Diels–Alder Reactions

The thermal risk assessment of the Diels–Alder reaction of acetoxyacrylonitrile, acrylonitrile, and chloroacrylonitrile with the diene (cyclohexa-1,5-dien-1-loxy)trimethylsilane (1) is presented. Starting with the conceptualization of the problem, a step-by-step approach serves as an example for a sound and systematic evaluation of risks. A holistic view of the relevant data ranging from thermokinetics, storage, availability, costs, and throughput shows that the choice of a safe route is a multi-dimensional task. In a second part, a novel synthesis of spiro[2.4]hepta-4,6-diene 6 is described. This highly reactive diene has a large thermal potential. A systematic thermal stability study of both the reaction mixture and the product led to recommendations for safe processing, including the highly exothermic synthesis and the distillation. In both cases, the safe processing of hazardous chemistry at the tolerated scale was pivotal for the expeditious delivery of material for the production of API (Active Pharmaceutical Ingredients).