Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry
Traditionally there are many transformations that employ hazardous reagents. Some of the transformations that afford important categories of organic building blocks useful for the synthesis of pharmaceutical intermediates and APIs cannot be performed due to the hazardous nature of reagents and conditions. Reactions whose reagents lead to the formation of highly reactive or highly exothermic intermediates typically are not suitable for implementation on a large scale because of the hazards that they pose. Efforts are ongoing in both industrial and academic settings to develop alternative approaches to help enable these transformations to be performed safely on a commercial scale. Examples include developing new forms of hazardous reagents that are stable and can readily be manipulated in the plant setting, within the scope of the transformation, changing the process landscape towards avoiding hazardous reagents, identifying new reaction conditions such as the use of flow chemistry that helps reduce the quantities of hazardous reagents and/or provide highly controlled conditions for energetic reactions and identifying entirely new routes that do not have these issues. While the selection of non-hazardous reagents and reaction conditions are critically determined by innate reactivity of the functional groups, solvents also play a pivotal role in determining the outcome of reaction and product. Therefore the selection of a solvent that does not pose health, safety and environmental challenges is extremely important. Understanding of the physicochemical characteristics of the solvents and other reaction components sets the stage for the selection of reaction attributes for a particular transformation.