The application of modern reactions in large-scale synthesis

In the past decade, the field of organic synthesis has witnessed tremendous advancements in the areas of photoredox catalysis, electrochemistry, C–H activation, reductive coupling and flow chemistry. While these methods and technologies offer many strategic advantages in streamlining syntheses, their application on the process scale is complicated by several factors. In this Review, we discuss the challenges that arise when these reaction classes and/or flow chemistry technology are taken from a research laboratory operating at the milligram scale to a reactor capable of producing kilograms of product. We discuss how these challenges have been overcome through chemical and engineering solutions. Specifically, this Review will highlight key examples that have led to the production of multi-hundred-gram to kilogram quantities of active pharmaceutical ingredients or their intermediates and will provide insight on the scaling-up process to those developing new technologies and reactions. State-of-the-art synthetic methods regularly encounter challenges associated with cost, safety and/or efficiency when proposed for large-scale applications. This Review highlights recent applications of novel reactions/technologies (e.g. photoredox, electrochemistry, C–H activation, reductive coupling and flow chemistry) on the process scale.