From Milligrams to Tons: The Importance of Synthesis and Process Research in the Development of New Drugs

Synthetic chemistry plays a key role in the multidisciplinary development process of new small molecule pharmaceuticals. In this context, organic synthesis is not only the essential tool to find potential drug candidate molecules but is also in charge of the subsequent creation, exploration, and evaluation of short, efficient, safe, reproducible, scalable, ecological but still economical syntheses for the selected clinical candidates. This second activity generally named synthesis and process research or just process research is the indispensable link between discovery chemistry and technical development heading toward future large-scale industrial production. In addition to solving the gradually rising synthetic problems associated with the ever increasing structural complexity of new potential drug molecules, the resulting synthesis has to show technical potential and has, particularly, to take into account the basic requirements and limitations of a prospective technical process. In this chapter, the role and importance of synthesis and process research in the development process of new drugs from discovery chemistry (medicinal chemistry) synthesis up to the technical route will be outlined and exemplified with specific examples also taking into account large-scale production requirements. The chapter concentrates on the synthetic strategies and tactics applied to drug candidates in order to create efficient chemical syntheses with technical potential suitable for further technical optimization aiming at the large-scale industrial production of new pharmaceuticals. Owing to the permanently changing environment of the pharmaceutical industry and the tremendous advancements of science, neither general rules nor final or permanent principles and recipes for the successful transformation of a synthetic process from milligrams to tons or from discovery chemistry to production can be provided. Synthetic organic chemists know too well that molecules frequently behave incalculably, and that they are usually hard to control and therefore deserve individual treatment.

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