High-Throughput Organic Synthesis in Microreactors
Abstract With an average lead time of 10–12 years for a compound to progress from initial identification through clinical trials and finally into a medicine, the pharmaceutical industry are interested in the development of techniques which have the potential to reduce the time taken to generate prospective lead compounds and translate the protocols into production. As such, one of the areas of synthetic chemistry that has benefited greatly from microreaction technology (MRT), over the past 15 years, has been that of pharmaceutical research and development (Glasnov and Kappe, 2007; Mason et al., 2007); with interest in the technology stemming from the perceived ease with which reaction conditions can be optimized and subsequently employed across a range of substrates in order to generate compound libraries (Kirschning et al., 2006; Wiles and Watts, 2007a; Wiles and Watts 2008a). The rapid translation of reaction methodology from the microreactors employed within an R&D facility to production, achieved by a process referred to as scale-out, numbering-up, or upscaling, also has the potential to reduce the time taken to take a compound to market (Yoshida, 2008). Based on this notion, research into the use of microreactors as tools for high-throughput organic synthesis has grown in popularity, with the last 5 years seeing an emerging trend in the types of compounds prepared changing from proof of concept reactions, to the synthesis of molecules of direct relevance to the pharmaceutical industry. With this in mind, the chapter begins with an overview of the seminal examples that helped to foster interest in microreactors as high-throughput tools, illustrating liquid phase (Sections 2.1–2.3), catalytic (Section 2.4) and photochemical (Section 2.6) reactions, and concludes with a selection of current examples into the synthesis of industrially relevant molecules using MRT (Section 3).