Exploring Flow Chemistry for the Synthesis and Scale-up of Small Organic Molecules

By the late ‘90s flow chemistry had established itself as a powerful tool for organic synthesis in academia and had started to progressively attracted the interest of the industry due to the advantages that it could potentially offer compared to batch processing; among these it is worth mentioning its intrinsic ability to reduce the solvent usage and to dramatically cut the reaction time alongside providing higher purity and selectivity due to the more regulated processing conditions. In addition, it provides a safer way to handle dangerous and hazardous reagents/intermediates and simplifying the scaling up of the process. This thesis presents a series of molecular preparations involving flow chemistry to expedite the transformation to generate molecules of interest to the pharmaceutical industry. All the work disclosed has been carried out in the Baxendale’s research group at the University of Durham, under the supervision of Professor Ian R. Baxendale. The research has been partially funded and conducted in collaboration with AbbVie under the supervision of Dr Amanda W. Dombrowski and Prof. Stevan W. Djuric. Chapter 1 describes the first use of flow chemistry for performing Norrish-Yang reactions. The transformation has been exploited to synthetize a range of 3-hydroxyazetidines. The high reproducibility and short residence times of the continuous process enables easy scaling of the transformation allowing easy access to these valuable chemical entities at synthetically useful multi-gram scales. Moreover, a systematic exploration of the constituent structural components was undertaken allowing an understanding of the reactivity and functional group tolerance of the transformation. Chapter 2 details the chemistry of a novel rearrangement of the previously obtained 3-hydroxyazetidines (Chapter 1) via a Ritter initiated cascade to provide highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle. The final cyclization step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and a simple direct scale-up. Chapter 3 deals with the nitrosation of several alkanes with tert-butyl nitrite under flow processing conditions. The continuous approach enabled a marked reduction in the reaction time compared to the analogous batch process. In addition, in order to address the necessity for large excesses of the alkane starting material a continuous recycling process was developed thus allowing the preparation of larger quantities of material in a more atom economic and cost-effective process.