UTILIZING PACKED BED REACTORS FOR THE EMPLOYMENT OF C–H FUNCTIONALIZATION IN CONTINUOUS PROCESSING
Hatridge, Taylor A.
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Pharmaceutical synthesis typically exhibits low process efficiency and creates large amounts of waste, as complex biologically active molecules are produced through many reaction and purification steps to yield a product with desired stereochemistry and high purity. The past few decades have seen a rise in the development of methods to achieve atom-efficient synthesis via carbon–hydrogen (C–H) functionalization. In particular, dirhodium(II) (Rh2L4) catalysts with donor/acceptor diazo compound precursors enable the insertion of dirhodium carbenes into C–H bonds with high regio- and stereoselectivity. However, the industrialization of this synthesis technique has been limited due to high costs of Rh2L4 catalysts and safety concerns associated with handling large quantities of energetic diazo compounds. This thesis aims to contribute to the resolution of these challenges by demonstrating the application of C–H functionalization to continuous processing via utilization of packed bed reactors. To this end, an immobilized Rh2L4 catalyst was implemented in a packed bed with a process performance commensurate to the homogeneous catalyst employed in batch, although slow catalyst deactivation was observed. Additionally, a three-phase packed bed reactor was employed for the efficient synthesis of diazo compounds via a catalytic, aerobic hydrazone oxidation. Finally, the diazo synthesis was placed upstream of a semi-batch Rh2L4-catalyzed reaction, exhibiting the potential utility of this method in industrially applicable synthetic transformations. The demonstrated flow to semi-batch cascade may enable industrial adoption of C–H functionalization, as the direct utilization of diazo compounds alleviates safety concerns, and low Rh2L4 catalyst loadings may be employed to increase TON for a lower capital cost.