Technology-assisted methodology in the synthesis of medicinally relevant N-heterocycles

In recent years, modern technology such as microwave irradiation and continuous flow processes have emerged as valuable tools in chemical and pharmaceutical industry, facilitating the ever increasing demand for faster, greener and reproducible chemistry. This dissertation will discuss three projects that used technology platforms to synthesize medicinally relevant heterocycles. The first is the microwave and flow assisted synthesis of substituted indoles, aza-indoles and indole-2-carboxamides using the Hemetsberger-Knittel (HK) reaction. The indole ring is one of the most abundant heterocyclic scaffolds found in nature and forms an essential component of the framework of higher order protein structures. The HK indole synthesis is a popular method used to obtain indole-2-carboxylates that involves Knoevenagel condensation of an aryl aldehyde with an azidoacetate and subsequent cyclization of the resulting azidocinnamate to afford indole-2-carboxylates. Traditionally, this process is conducted at higher temperatures often leading to decomposition of the product and poor yields. The subsequent conversion of indole-2-carboxylates into corresponding indole-2-unsubstituted product is often a problematic transformation due to decomposition of the product during thermolysis. This work has investigated the utilization of flow and microwave methodology to improve the HK process. Tandem cyclization-decarboxylation can be effected to provide access to substituted and 2-unsubstituted indoles and related heterocycles. Application of the process to the synthesis of analogs of the known aza-indole based antitumoral agent PLX 4032 was demonstrated. The versatility of HK substrates in bioconjugation and cycloaddition through Huisgen type chemistry and subsequent introduction of an F label was investigated. The second project involves MWA process for the synthesis of adenosine A2A receptor antagonists directed towards anti-hypoxia-adenosinergic combined immunotherapy. This work presents the development of PEGylated versions of the A2A antagonist preladenant, along with preliminary mouse data and preparation of PET probes as tumor imaging agents. The third project, a novel route to fused triazolo-pyridobenzoxepans has been developed using microwave and flow methods. Fused heterocycles of benzodiazepine and benzoxazepine class are of considerable interest in antipsychosis drug development due to their favorable pharmacologic and metabolic profiles. Analogs with a pendant basic nitrogen atom in the side chain were synthesized based on comparative analysis of the current atypical anti-psychotic drug JL-13. Comparison of conventional, microwave and flow processes and preliminary 5HT2A binding data will be discussed. Additionally, microwave mediated fluorodenitration has been demonstrated on a select substrate as a proof-of-principle study to demonstrate the possible introduction of radiolabels for use in central nervous system research.