Efforts in Thompson group are focused on utilizing high throughput experimentation for active pharmaceutical ingredients and lead compounds to support <i>in vivo</i> studies and preclinical evaluation for enhancement of drug discovery efforts. Our research work aims to develop a continuous flow synthesis of an alkynylnaphthyridine lead compound which has the potential for the treatment of fms-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia. High-throughput experimentation (HTE) was used as a key strategy for optimization along with design of experiments and desorption electrospray ionization mass spectrometry (DESI-MS) to optimize Sonogashira couplings to prepare the target lead compound, HSN-608 in high yield. Findings from the statistical design and automation studies helped to streamline our workflow to achieve 10-fold and 5-fold reductions in the palladium catalyst and copper co-catalyst loadings, respectively along with a deeper mechanistic understanding to eliminate the formation of homocoupling by-product. The application of high throughput tools combined with a telescoped continuous synthesis enabled us to develop an efficient, safe, and rapid synthesis of a potential drug lead.

High-throughput experimentation utilizing Sonogashira couplings for telescoped continuous flow synthesis of an alkynylnaphthyridine anticancer agent, HSN608

ACS Fall 2021

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