Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used to develop the route, including Design of Experiments (DoE), high-throughput experimentation (HTE), and application of desorption electrospray ionization mass spectrometry (DESI-MS) to optimize and telescope the amidation and Sonogashira couplings to prepare the target compound, HSN608, a potent FLT3 inhibitor. Findings from these statistical design and automation studies helped streamline our workflow to achieve 10-fold and 5-fold reductions in the catalyst and cocatalyst loadings, respectively, in the synthesis. The application of high-throughput tools combined with a telescoped continuous synthesis method enabled an efficient and safe synthesis of this lead compound using the hazardous coupling reagent HATU while minimizing byproduct formation.

Phenols and their derivatives are the elementary building blocks for several classes of complex molecules that play essential roles in biological systems. Nature has devised methods to selectively couple phenolic compounds, and many efforts have been undertaken by chemists to mimic such coupling processes. A range of mechanisms can be involved, and with well-studied catalysts, reaction outcomes in phenol−phenol oxidative coupling reactions can be predicted with a good level of fidelity. However, reactions with catalysts that have not been studied or that do not behave similarly to known catalysts can be hard to predict and control. This Perspective provides an overview of catalytic methods for the oxidative coupling of phenols, focusing on the last 10 years, and summarizes current challenges.

A photocatalytic method for phenol and alkenylphenol oxidative coupling is reported using an inexpensive heterogeneous titanium dioxide photocatalyst with air and visible light. During the coupling process, the Ti−substrate complex is activated under visible light through a ligand to metal charge transfer effect, and the diphenol adduct is proposed to form through a radical cation. The heterogeneous TiO 2 catalyst remains stable throughout the reaction and can be easily removed and reused multiple times.