Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608

• DOI: 10.1021/acs.oprd.0c00289
• Publication Date: 2020-10-07T03:29:55Z
• Authors: Shruti A. Biyani; Qingqing Qi; Jingze Wu; Yuta Moriuchi; Elizabeth A. Laro...; Herman O. Sintim; David H. Thompson
• Keywords: Combinatorial synthesis

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