期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 24, 期 10, 页码 2240-2251出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00289
关键词
high-throughput experiment; continuous flow synthesis; Sonogashira coupling; Design of Experiments; FLT-3 inhibitor
资金
- Defense Advanced Research Projects Agency [W911NF-16-2-0020]
- Center for Cancer Research at Purdue University [P30 CA023168]
- Boilermaker Health Innovations
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 (DESIMS) 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.
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