Moriuchi, Yuta W.; Biyani, Shruti A.; and Thompson, David H., "Development of Continuous Flow Sonogashira Coupling of lead Anti-Cancer Small Molecule Inhibitors for Potential Treatment of Acute Myeloid Leukemia" (2021). Discovery Undergraduate Interdisciplinary Research Internship. Paper 44.
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Sonogashira Cross-Coupling, Amide Cross-Coupling, HTE, High throughput Experimentation, Continuous Flow Chemistry, Green Chemistry, Acute Myeloid Leukemia
As the technology for science develops, the research strategy in medicines and therapeutics also improves. In this paper, I will cover the process of Sonogashira cross-coupling and Amide Coupling reaction for an anticancer agent in both batch and flow chemistry. Continuous Flow Chemistry has advantages such as being more efficient, safer, and faster. This paper studies the synthesis of HSNO608, an anticancer lead compound for Acute Myeloid Leukemia (AML), which has a specific potent activity to FTL3 Kinase. Inhibition of FLT3 Kinase leads to inhibition of downstream pathways such as MPK and P13K pathways. In this two-step experiment, the Sonogashira cross-coupling reaction is a crucial step in the flow process. For the amidation reaction, it favored high retention time and low temperatures. For the Sonogashira cross-coupling reactions, different types of Palladium Catalyst and Copper Co-catalyst were screened. The best catalyst found was PdCl2(MeCN)2 with the ligand of [(t-Bu)3PH]BF4 giving us a yield of 88% with high loading (%10) of Copper and Pd catalyst. This condition was further optimized to reduce the catalyst loading to 1%. In conclusion, we were able to optimize and create methods to synthesize lead medicinal compounds. In the future, this approach could be applied to other anticancer targets and other medicinal chemical targets.