Scalable Synthesis of Antiviral Compounds (COVID-19)

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The COVID-19 pandemic has relatively quickly become a worldwide threat to human health and the economy. Because of the long timeline for vaccine development, and the very real possibility that any vaccine developed may confer limited immunity, other approaches for containing the disease are needed. Here we propose a program to develop efficient synthetic routes to two novel small molecule compounds that have been shown to inhibit infectivity of SARS-CoV-2 in cell culture. These compounds were originally prepared in milligram quantities, using synthetic routes that were unoptimized and not suitable for larger-scale synthesis. For this Alliance Grant project, we will reexamine the synthetic routes to two target compounds 3 and 5 (see proposal). There are several problems with the existing routes, including expensive reagents that need to be used in excess, and very low yields for several of the steps. We will attempt to optimize the low-yielding steps, and explore alternative starting materials that will not require the expensive coupling reagent EDCI. We will also attempt to develop a robust purification protocol for both target compounds that does not require large-scale chromatography. Throughout the course of the project, trainees in the West group will meet with scientists at the partner organization, IntelliSyn RD. These chemists have extensive experience with scale-up problems and route challenges that could negatively impact eventual GMP manufacture, if these compounds are selected for further development. This collaboration will offer a strong training opportunity for trainees involved, exposing them to the kinds of R&D problems that are frequently encountered in a pharmaceutical setting, which could serve them well in future career choices. It also enhances Canada's biopharmaceutical sector by establishing a strong academic-industrial partnership and providing a growing company with the opportunity to partner in moving forward a promising new technology.