A four-step synthesis of Remdesivir (1) is presented. This work focuses on the yield improvement of step 1, flow chemistry development of step 2 and 3, process optimization of step 4. The literatures reported (https://dx.doi.org/10.1021/acs.oprd.0c00310 and https://dx.doi.org/10.1021/acs.oprd.0c00172: SI part) step 1 was repeated, but failed in the crystallization, eventually step 1 product was obtained by column chromatography with >98% HPLC purity and 40% IY. The flow chemistry development of step 2(IY: 84%) and 3 (IY: 63%) was achieved and the release of toxic HCN was avoided, the process robustness was improved by flow chemistry. Step 4 was simplified to apply primary alcohol 6 directly (without protection) to react with chiral SM 8. Lewis acid catalysts were screened by HTS and MgI2 gave 50% AY. Cheap and commercially available MgCl2 and NaI were used to replace MgI2, finally Remdesivir (1) was obtained in >99% purity with 40.3% IY.
Development Report for Remdesivir ASYM125666 03-31-2021
Supporting-Information for Remdesivir ASYM125666 06-07-2021