Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis

Abstract

Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.

COVID‐19 into Chemical Science Perspective: Chemical Preventive Measures and Drug Development

“…In order to strengthen the supply chain of Remdesivir, the ideal route to pyrrolotriazine should initiate from commodity materials and have improved overall yield with reduced step count. Very recently Snead and coworkers investigated the bond‐forming steps to do so from pyrrole which is highly abundant and commoditized raw material (Scheme 6b) [114] . Aldehyde group is generally easily introduced at the 2‐position of pyrrole, and the resulting aldehydes can be oxidized to the corresponding nitriles through aldoxime intermediates.…”

“…Very recently Snead and coworkers investigated the bond-forming steps to do so from pyrrole which is highly abundant and commoditized raw material (Scheme 6b). [114] Aldehyde group is generally easily introduced at the 2-position of pyrrole, and the resulting aldehydes can be oxidized to the corresponding nitriles through aldoxime intermediates. Herein, authors have developed one-pot nitrile (2.18) formation by using oxidative Vilsmeier cascade strategy.…”

Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir

“…MTSR is found to be less than the MTT (152 ﾟC) and hence it is safe to handle. There is nominal thermal accumulation (~6%) after the dosing of 2-cyanopyrrole (3). This renders the reaction a low safety risk for scale up to produce 8.…”

Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir

“…The process research community has embarked on rapid development of a practical commercial route to remdesivir since it emerged as a COVID-19 therapeutic. 1,2 We recently published a route to construct pyrrolo[2,1-f][1,2,4]triazine (1) from commodity starting materials 3 and the retrosynthetic analysis of the triazine 1 as shown in Figure 1. 2,5-Dimethoxytetrahydrofuran, tert-butylcarbazate, and chlorosulfonyl isocyanate were replaced with the readily available pyrrole, dimethylformamide, hydroxylamine, ammonia and bleach in an effort to secure supply of this important regulatory starting material 1.…”

“…1 Our recent publication highlighted the feasibility of assembling the triazine moiety from pyrrole and other commodity chemicals. 3 This work describes our process research and development program followed by scale-up and feasibility studies for large scale operation. Furthermore, scale-up implementation, safety concerns, removal of impurities generated during the synthetic process development, and ability to make substantial quantities of high quality triazine 1 are addressed.…”