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. 2020 Oct 2;22(19):7656-7661.
doi: 10.1021/acs.orglett.0c02848. Epub 2020 Sep 15.

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

Dinesh J Paymode  1 , Flavio S P Cardoso  1 , Toolika Agrawal  1 , John W Tomlin  1 , Daniel W Cook  2 , Justina M Burns  2 , Rodger W Stringham  2 , Joshua D Sieber  1 , B Frank Gupton  1 , David R Snead  1
Affiliations

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

Dinesh J Paymode et al. Org Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
An atom economic route to triazine from abundant chemicals.
Figure 2
Figure 2
A simple one-pot cyanation.
Figure 3
Figure 3
Clean amination of pyrrole from bleach and ammonia under highly dilute conditions.
Figure 4
Figure 4
(a) Lower equivalents of chloramine can be used at lower loadings of NaH. (b) Addition of NH2Cl in multiple charges with subsequent solvent recycle increases throughput and decreases solvent consumption.
Figure 5
Figure 5
Steady state operation of chloramine CSTR and schematic for chloramine generator.
Figure 6
Figure 6
One-pot triazine synthesis from cyanopyrrole 4.
See this image and copyright information in PMC

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