Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jan 21;26(1):82-90.
doi: 10.1021/acs.oprd.1c00071. Epub 2022 Jan 7.

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

Sarabindu Roy  1 , Ajay Yadaw  1 , Subho Roy  1 , Gopal Sirasani  2 , Aravind Gangu  2 , Jack D Brown  2 , Joseph D Armstrong 3rd  2 , Rodger W Stringham  3 , B Frank Gupton  3 , Chris H Senanayake  2 , David R Snead  3
Affiliations
Review

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

Sarabindu Roy et al. Org Process Res Dev. .

Abstract

Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Retrosynthetic analysis of remdesivir from subunits lactone and triazine 1.
Figure 2
Figure 2
Current route to make triazine 1.
Figure 3
Figure 3
(A–C) Products and impurities.
See this image and copyright information in PMC

References

    1. Siegel D.; Hui H. C.; Doerffler E.; Clarke M. O.; Chun K.; Zhang L.; Neville S.; Carra E.; Lew W.; Ross B.; Wang Q.; Wolfe L.; Jordan R.; Soloveva V.; Knox J.; Perry J.; Perron M.; Stray K. M.; Barauskas O.; Feng J. Y.; Xu Y.; Lee G.; Rheingold A. L.; Ray A. S.; Bannister R.; Strickley R.; Swaminathan S.; Lee W. A.; Bavari S.; Cihlar T.; Lo M. K.; Warren T. K.; Mackman R. L. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J. Med. Chem. 2017, 60, 1648–1661. 10.1021/acs.jmedchem.6b01594. - DOI - PubMed
    1. Vieira T.; Stevens A. C.; Chtchemelinine A.; Gao D.; Badalov P.; Heumann L. Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir. Org. Process Res. Dev. 2020, 24, 2113–2121. 10.1021/acs.oprd.0c00172. - DOI - PubMed
    2. Xue F.; Zhou X.; Zhou R.; Zhou X.; Xiao D.; Gu E.; Guo X.; Xiang J.; Wang K.; Yang L.; Zhong W.; Qin Y. Improvement of the C-glycosylation Step for the Synthesis of Remdesivir. Org. Process Res. Dev. 2020, 24, 1772–1777. 10.1021/acs.oprd.0c00310. - DOI - PubMed
    3. Wang M.; Zhang L.; Huo X.; Zhang Z.; Yuan Q.; Li P.; Chen J.; Zou Y.; Wu Z.; Zhang W. Catalytic Asymmetric Synthesis of the anti-COVID-19 Drug Remdesivir. Angew. Chem., Int. Ed. 2020, 59, 20814–20819. 10.1002/anie.202011527. - DOI - PubMed
    4. Bigley A. N.; Narindoshvili T.; Raushel F. M. A Chemoenzymatic Synthesis of the (RP)-Isomer of the Antiviral Prodrug Remdesivir. Biochemistry 2020, 59, 3038–3043. 10.1021/acs.biochem.0c00591. - DOI - PMC - PubMed
    5. von Keutz T.; Williams J. D.; Kappe C. O. Continuous Flow C-Glycosylation via Metal-Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir. Org. Process Res. Dev. 2020, 24, 2362–2368. 10.1021/acs.oprd.0c00370. - DOI
    6. De Savi C.; Hughes D. L.; Kvaerno L. Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply. Org. Process Res. Dev. 2020, 24, 940–976. 10.1021/acs.oprd.0c00233. - DOI - PubMed
    1. Paymode D. J.; Cardoso F. S. P.; Agrawal T.; Tomlin J. W.; Cook D. W.; Burns J. M.; Stringham R. W.; Sieber J. D.; Gupton B. F.; Snead D. R. Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis. Org. Lett. 2020, 22, 7656–7661. 10.1021/acs.orglett.0c02848. - DOI - PMC - PubMed
    1. Dixon J. A.; Phillips B.; Achebe F.; Kluender H. C. E.; Newcom J.; Parcella K.; Magnuson S.; Hong Z.; Zhang Z.; Liu Z.; Khire U.; Wang L.; Michels M.; Chandler B.; O’Connor S.. Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis. U.S. Patent 8,143,393 B2, 2006.
    2. O’Connor S.; Dumas J.; Lee W.; Dixon J.; Cantin D.; Gunn D.; Burke J.; Phillips B.; Lowe D.; Shelekhin T.; Wang G.; Ma X.; Ying S.; McClure A.; Achebe F.; Lobell M.; Ehrgott F.; Iwuagwu C.; Parcella K.. Pyrrolo[2,1-f][1,2,4]triazin-4-ylamines IGF-1R kinase inhibitors for the treatment of cancer and other hyperproliferative diseases. U.S. Patent 8,431,695 B2, 2006.
    1. Achmatowicz M. M.; Thiel O. R.; Colyer J. T.; Hu J.; Elipe M. V. S.; Tomaskevitch J.; Tedrow J. S.; Larsen R. D. Hydrolysis of Phosphoryl Trichloride (POCl3): Characterization, in Situ Detection, and Safe Quenching of Energetic Metastable Intermediates. Org. Process Res. Dev. 2010, 14, 1490–1500. 10.1021/op1001484. - DOI