Advertisement

Chemical Papers

, Volume 73, Issue 5, pp 1043–1051 | Cite as

The complete synthesis of favipiravir from 2-aminopyrazine

  • Qi Guo
  • Mingshuo Xu
  • Shuang Guo
  • Fuqiang Zhu
  • Yuanchao XieEmail author
  • Jingshan Shen
Original Paper
  • 121 Downloads

Abstract

Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme 4 consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile 8. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate 8, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate 8. However, the key step of monofluorination at the pyrazine C6 position of intermediate 19 or 22 was not achieved.

Keywords

Favipiravir 2-Aminopyrazine Fluorination Sandmeyer reaction 

Notes

Acknowledgements

This work was supported by National Science Foundation for Young Scientists of China (Grant no. 21502209). The authors gratefully acknowledged Topharman Shanghai Co., Ltd for collaboration.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

11696_2018_654_MOESM1_ESM.docx (1.3 mb)
Supplementary material 1 (DOCX 1315 kb)

References

  1. Bai CQ, Mu JS, Kargbo D, Song YB, Niu WK, Nie WM, Kanu A, Liu WW, Wang YP, Dafae F, Yan T, Hu Y, Deng YQ, Lu HJ, Yang F, Zhang XG, Sun Y, Cao YX, Su HX, Sun Y, Liu WS, Wang CY, Qian J, Liu L, Wang H, Tong YG, Liu ZY, Chen YS, Wang HQ, Kargbo B, Gao GF, Jiang JF (2016) Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra leone, 2014. Clin Infect Dis 6310:1288–1294.  https://doi.org/10.1093/cid/ciw571 CrossRefGoogle Scholar
  2. Beldar SV, Jordis U (2009) Synthetic studies towards the antiviral pyrazine derivative T-705. Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, p 13Google Scholar
  3. Cai L, Pike V W, Innis R B (2007) (Aminophenyl)imidazo[1,2-a]pyridine derivatives useful as beta-amyloid PET imaging agents and their preparation. WO2007124345A2 (issued November 1, 2007)Google Scholar
  4. El-Nahas A, Hirao K (1999) A theoretical study on 2-hydroxypyrazine and 2,3-dihydroxypyrazine: tautomerism, intramolecular hydrogen bond, solvent effects. J Mol Struct 4591:229–237.  https://doi.org/10.1016/s0166-1280(98)00270-x CrossRefGoogle Scholar
  5. Furuta Y, Egawa H (2000) Nitrogenous heterocyclic carboxamide derivatives or salts thereof and antiviral agents containing both. European Patent Office WO, 00/10569 (issued March 2, 2000)Google Scholar
  6. Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD (2009) T-705 (favipiravir) and related compounds: novel broad-spectrum inhibitors of RNA viral infections. Antivir Res 823:95–102.  https://doi.org/10.1016/j.antiviral.2009.02.198 CrossRefGoogle Scholar
  7. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL (2013) Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antivir Res 1002:446–454.  https://doi.org/10.1016/j.antiviral.2013.09.015 CrossRefGoogle Scholar
  8. Gao J, Luo X, Li Y, Gao R, Chen H, Ji D (2018) Synthesis and biological evaluation of 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers as inhibitors of influenza a viruses. Chem Bio Drug Des 853:245–252.  https://doi.org/10.1111/cbdd.12382 Google Scholar
  9. Hara T, Norimatsu N, Kurushima H, Kano T (2010) Method for producing dichloropyrazine derivative. European Patent Office WO2010087117 (issued August 2, 2012)Google Scholar
  10. Huchting J, Winkler M, Nasser H, Meier C (2017) Synthesis of T-705-ribonucleoside and T-705-ribonucleotide and Studies of chemical stability. ChemMedChem 129:652–659.  https://doi.org/10.1002/cmdc.201700116 CrossRefGoogle Scholar
  11. Huchting J, Vanderlinden E, Winkler M, Nasser H, Naesens L, Meier C (2018) Prodrugs of the phosphoribosylated forms of hydroxypyrazinecarboxamide Pseudobase T-705 and its de-fluoro analogue T-1105 as potent influenza virus inhibitors. J Med Chem 61:6193–6210.  https://doi.org/10.1021/acs.jmedchem.8b00617 CrossRefGoogle Scholar
  12. Jin Z, Tucker K, Lin X, Kao CC, Shaw K, Tan H, Symons J, Behera I, Rajwanshi VK, Dyatkina N, Wang G, Beigelman L, Deval J (2015) Biochemical evaluation of the inhibition properties of favipiravir and 2′-C-methyl-cytidine triphosphates against human and mouse norovirus RNA polymerases. Antimicrob Agents Chemother 5912:7504–7516.  https://doi.org/10.1128/aac.01391-15 CrossRefGoogle Scholar
  13. Klejch T, Pohl R, Janeba Z, Sun M, Keough D, Guddat L, Hockova D (2018) Acyclic nucleoside phosphonates with unnatural nucleobases, favipiravir and allopurinol, designed as potential inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases. Tetrahedron 74:5886–5897.  https://doi.org/10.1016/j.tet.2018.08.014 CrossRefGoogle Scholar
  14. Li M (2017) Synthetic method of favipiravir. State Intellectual Property Office of the P.R.C. CN107226794A (issued October 3, 2017)Google Scholar
  15. Liu F-L, Li C-Q, Xiang H-Y, Feng S (2017) A practical and step-economic route to Favipiravir. Chem Pap 7111:2153–2158.  https://doi.org/10.1007/s11696-017-0208-6 CrossRefGoogle Scholar
  16. Naesens L, Guddat LW, Keough DT, van Kuilenburg AB, Meijer J, Vande Voorde J, Balzarini J (2013) Role of human hypoxanthine guanine phosphoribosyltransferase in activation of the antiviral agent T-705 (favipiravir). Mol Pharmacol 844:615–629.  https://doi.org/10.1124/mol.113.087247 CrossRefGoogle Scholar
  17. Palamidessi G, Bernardi L (1964) On 2, 5-dichloropyrazine. J Org Chem 298:2491–2492CrossRefGoogle Scholar
  18. Plebanek E, Lescrinier E, Andrei G, Snoeck R, Herdewijn P, Jonghe SD (2017) Emimycin and its nucleoside derivatives: synthesis and antiviral activity. Eur J Med Chem 144:93–103.  https://doi.org/10.1016/j.ejmech.2017.12.018 CrossRefGoogle Scholar
  19. Pu X, Li Q, Lu Z, Yang X (2016) N-Chloro-N-methoxybenzenesulfonamide: a chlorinating reagent. Eur J Org Chem 36:5937–5940.  https://doi.org/10.1002/ejoc.201601226 Google Scholar
  20. Sangawa H, Komeno T, Nishikawa H, Yoshida A, Takahashi K, Nomura N, Furuta Y (2013) Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob Agents Chemother 5711:5202–5208.  https://doi.org/10.1128/aac.00649-13 CrossRefGoogle Scholar
  21. Sato N, Takeuchi R (1990a) Studies on pyrazines; part 20.1 a simple synthesis of 5-substituted 2-amino-3-cyanopyrazines: useful intermediates for pteridine synthesis. Synthesis 199008:659–660CrossRefGoogle Scholar
  22. Sato N, Takeuchi R (1990b) Studies on pyrazines; Part 20.1 a simple synthesis of 5-substituted 2-amino-3-cyanopyrazines: useful intermediates for pteridine synthesis. Synthesis 199008:659–660CrossRefGoogle Scholar
  23. Smither SJ, Eastaugh LS, Steward JA, Nelson M, Lenk RP, Lever MS (2014) Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antivir Res 104:153–155.  https://doi.org/10.1016/j.antiviral.2014.01.012 CrossRefGoogle Scholar
  24. Wang G, Wan J, Hu Y, Wu X, Prhavc M, Dyatkina N, Rajwanshi VK, Smith DB, Jekle A, Kinkade A, Symons JA, Jin Z, Deval J, Zhang Q, Tam Y, Chanda S, Blatt L, Beigelman L (2016) Synthesis and anti-influenza activity of pyridine, pyridazine, and pyrimidine C-nucleosides as favipiravir (T-705) analogues. J Med Chem 5910:4611–4624.  https://doi.org/10.1021/acs.jmedchem.5b01933 CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2019

Authors and Affiliations

  • Qi Guo
    • 1
    • 2
  • Mingshuo Xu
    • 1
    • 2
  • Shuang Guo
    • 1
    • 2
  • Fuqiang Zhu
    • 3
  • Yuanchao Xie
    • 1
    Email author
  • Jingshan Shen
    • 1
    • 2
  1. 1.CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia MedicaChinese Academy of Sciences (CAS)ShanghaiPeople’s Republic of China
  2. 2.University of Chinese Academy of SciencesBeijingPeople’s Republic of China
  3. 3.Topharman Shanghai Co., LtdShanghaiPeople’s Republic of China

Personalised recommendations