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An Efficient 4-Step Synthesis of Favipiravir with Industrial Potential
Corresponding Author(s) : Naresh Kumar Katari
Asian Journal of Chemistry,
Vol. 35 No. 5 (2023): Vol 35 Issue 5, 2023
Abstract
An efficient, economical synthetic route is developed for the antiviral drug favipiravir using a four-steps instead of a six-step protocol. Starting with 6-bromo-3-hydroxypyrazine-2-carboxamide the method offers an overall 65% molar yield. The prime intermediate 3,6-difluoropyrazine-2-carbonitrile was synthesized by reacting 3,6-dichloropyrazine-2-carbonitrile with potassium fluoride using tetrabutyl- ammonium bromide (TBAB) as a phase transfer catalyst in toluene and DMSO medium at reflux temperature (120 ºC). A simple purification method from fluoro intermediate was developed by making dicyclohexylamine salt and a neutral compound using hydrogen peroxide. The prepared pure favipiravir is fully characterized using NMR Mass and IR techniques. Validated analytical HPLC methods assessed the purity of the drug. The quality of the drug synthesized in terms of assay and impurities is well within the ICH and pharmacopeia standards.
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- Q. Chen and Y. Guo, ACS Infect. Dis., 2, 187 (2016); https://doi.org/10.1021/acsinfecdis.5b00139
- A.S. Monto, Vaccine, 26, D45 (2008); https://doi.org/10.1016/j.vaccine.2008.07.066
- N.M. Bouvier and P. Palese, Vaccine, 26, D49 (2008); https://doi.org/10.1016/j.vaccine.2008.07.039
- Y. Wu, Y. Wu, B. Tefsen, Y. Shi and G.F. Gao, Trends Microbiol., 22, 183 (2014); https://doi.org/10.1016/j.tim.2014.01.010
- World Health Organization, Influenza (seasonal) fact sheet 211, March 2014); http://www.who.int/mediacentre/factsheets/fs211/en/
- K. Das, J. Med. Chem., 55, 6263 (2012); https://doi.org/10.1021/jm300455c
- M.G. Ison, Curr. Opin. Virol., 1, 563 (2011); https://doi.org/10.1016/j.coviro.2011.09.002
- Y. Furuta, B.B. Gowen, K. Takahashi, K. Shiraki, D.F. Smee and D.L. Barnard, Antiviral Res., 100, 446 (2013); https://doi.org/10.1016/j.antiviral.2013.09.015
- F.G. Hayden and N. Shindo, Curr. Opin. Infect. Dis., 32, 176 (2019); https://doi.org/10.1097/QCO.0000000000000532
- Y.-X. Du and X.-P. Chen, Clin. Pharmacol. Ther., 108, 242 (2020); https://doi.org/10.1002/cpt.1844
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- G. Poland, R. Jacobson and I. Ovsyannikova, Clin. Infect. Dis., 48, 1254 (2009); https://doi.org/10.1086/598989
- M. Memoli, R. Hrabal, A. Hassantoufighi, M. Eichelberger and J. Taubenberger, Clin. Infect. Dis., 50, 1252 (2010); https://doi.org/10.1086/651605
- Y. Furuta, T. Komeno and T. Nakamura, Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci., 93, 449 (2017); https://doi.org/10.2183/pjab.93.027
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- F. Shi, Z. Li, L. Kong, Y. Xie, T. Zhang and W. Xu, Drug Discov. Ther., 8, 117 (2014); https://doi.org/10.5582/ddt.2014.01028
- T. Zhang, Kong, L. Li, Z. Yuan and H. Xu, Chin. J. Pharm., 44, 841 (2013).
- F.-L. Liu, C.-Q. Li, H.-Y. Xiang and S. Feng, Chem. Pap., 71, 2153 (2017); https://doi.org/10.1007/s11696-017-0208-6
References
Q. Chen and Y. Guo, ACS Infect. Dis., 2, 187 (2016); https://doi.org/10.1021/acsinfecdis.5b00139
A.S. Monto, Vaccine, 26, D45 (2008); https://doi.org/10.1016/j.vaccine.2008.07.066
N.M. Bouvier and P. Palese, Vaccine, 26, D49 (2008); https://doi.org/10.1016/j.vaccine.2008.07.039
Y. Wu, Y. Wu, B. Tefsen, Y. Shi and G.F. Gao, Trends Microbiol., 22, 183 (2014); https://doi.org/10.1016/j.tim.2014.01.010
World Health Organization, Influenza (seasonal) fact sheet 211, March 2014); http://www.who.int/mediacentre/factsheets/fs211/en/
K. Das, J. Med. Chem., 55, 6263 (2012); https://doi.org/10.1021/jm300455c
M.G. Ison, Curr. Opin. Virol., 1, 563 (2011); https://doi.org/10.1016/j.coviro.2011.09.002
Y. Furuta, B.B. Gowen, K. Takahashi, K. Shiraki, D.F. Smee and D.L. Barnard, Antiviral Res., 100, 446 (2013); https://doi.org/10.1016/j.antiviral.2013.09.015
F.G. Hayden and N. Shindo, Curr. Opin. Infect. Dis., 32, 176 (2019); https://doi.org/10.1097/QCO.0000000000000532
Y.-X. Du and X.-P. Chen, Clin. Pharmacol. Ther., 108, 242 (2020); https://doi.org/10.1002/cpt.1844
V. Deyde, X. Xu, R. Bright, M. Shaw, C. Smith, Y. Zhang, Y. Shu, L. Gubareva, N. Cox and A. Klimov, J. Infect. Dis., 196, 249 (2007); https://doi.org/10.1086/518936
G. Poland, R. Jacobson and I. Ovsyannikova, Clin. Infect. Dis., 48, 1254 (2009); https://doi.org/10.1086/598989
M. Memoli, R. Hrabal, A. Hassantoufighi, M. Eichelberger and J. Taubenberger, Clin. Infect. Dis., 50, 1252 (2010); https://doi.org/10.1086/651605
Y. Furuta, T. Komeno and T. Nakamura, Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci., 93, 449 (2017); https://doi.org/10.2183/pjab.93.027
V. Madelain, T.H.T. Nguyen, A. Olivo, X. de Lamballerie, J. Guedj, A.-M. Taburet and F. Mentré, Clin. Pharmacokinet., 55, 907 (2016); https://doi.org/10.1007/s40262-015-0364-1
F. Shi, Z. Li, L. Kong, Y. Xie, T. Zhang and W. Xu, Drug Discov. Ther., 8, 117 (2014); https://doi.org/10.5582/ddt.2014.01028
T. Zhang, Kong, L. Li, Z. Yuan and H. Xu, Chin. J. Pharm., 44, 841 (2013).
F.-L. Liu, C.-Q. Li, H.-Y. Xiang and S. Feng, Chem. Pap., 71, 2153 (2017); https://doi.org/10.1007/s11696-017-0208-6