An Efficient 4-Step Synthesis of Favipiravir with Industrial Potential

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.