The complete synthesis of favipiravir from 2-aminopyrazine

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 POCl 3 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.

Cyanorona-20: The first potent anti-SARS-CoV-2 agent

“…Cyanorona-20, quite like its parent compound favipiravir, is expected to be a tautomeric molecule [29] . According to the computational simulations studies, in almost all cases the molecule favors the enol-like tautomeric structure (the predominant form), which is substantially much more stable in the aqueous media as compared to the keto-like tautomeric structure as shown in Fig.…”

Recent advances made in the synthesis of small drug molecules for clinical applications: An insight

“…In 2019 Guo et al. developed a new approach [ 66 ] which involved the conversion of pyrazin-2-amine into Favipiravir through a number a reactions such as regioselective chlorination, bromination, Pd-catalyzed cyanantion, Sandmeyer reaction for conversion of amine group into chlorine via diazotization, replacement of chlorine group with fluorine through aromatic nucleophilic substitution reaction followed by hydrolysis reaction, etc. Finally, thus obtained 3,6-difluoropyrazine-2-carboxamide was converted into Favipiravir in presence of sodium bicarbonate and 1,4-dioxane-water system ( Scheme 10 ).…”

Tackling COVID‐19 Using Remdesivir and Favipiravir as Therapeutic Options

“…In both routes, a large amount of phosphoryl chloride (POCl 3 ) is used and this raises environmental concerns. More recently, Guo and co‐workers have synthesized FPV by using 2‐aminopyrazine as a starting material, providing a simple route for the generation of 8 [45] . This new process does not involve the use of POCl 3 and gives a good yield (Figure 2, Route 4).…”