Target favipiravir

Target favipiravir
21 March 2020 - X days to Doomsday

New wonder drug Favipiravir is making the rounds in Corona land. (link) Produced by Japanese Toyama Chemical, the drug killed of the virus within 4 days in a Chinese human trial. The firm is a subsidiary of Fujifilm a rare example of obsolete photographic film maker reinventing itself as a hip antiviral drug manufacturer. (How?) The drug has been around for a while and has been found effective for other viruses such as Ebola. The first patent can be traced back to 1999! The compound is surprisingly simple: 6-Fluoro-3-hydroxypyrazine-2-carboxamide and the synthetic procedure reads like an orgchem I exercise in aromatic substitutions.

Methyl 3-amino-2-pyrazinecarboxylate is commercially available, it takes 42 euro to call 1 gram your own. The 1999 patent mentions a 1949 publication for the first bromination step to methyl 6-bromo-3-amino-2-pyrazinecarboxylate (DOI) but as my local library has closed down (quarantine) it is unavailable to me (digital access yes but only through local wifi, works in peace time but obviously not now). As a workaround a 2004 patent describing the same step will have to do (Link) using N-Bromosuccinimide:

The next step converting the amino group to a methoxy group is a Sandmeyer reaction:

Then a Buchwald-Hartwig amination with benzophenone imine:

Then reaction with ammonia converting the ester to the amide to 6-amino-3-methoxy-2-pyrazinecarboxamide:

Then the Olah reagent replaces the amino group with a fluorine group:

Finally, methoxy cleavage with trimethylsilyl chloride / sodium iodide, another George Olah invention (DOI):

The total yield is disappointing: 1 x 0.84 x 0.35 x 0.43 x 0.96 x 0.85 x 0.15 = 0.0054 x 100% = 0.54%. It would set the favipiravir raw material costs for a gram at 7777 euro. A lot of patents have appeared since, next objective is to find out where the improvements (if any) are.

Rik