Synthesis of Fomepizole

Hi all,

I have a friend that suffers from a severe case of "asian glow", to the point where even a few sips of beer will put them out of commission with a flushed face, headache, and nausea. While I would never consider administering anything I might make to this person, it got me thinking about possible solutions to my friend's problem. AFAIK, "asian glow" is caused by a buildup of acetaldehyde in the body, due to a more active version of the alcohol dehydrogenase enzyme that some asian people possess. Inhibiting the alcohol dehydrogenase enzyme should reduce the rate at which acetaldehyde is produced, allowing the body to process the acetaldehyde as it is formed, solving the problem.

An example of an alcohol dehydrogenase inhibitor already used in medicine is Fomepizole, or 4-methylpyrazole. An example synthesis is shown below:



This route doesn't seem very OTC, so I wanted to hear your thoughts on an alternate synthesis pathway I've been trying to come up with.

To start, one would first synthesize methylmalonic acid by performing a Claisen Condensation with methyl acetate and methyl propionate to form the beta-ketoester, methyl acetopropionate. Then using hypochlorite, one should be able to perform a haloform reaction to reach a methylmalonic acid (Fig. 1).



By condensing methylmalonic acid with hydrazine acidified with sulfuric acid, one should arrive at a pyrazole derivative, in a similar way to the reaction shown below:



Finally, assuming it is similar enough, one would perform a reduction like the one described here for barbituric acid to arrive at Fomepizole:



I feel like it's a little thrown together, but do you guys think I'm on the right track with this?

I guess one of my questions is, can you perform a condensation with methylmalonic acid and hydrazine, or does the methylmalonic acid have to be an ester first?

While this might be more amateur friendly, (no BF₃), I see it still uses POCl₃, which is still a problem.