The Half Decent Pharmaceutical Chemistry Blog

Good evening and welcome! Chemical Forums supremo Mitch recently defined this blog as full of "hard-core pharmaceutical" stuff. I must say I really like this definition.
I have liked it so much that, tonight, I've got something even more radical for you. Tonight, SNS gets INSANE! Frankly, I can't find a better way to describe this synthesis of an already genuinely insane drug: Atracurium

Yes, another curare-like substance, a non-depolarising neuromuscular blocker used in hospitals to relax skeletal muscles.

I said this is insane because the drug was designed to look like an outrageous poison such as curare and because this (total) synthesis starts from a simple substance your grandma may use to prepare sweet cakes and other highly gratifying stuff: vanillin.
We therefore turn it into a derivative of less-likely-to-be-found-at-grandma's-house papaverine: tetrahydropapaverine. Oh, well, it depends on your grandparents, of course...

So, let's put an end to this talking: it's time to drown into madness.



The first steps are common and quite boring, although, as my professor kindly pointed out, you'd better make sure you don't have acid in your mixture when adding KCN.

The solution of cyanide is separated in two groups (no idea about the ratio): the former undergoes hydrogenation, whereas the latter is put in an aqueous solution of sulphuric acid. Neither HCl nor nitric acid: frankly, I inferred the reason is because my professor doesn't like them. Oh, well, he said HCl may hydrolyze the ether, even if diluted, and nitric acid is annoyingly photosensitive...
Then, the acid is converted into the more reactive acyl chloride and reacts with the amine.

Here comes the tricky part: phosphoric trichloride acts as a Lewis acid (yes, I said acid, not base) and as a dehydrator. Phosphorus activates the carbon and, in my opinion, the tertiary hydroxyl facilitates the following dehydration.

What I labelled an insane reactant is yielded by a reaction between two equivalents of but-2-enoyl chloride and one of pentandiol.

That's it: we methylate and here is our final, outrageous, insane product.