Saturday Night Synthesis: Cimetidine
Good evening and welcome! Tonight we have a good, old friend of this blog: Cimetidine. If you remember, H2 antagonists were the first protagonists of Sunday's Family Reunion.
However, not only do these molecules have interesting pharmacological properties, but they also have pretty awesome syntheses.
More than that, Cimetidine was the very first member of this class of drugs, so, it deserves to be the first to be featured here.
Predictably, being the first means it's also the weakest: it needs the highest frequency of administration (or quantity of substance), because it has the lowest bioavailability, half-time and area under curve.
Moreover, whereas all the other H2 antagonists were remarkably improved, for what concerns the interactions, Cimetidine remains, sadly, a potent inhibitors of many members of the P450 enzyme family.
This means, in a nutshell, it dramatically increases the half-life of an enormous number of different types of drugs: warfarin, theophylline, lidocaine, quinidine, propranolol, all the tricyclic antidepressants, benzodiazepines and calcium channel blockers.
Even the adverse effects: in fact, it's the only H2 antagonist capable of inducing gynecomastia, impotence and galactorrhea, since inhibits the binding of dihydrotestosterone to androgen receptors, the metabolism of estradiol and increases serum levels of prolactin.
So, here we are: an old drug that should be handled like, say, a 400-lb. dewar of liquid nitrogen down a flight of stairs. You know what I mean, don't you?
However, as the oldest member of such an important group, as I said, it deserves to be the protagonist of this episode.
So, let's take a look at how the Koreans have managed to synthesize it.
We begin with a very smart reactant, formamidine, which reacts with an alpha bromo ketone. Their reaction leads to a substituted imidazole, which closely resembles histamine.
We must, then, get rid of the ether.
The use of concentrated hydrobromic acid doubles as a sort of protection for the cysteamine. Let me explain: once the ether is gone, the solution has still very low pH, which is precisely what we need to avoid the amino group reacting with our imidazole.
To sum up, the acid guarantees that only one product will be yielded, in the end.
Cimetidine was the first derivative of guanylhistamine, the lead for all the H2 antagonists, with a cyanamide motif: this group was a terrific improvement of metiamide, which was theoretically effective as H2 antagonist, but so toxic (due to reactions involving its tautomer) that it never became a drug.
A simple reaction of our adduct with the cyanamide of dithiocarboxylic acid results in the perfect substrate for the final step, which involves, simply, methylamine.
Genial and smooth.
