The Half Decent Pharmaceutical Chemistry Blog

Yes! It’s good to be back! Now, before we kick things off with tonight’s show, let’s take a look outside with our correspondent from the red carpet. “Yes, here all the celebrities rushed in as the doors were opened. The fever is high as you can see from They literally couldn’t wait to see what’s new this year and, frankly, I, too, am looking forward to hearing from you! Oh, and your new haircut is very glamorous”

Thanks! Now, after last year’s success, we’ve thought it was time to refresh the show a little bit. So, on this season, every synthesis will have a matching song (ideally) played by the Synthetic Band (hello guys!): this is what you should listen to either reading and, more importantly, doing the synthesis in your homemade, illegal lab. What’s more, this being a pharmaceutical blog, not a chemical one, the drug will also by properly introduced, briefly discussing its pharmacology. Then, the layout: out there, there are countless blogs with syntheses displayed in an undoubtedly simple, user-friendly way, but this isn’t appropriate for a Saturday night show, is it? So, every week, the pathway will be presented in a very user-unfriendly, but very elegant, shape: instead of being white, the background will always be colourful and meaningful, since we’ll try to establish weird link between the synthesis and anything.
Last but not least, we’ve got ourselves an official logo!

Tonight: Touching the monolith will heal your nasty tinea versicolor.
Ketoconazole is certainly a drug that deserves to be treated with a lot of respect: this oral azole was the first to be clinically utilized as antifungal. Generally speaking, azoles act through a selective inhibition of fungal homologue of mammalian cytochrome P450 but, as the differences are just a few, sensitivity is an issue. Predictably, Ketoconazole, oldest member of the family, bears the least degree of specificity. As a result, it’s no longer clinically prescribed for systemic fungal infections. This, however, doesn’t mean it’s no longer present on the market: shampoos and ointments with this molecule are still widely available. In particular, a shampoo can be useful to treat seborrheic dermatitis, while dermatophytosis and candidiasis might be tackled with ointments.

Looking at the structure of the molecule, I find amazing that it’s synthesized from dichlorobenzene. And there are one or two characteristics which have always made me think of the superb sequence of “2001: A Space Odyssey”, with Johann Strauss’s waltz underlining the harmonious ballet of the small shuttle entering the docking site of a much bigger station. First, I like to imagine the imidazole as docking, rather than binding, to the rest of the growing molecule. Then, the final 1- parahydroxyphenyl - 4 - acetyl-piperazine, reminds me of the spaceship USS Discovery 1. So, tonight’s song is Johann Strauss’s “The Blue Danube Waltz”.

As said, the synthesis begins with a Friedel-Craft acylation of a benzene derivative, which yields an ortho acylated product. This, then, undergoes halogenation, so that a lovely ketal.
Then, the diastereoisomers must be separated through fractional crystallization, given that only 2S, 4R and 2R, 4S – Ketoconazole are active. Hydrolysed the ester, the imidazole docks and the hydroxyl group is modified so that a better leaving group is yielded with the mesylate.
Finally, the massive 1- parahydroxyphenyl - 4 - acetyl-piperazine appears and reacts with the mesylate, with a little help from NaH.
Symphonic synthesis!

Good evening and welcome to this very special episode of Saturday Night Synthesis! For the grand finale of the first series we have invited a great guest, tonight.

This molecule is not even a proper drug, but is likely to be the coolest I've EVER described. It was, in fact, designed by the Head of the Department of Pharmaceutical Chemistry of my university, the same man who lectured me on my last course of pharmaceutical chemistry.

This has some consequences: I have the opportunity to describe every detail of tonight's prep and how this molecule was designed.

I begin with the latter. Here is the aim: to find an M2 receptor antagonist with the highest selectivity.

This was their starting point. It's called benextramine, it's an irreversible alpha-1 antagonist: its four amino groups are all protonated at physiologic pH and, through an induced fit mechanism, force the receptor to expose four cysteines, which react with the disulfide, binding covalently.

Now, that's fine, but researchers realised this molecule has competitive antagonism on muscaric receptors as well.

So, they threw away most of the functional groups and reduced everything to a polyamine.



Such a simple backbone is what they later called the (perfect) universal template: theoretically, it could react with any receptor, it actually has specific carriers, all the amines are protonated (only if n > 3, though) so that they could react with carboxyls, hydroxyls, thiols and aromatics.

What's more, the structure is extremely flexible and easy to modify, so it is NOT a toxin.
You can, in fact, vary the distance between the amines and/or add functions to achieve selectivity.

So, there you are: a pretty easy operation. They came up with a simple polyamine, as a base, and turn it into this!



It's called, simply, Methoctramine and I'm glad to report that it's just uncanny.

Its structure can remind you of benextramine but the disulfide bond is gone, so there's no risk of covalent bonds any more.

The result is dramatic. It's, almost equally, incredibly selective for either M2 and M4 receptors and the pA2 is just astonishing: 7.52 on guinea-pig atria (M2).

To sum up, it's not a drug, but a glimpse into the future of M2-selective drugs.

And now, let the synthesis begin!



First of all, if you, too, can't see almost anything of what's written on the arrows, here is a bigger picture.

The first two reagents are rather simple: a diamine and the product of a banal reaction between aminocaproic acid and benzyloxycarbonyl chloride. The ratio is 1:2.

For this first step, we must use dioxane as solvent of either the salification of the acid and its actvation (through an anhydride).
The amide will be easily yielded, thanks to the fact that ethanol and CO2 are released.

Then, the carbamate is removed: my professor said at this point you can't opt for hydrogenolysis, because the adduct isn't soluble in the solvent we should use.
So, they chose HBr in acetic acid.

Moving on, prolonged extraction is needed to achieve a decent final yield. After that, we yield an aromatic Schiff base, which is stabilized by resonance.

Once the said Shiff base has been treated with sodium borohydride, the amide is reduced with borane, at 110*C, in diglyme.

What a massive synthesis, isn't it?

So, that's it for this series: SNS will be back next October.

Meanwhile, I hope you will enjoy my other posts as well: don't worry, pharma chem freaks, because there will always be room for such an important subject here!

Hello and welcome! It's not unusual for this series to feature rubbish drugs with great synthesis: pancuronium, for example, and cyproheptadine, more recently.

Now, it's time for another one: dicycloverine.

At this point, you might be taken aback thinking: "God, I've never heard this name!"

Well, you actually have a point. Dicycloverine is just another name for the very famous...ehm...dicyclomide!

Dicycloverine is a M1-selective antagonist drug solely used for the treatment of irritable bowel syndrome, whose hallmarks are abdominal discomfort, alliterated habitat and abnormal frequency and consistency of bowel movements.

Oddly, either diarrhea or constipation can be a feature. This particular drug, for example, as a parasympatholytic, is useful only when IrBS is characterised by the latter and hypermotility.

This, though, remains an infrequently prescribed drug.

So, let chemistry explain why I chose this very synthesis!

Benzyl chloride is the starting compound. Its reaction with KCN yields the nitrile derivative, which will be useful later on.

The following step has to be performed with a low concentration of sodium amide, so that only the intramolecular cyclization takes place.
Let me tell you I like when such simple reactions result so smoothly in a much more complicated product.

Now, it's time to hydrolyze the nitrile with sulphuric acid and ethanol.

We then add a derivative of ethanolamine: everything has to be carried out in toluene in the presence of metallic sodium, in order to deprotonate the said ethanolamine.
So, you will have the priceless opportunity to prepare the mixture on your own.

For the grand finale, here comes the reaction which stole my heart (this week). What's more thrilling than a benzene reduced to cyclohexane? Moreover, it's not the most common of the  reactions.
This hydrogenation requires platinum oxide in acetic acid, which is undoubtedly a nice choice, I think.

Witty and rather handsome.

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.

Hello and welcome! Today has been the coldest day of this winter so far, here in sleepy Bologna. Spring looks incredibly far-off, as you can see.

That's the reason why I chose a typically spring drug, Cyproheptadine: because discussing such a spring drug will eventually warm your heart a little bit. Or make you be grateful for the fact that it's winter now, if you are an asthmatic or suffer from hay fever.

In fact, as you might know, this drug belongs to the group of first-generation antihistamines, as these mlecules are named after their main characteristic: H1 receptor antagonism.

Generally speaking, they block part of those phenomena commonly experienced while histamine release is disproportionated and massive (i.e. allergy): bronchoconstriction, increased secretion of mucous and contraction of gastrointestinal smooth muscle.

Cyproheptadine, in particular, has antiserotonin activity too, which explains why it can be useful in the treatment of so-called cold-induced urticaria; on the other hand, it has very mild anticholinergic activity: this means it's unlikely to be effective in the treatment of, say, non-allergic rhinorrhea at therapeutic dose.

On the other hand, though, it nicely induce moderate sedation only: this feature is emphasized when compared to, for example, diphenydramine or the vast majority of (old and cheap) antihistamines.

But, hey, it's time to take a look at how we synthesize this drug...before pollen arrives.



This synthesis begins with two common substances: phenylacetic acid and phthalic anhydride. Now, the former has acidic benzylic hydrogens and that's the key to understand the very first step, which takes place at high temperature.

The reaction is thermodynamically favourable since it releases water and carbon dioxide.

Then, an unusual opening is carried out: hydroiodic acid and elemental phosphorus are involved. Not only do these reactants open the former anhydride, but they also reduce the double bond.

Well, actually that doesn't help that much, but the said bond will be easily yielded once again later and, in my opinion, this whole reaction is rather elegant.

At this point, we must close the structure through a simple intramolecular Firedel-Craft acylation.

Bromosuccinimide is then used to brominate the cycloheptanone. In order to yield the double bond, I propose a mixture of tert-butanol and its potassium salt.

Lastly, the Grignard reagent. I'm just thinking: curiously, this is the very first time a Grignard appears in one of our weekly syntheses, isn't it? Well, the attack quickly leads to a dehydration, which results in the second double bond.

Nimble and elegant.