The Half Decent Pharmaceutical Chemistry Blog

Good evening and welcome. We start tonight pretty much where we left yesterday: with antipsychotics.
Among these amazing molecules, I have chosen Haloperidol, because it's a drug with very interesting features.

It made history (it was the first butyrophenone to be marketed), it's well-priced (generics are available), it's very dangerous (being one of the oldest, it has an enormous extrapyramidal toxicity: in fact, I think it's THE most extrapyramidally toxic neuroleptic, ever!), it perfectly sticks to the dopamine hypothesis (activity on 5-HT2 and alpha1 receptors is neglegible, whereas it has a whopping pA2 of 8.4 for D2 receptors!) and its synthesis is very, very weird.

So, let's check out how to synthesize this drug.

I must tell you something that might shock you: I was literally taken aback when I saw the beginning of this prep. Frankly, I can't see the rationale behind it.
I mean: the very first product is really unexpected and, I guess, dramatically unstable.

Then, there's the dehydroxylation.
I'm used to them whenever there are tertiary hydroxyls or when they eventually yield a tremendously favouable product after some lovely rearrangement. But this particular one leaves me wordless and confused.

No matter, we move on and find a much more friendly series of rearrangements (check out the by-product). Moreover, throughout the synthesis, amazingly stable tertiary carbocations appear.

Oh, and that makes me feel good!

I must say that all the intermediate products before the double bond is ready for adding the tertiary hydroxyl have been only guessed. That's the same for the mechanism of the said rearrangements, of course, but they seem plausible, don't they?

Then the synthesis is almost over: we yield the other half molecule through a simple Friedel-Craft acylation and it'll react with the one we have yielded nicely.

Mind-blowing, that's for sure.

Good evening and welcome. Our protagonist, tonight, is an old friend of this blog: Physostigmine.
It was the main character of one of my "philosophical" posts and it will appear, again, tomorrow, in our New Year's Eve special of Sunday's Family Reunion.

That's why I am not to annoy you with the usual overwhelming list of pharmacological properties.

All I want to point out is that this has been the lead for almost every cholinesterase-inhibiting drug. Like most of leads, physostigmine is a natural substance, found in Calebar beans, an African leguminous plant, also known as physostigma venenosum.

One of its first clinical uses was the treatment of glaucoma, and that's obvious, considering it acts, in the end, by increasing muscarinic effects: in a nutshell, this would eventually result in the contraction of the ciliary body.

But, now, let the synthesis begin!



An indole is what we have in the beginning: however, we can easily add a side chain, which provides the easiest way to yield the third ring (and that aminal which explains its degradation at low pH).

First, however, we must make sure the product will present the right, active stereochemistry (3aS and 8aR, to be precise).
Two fractional crystallizations are carried out: in the former we precipitate (part of) the useless enantiomer as a oil. Then, we decant the solution, dry the supernatant and repeat the crystallization. Just in case...

Once with the right enantiomer, the rest is nicer and smoother: in fact, a smart reductive amination follows which, amazingly, is characterized by a cis-attack.
And this means no need to perform any additional fractional crystallization.

Finally, the carbamate, but, in order to yield it, we first have to get rid of that nasty ethoxyl  and get a hydroxyl.
Unfortunately, the aminal means you have to forget about acids. Or have you?

You see, aluminium chloride may not look like an acid, at first glance, but is, actually, a proper Lewis acid, which doesn't break the aminal, but does exactly what we need on the benzene ring.
Methyl Isocyanate concludes the synthesis with the final appsarance of the carbamate, the key factor of the whole drug.

Very beautiful, indeed.

Good evening and welcome to the Christmas's special of S.N.S. Now, the main feature of this special is that there is nothing which may even remotely remind you that Christmas is coming.

What we have, instead, is the nice synthesis of chlordiazepoxide. This is obviously a benzodiazepine, so, it has sedative properties. Because benzodiazepines will be featured in the Psycho Week, I'm not to describe their pharmacology.

For what concerns this particular drug, interestingly, it was the first benzodiazepine to be launched on the market and the biotransformations it undergoes, once absorbed, lead to remarkably active metabolites.

Now, let's take a look at this accidentally discovered synthesis.



We begin with a Friedel-Craft acylation, which requires zinc chloride, instead of traditional aluminum trichloride. However, because of the nature of the two molecules, the very first reaction taking place is between the amino group and the acyl chloride, yielding an amide. Then, the acylation occurs, but, because the solution will contains unreacted amines, these can attack the carbonyl.

Actually, this amino group will therefore yield an imine: the pH of the solution has been properly adjusted, I guess.
No matter, we end up with a very unstable adduct: that Schiff base easily reacts with water and this is very nice, since we finally have what we were looking for.

We add hydroxylamine and, then, that particular acyl chloride. And here comes the tricky question: which group will react with the carbonyl?

Now, this whole first part of the synthesis, so far, was designed so that the hydroxyl would  attack the carbonyl, but, surprisingly, it doesn't, whereas that nitrogen succeeds.

We've got now another adduct which is likely to lead to a much thermodynamically stabler molecule, the final product, luckily.
Methylamine sort of ignites this 'rearrangement' or intramolecular series of reactions, if you prefer.
Please forgive me if the arrows don't perfectly point towards the atom but they seem to indicate bonds: I'm still learning how to use that programme.

What I hope you to check is if I've correctly drawn what reacts with what.

To sum up, by the way, a pretty successful mistake, eh?

Good evening and welcome! We have a very special guest tonight: Ephedrine. I should say a Chinese guest, actually, since this drug has been used there for 2,000 years!
We had to wait until the 1920s, when it was launched on the Western markets as the very first sympathomimetic drug ever.

Interestingly, although a phenylisopropylamine and not a proper cathecolamine, ephedrine shows the same effectiveness of terrificly potent sympathomimetics. This drug has incredibly high bioavailability, its effect lasts many hours, it's a reliable decongestant, has a use in asthma and, but is generally considered an adverse effect, central stimulant. How it acts? It increases the release of norepinephrine.

Now, let's see how to synthesize it.



Well, it's certainly not the most advanced synthesis, but, none the less, I chose it because I find amazing these easy preps of natural drugs, in particular when they are so popular.

This one, besides, has some party pieces and it's likely to be the more useful I've discussed here, so far.

Although we begin with a banal Friedel-Craft acylation, the following step is just brilliant: a rather simple mechanism explains how our mighty phenyl ketone reacts with an alkyl nitrite.
However, you can't use ANY alkyl nitrite, but, apparently, R should present six carbons.

The oxime becomes a diketone thanks to mild acidic conditions. But this diketone is a definitely a cool molecule. The two carbonyls have slightly different reactivity: the later yielded is more likely to react, because it is more aliphatic.
Thus, it will be the only one reduced by the final reductive amination.

Good evening and welcome! Tonight we have a very smart drug with a pretty mysterious synthesis (you'll understand soon).

Fluphenazine is an antipsychotic phenothiazine, one of the safest, actually. Still, those phenothiazines with piperidine in their side chain are less potent than aliphatic derivatives, but they are also more selective and have less adverse effects.

Phenotiazines are the first drugs designed for the treatment of schizophrenia. The dopamine hypothesis, now proved partly wrong and simplistic, clarified the paramount importance dopamine antagonists can have in this disorder. Consistently, phenotihiazine are all dopaminergic antagonists.

Fluphenazine is no exception, but it has an additional feature. I circled the very last part of the side chain because the hydroxyl group is very useful: pharmacokinetics has been dramatically improved by pharmaceutical industries which launched esters of fluphenazine (decanoate and enanthate, namely) with remarkable retard-effect.
That was why a common problem with neuroleptic lies in their dosage: the patient often refuses to take medications or is unable to take them regularly.

To sum up, a very smart drug: selective, less dangerous and with long-lasting effects. And here is its synthesis.

We start with an Ullmann reaction: the carboxyl group provides a lovely activating function since this is basically a particular SNA.
The aforementioned group is then removed without the use of any chemical: heat is sufficient with benzoic acid derivatives. How smart, isn't it?

Now, here is the mysterious step. My professor of pharmaceutical chemistry admitted he had no clue, so, I expect you, proper organic chemists, to come up with a brilliant explanations: how can sulfur (at high temperature) promote this cyclization?

Having pointed this out, let's move on. What we have described so far is a standard procedure to yield the common backbone: phenothiazine.
We must now deprotonate phenothiazine and add the first part of the side chain.

For what concerns the second half, before the retrosynthesis could occur, we have to carry out a reaction between piperazine and ethyl chloroformate, at pH 5.5, as we did for Prazosin, to 'protect' a nitrogen.
Then, this amazing prep ends with a reaction between the two by-products, which, I think, is performed in mild basic conditions.