The Half Decent Pharmaceutical Chemistry Blog

Hello and welcome! There aren't many indirect histaminergic antagonists out there: one of these is disodium cromoglycate.
A pretty foundamental drug, actually: used prophilactically to treat asthma, in children, and allergic rhinitis.

The substance is directly inhaled with a nebulizer (to avoid adverse effects and achieve high concentration where it's needed) and inhibits the release of chemical mediators from mast cells (that's why it's an indirect antagonist).
In particular, it may block acid phosphodiesterase, which results in increase concentration of c-AMP. This prevents the release of allergic mediator. In fact, this is a hypothesis. Which I consider plausible.

Now, let's begin with the synthesis of this good-looking, well-proportioned, symmetric molecule.



I propose the above mechanism for the first step (no idea whether there's another, more correct one reported somewhere): a transesterification seems a reasonable beginning. It's therefore followed by an intramolecular Friedel-Craft acylation (thanks to the low pH) and, for the grand finale, that lovely tertiary hydroxyl group seems to say: "I wanna feel free!"

Mind you, the whole reaction solely provides a very effective protecting unsaturated lactone for the subsequent Fries rearrangement: apparently, we don't want to raise the temperature and we are looking for high (yield and) specificity.

Once we have deprotected our molecule, we treat it with epichlorohydrin and catalyze the reaction with a little bit of piperazine.

Now we need to yield the second ring. Sodium deprotonates the two methyls, which now, being negatively charged, can react with ethyl oxalate.

Finally, we close the ring through another nice intramolecular reaction and dehydration with hydrochloric acid. Final touch, saponification with NaOH.

Nice and smooth, eh?

Good evening and welcome! This week, one of the posts outlined an important feature of physostigmine, so, I've decided to complete the cycle by making of atropine, an important antidote of the aforementioned AChE inhibitor, the protagonist of tonight's SNS.

Atropine is one of the first drugs in the history: a great cosmetic for women, a reliable poison for men and women who had enemies (mm, sounds interesting...). It still has to be considered the leading compound in the design of most of muscarinic antagonists.
Moreover, the drug can be used as a mydriatic or to treat bradycardia, poisoning with AChE inhibitors (including some of those you can find in chemical weapons) and muscarine-producing mushrooms.

Although we are about to start synthesizing it, it has to be said that atropine can be found in fascinating Atropa Belladonna (one of the best-looking plants I've ever seen). Only the levo enantiomer, which is the active one, but the base used for the extraction deprotonates the chiral carbon and, due to the position of the ester, you'll certainly understand while you always get the chiral mixture.

Let's take a look at this (total) synthesis.



The first part of the synthesis begins with phenylacetic acid: two equivalents of a Grignard reagents, basically, are used in a quite uncommon acid-base reaction. We complete the synthesis of tropic acid with formaldehyde and hydrochloric acid. The product will obviously have to undergo chiral resolution, since we need L-hyoscyamine only.

Now let's start to discuss the cool stuff.
An acetal of succinic aldehyde is opened and treated with methylamine and acetone dicarboxylic acid. I must say, I like the proposed mechanism very much and it's, to be honest, the reason why I chose this very synthesis, this week.
I mean, one of my professors of organic chemistry used to say he didn't believe in most of proposed mechanisms (especially when it comes to name reactions). Here I find it extremely plausible, considering that water and CO2 are released.

By the way, after this superb mechanism, we end up with tropinone: hydrogenation will yield two geometric isomers, pseudotropine (which isn't needed) and tropine, we must separate.

Finally, tropine reacts with the tropic acid and we yield atropine, or, to be precise, L-hyoscyamine.

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.

Good evening and welcome! On tonight's episode of SNS we have something slightly different from the previous syntheses. First of all, it's a steroid compound and, secondly, it acts on the cholinergic system, being a competitive antagonist of nicotinic receptors.
Yes, tonight's molecule is Pancuronium.

I definitely chose this molecule more for its synthesis rather than for its pharmacological features. Pancuronium is a curaremimetic and it's generally administered with anesthetics: like tubocurare, its effect is to induce muscle relaxation, which makes easier the work of the surgeon and helps to intubate unconscious patients.

Now, here is the prep. And isn't it a beauty?



We start from a simple steroid that undergoes an esterification with quite an interesting compound: an ester yielded from acetic acid and the enol form of acetone. Only with this kind of ester the reaction is possible.

Steric hindrance plays a key role in the subsequent epoxidation: thanks to the two methyls we can synthesize two epoxyethane in alpha. As oxidizer, we could choose any peroxyacid, unless a derivative of a strong acid.

We need to say something about the opening of the two oxacyclopropanes: the 16-17 one is opened by piperidine on the less substituted carbon. No surprise since piperidine is a base. The other oxacyclopropane (2-3), however, shows a completely different reactivity, because of thermodynamic reasons... Thing is my professor didn't say anything more: so, if you have ideas, please, post a comment.
By the way, this particular reactivity is simply perfect for our purpose, isn't it?

I highlighted the temperature in the concluding step. In fact, at 40°C we methylate both nitrogens, while at 20°C only the one bound to the C16: in a nutshell, as I showed with the synthesis of atenolol, the same pathway leads to molecules of the same family.

Recently this blog has been added to the links list of Totally Synthetic. First of all, I'd like to thank Paul for believing in this project and officially welcome all the usual readers of TS, who, perhaps, have been looking forward to syntheses, found neuroscience instead.

For such a particular occasion, I chose something new here and, I hope, something interesting. What I am going to describe, tonight, is an asymmetric synthesis, the very first one on this blog. In fact, all the previous synthesis, as posted, yielded racemic mixtures. So, you may point out they were unfinished business. Tonight, though, we want final products and that's precisely what we'll get.

The synthesized molecule is atenolol, a beta-1-adrenergic antagonist or, as these drugs are generally called, a beta-blocker. It is widely used in the treatment of cardiovascular diseases, such as hypertension and arrhythmia, but also anxiety.

Now, let's start with the chemical stuff.

As I said, we begin with a reaction involving a chiral compound: a cyclic ketal which is a derivative of S glycerol (since the final product has to be the S enantiomer only). With this chiral molecule we perform a Williamson synthesis in order to add a protecting group.
Then, we open the ketal and activate solely the primary hydroxyl (with tosyl chloride) using pyridine at O°C.
The following reaction is carried out in a mixture of NaOH in ethanol, to promote the formation of a more reactive phenate.
Finally, we deprotect the other primary hydroxyl group with a catalytic hydrogenation and simply repeat what previously done to activate the hydroxyl, so, that it could react with an excess of isopropylamine (ratio 1:10).

Interstingly, varying the para substituent on the phenate will make possible to yield metoprolol or practolol.

Very nice, isn't it?