The Half Decent Pharmaceutical Chemistry Blog

Pharmaceutical chemistry is back! So far, I've described syntheses of rather banal molecules (although aspirin is obviously the cornerstone of any pharmaceutical chemist), but today, I'm going to discuss how we prepared a proper drug: tacrine.

What's more, there were rumours circulating during the lab course that this particular way of synthesizing this cholinesterase inhibitor was based on an article written by one of the two professors who looked after us. Whether this true true or not, this preparation is alternative to that I studied in one of my Pharma Chem courses.

How can I sum up this drug? It was the very first molecule to be used in the treatment of Alzheimer's disease. Tacrine is an indirect-acting cholinomimetic and (reversibly) binds to the active site of cholinesterase, through a cation-pi interaction and a hydrogen bond, the enzyme which performs the degradation of the neurotransmitter acetylcholine, hence, blocking it.

Cholinesterase was thought to play a major role in the development of Alzheimer's disease.
Although, nowadays, we have realised the progressive degeneration of cholinergic neurons isn't the sole phenomenon occurring in this pathology and tacrine isn't even the cholinesterase inhibitor of choice (due to adverse effects and pharmacokinetics) any more, this drug led the way in the development of many drugs and therapies to tackle this neurodegenerative disease. So, it does deserve a lot of respect.

0.5966 g of 2-aminobenzonitrile were put in a 100 mL round-bottom flask. Then, 1.733 g of zinc chloride powder, which catalyzes the reaction, were added.

The second reagent is ciclohexanone: 0.54 mL were introduced, drop by drop, in the flask.

Then, it was time to heat the mixture and let the reaction occur: the flask was fixed, closed, put in a silicon oil bath and we set the hot plate stirrer to 210°C for a couple of hours.

That was the end, because the synthesis covered two days (we were doing more than a synthesis a day). So, we went home and, on the next day, before we arrived, all the hot plates were turned on again.



At this point, a tough, crunchy, thick and brownish precipitate was stuck onto the inner surface of the flask. To quench the reaction and recover the product, the flask first allowed to cool to room temperature and, then, approximately 10 mL of water and 10 mL of a 5M NaOH solution were added: in these conditions, water quenches the reaction, inactivating zinc chloride.

Predictably, that wasn't sufficient to remove the precipitate from the bottom of the flask, so I had to spend some time removing it with a glass rod, scratching hard.

At last, all the product was dissolved and we stirred the white solution we ended up with for 30 minutes.



The resulting white powder was filtered with a Büchner funnel and suspended in ethanol (using four times the volume of the product, although, theoretically, twice should have been enough). Given that our aim is to synthesize tacrine as its hydrochloride, we added concentrated HCl until the pH of the (orange or red) suspension was undoubtedly acid.

The beaker were all these operations had been performed was carefully placed in a drawer and the yellowish crystal of tacrine hydrochloride were allowed to form and precipitate for approximately 20 minutes.

The product was filtered and we calculated the yield and determine its purity.



Weirdly, no one told us what the yield was supposed to be, so I can't say whether our 52.98% (0.628 g) was a huge success or a pathetic result. Moreover, a PhD student, who was helping the professor, told us that, in her opinion, the scheme we were following was wrong...

Nevertheless, the melting point (282-285°C) and the IR spectrum (I'm sorry for the nujol, Uncle Al) proved the product was at least pure.



A mixture (9:1:0.1) of dichloromethane/methanol/ammonia (to help bases to run, according to their properties) was the mobile phase for a TLC we did to get a better idea of the purity of our product (which was dissolved in hot methanol). The layer was, in the end, exposed to UV light and the stains were identified (picture coming soon).