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!