Terbinafine – mode of action

I watched as another in a series of ads to combat fungal infections and popped the question – what actually put into these wonderful antifungal preparations? As it turned out – there put things, but in many formulations (interestingly – use both indoor and outdoor) is terbinafine, usually in the form of the hydrochloride. Terbinafine structural formula is as follows:

Terbinafine

Curious, is not it? We got there and the naphthalene, a double bond and a triple – and tertiary amine allyl:

amine allyl

właśnie ten element struktury cząsteczki terbinafiny przyporządkowuje ją do grupy leków zwanej alliloaminami. Terbinafine is an inhibitor of squalene epoxidase and that activity by preventing the synthesis of ergosterol, the fungal cells. This affects the permeability of the cell membranes of fungi.

An interesting feature of this drug is, in my opinion, its ability to accumulate in the outer layers of the skin and the epidermis – as well as nails. And here we are talking not only about the situation when terbinafine is used as ointments, but also in tablet form.

However, we can not escape the question – how to plan the synthesis of this target … Let’s get to work.

retrosyntesis of terbinafinyThe center of the molecule falls more to me where we have a double bond. Well TM is divided into two fairly equal parts. In case of terbinafine by a double bond may be twisted as a result of a reaction between an aldehyde and an anion derived from an alkyne acetyl B. Dehydration of the resulting alcohol would allowed to obtain compound 1

4Now’s solve the problem of the synthesis of aldehyde A. Note interesting thing – the nitrogen atom is attached to the carbon atom beta to the carbonyl group. That is, the amine may be obtained by Michael-type addition of the secondary amine to an alpha, beta unsaturated carbonyl compound. I chose for this purpose methyl acrylate E, in order to avoid problems associated with the instability of such unsaturated aldehydes. This brings us to the amine D, which in turn can be prepared by reductive amination of a commercially available aldehyde F.

Let us get back now to the second to the alkyne B. You can not get a traditional method by alkylation acetylates. This would require the use of tertiary alkyl halide (e.g., tert-butyl bromide) and ended by elimination rather than substitution reaction. You should look for another way out.

Now, the terminal can be obtained by reacting the alkyne Corey-Fuchs from the corresponding aldehyde. In our case we had to use the aldehyde pivaloyl, which is commercially available. It can also be obtained by reducing considerably cheaper pivaloyl chloride (and has a pleasant smell as … as the acid chloride).

The key presented in the diagram below (I think I have a weakness for this kind of images).

If everything was as it had planned – is a synthesis would be as follows:

Commentary requires only the transition from the aldehyde 5 in organometallic compound 6 However, in the Corey-Fuchs reaction one of the intermediates is the derivative of the organolithium. Finally the reaction with the appropriate alkyne get water. In our case, but it is pointless because the alkyne, and so we have to convert into an organometallic compound. So it is better to use already in situ formed compound 6 to react with an aldehyde 4.