File:Pyrimethamine traditional synthesis.png

As described at OpenSourceMalaria:

The historic synthetic routes1,2 to pyrimethamine (Daraprim) generally start with an p-chlorophenylacetonitrile 1. This is condensed with ester 2 under strongly basic conditions to give 3 (tautomeric with a stabilised enol form), which is then methylated to give enol ether 4. This alkylation has most commonly been performed using toxic and explosive diazomethane1,3; something that should certainly be avoided in teaching laboratory classes. Another possible alkylation method uses orthoformates4,5, which are significantly less hazardous. However, other literature reports indicate that these conditions are not effective at alkylating the enol.

Finally, pyrimethamine 5 is obtained from the enol ether 4 by condensation with free guanidine in refluxing ethanol. As guanidine is strongly basic (the guanidinium ion being strongly resonance stabilised), the reaction mixture must first be prepared from a guanidine salt and an alkoxide base. Most of the literature reports involve dissolving sodium into ethanol to form sodium ethoxide, followed by addition of guanidine hydrochloride to form free guanidine. This mixture is reported to be very air sensitive, as dissolved atmospheric CO2 will quickly form the guanidinium carbonate.

In summary: the literature route involves three reaction steps, of which two require alkoxide bases, and one generally involves diazomethane. Each of these classes of reagents would be challenging to use in a teaching laboratory.

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