Lab Notes: Failing to make Pyrimethamine in 2-steps

Lab Notes: Failing to make Pyrimethamine in 2-steps
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    This lab notes video is sponsored by Air. Like money, air will not buy you happiness, but lack of air will bring you a lot of misery. Studies have shown that those without air are miserable for the rest of their lives. So please support Air by making non-polluting choices and encouraging sustainable development. We could all use some Air. Life is better with Air. Greetings fellow nerds. So i was revisiting making pyrimethamine. For those new to my channel or who don't remember, back in 2015 , I started a project to make the anti-protozoal drug pyrimethamine using entirely household chemicals. The drug was famous back then because it was featured in the news media as being a victim of monopolistic price gouging. In anycase, my project took about two years of work and indeed i was able to make a small amount of pyrimethamine from entirely domestically available chemicals like paint thinner and drain cleaner. Unfortunately, while making every precursor might be educational, it's extremely impractical especially if you could had actual access to laboratory chemicals. So I wanted to try making pyrimethamine again but this time trying to attempt it in as few steps as possible using whatever lab chemicals i could get my hands on. Interestingly enough the four thieves vinegar collective non-profit organization already found a relatively short pathway doing exactly that. Through my lab connections i was able to acquire all the precursors so i wanted to give it a try. Now spoiler alert, i'll tell you upfront that I failed, so by all means skip this video if you're looking for a working procedure. What follows is my lab notes for the process. While i have decided to abandon further work in this area someone else may pick up on it. So the idea is rather simple, chemically speaking. Perform a grignard reaction on p-chlorophenyl acetonitrile to form this ketone (p-chlorophenyl) 2-Butanone. Then react it with 2-cyanoguanidine, also known as dicyandiamide, to give our target pyrimethamine. If this works it's way simpler than running through NFL play by play analysis. So first let's make the grignard reagent. We start with 5g of magnesium turnings in 100mL of diethyl ether that was previously dried with sodium and distilled. On top we set up a condenser and addition funnel to which we have a solution of 25g of bromoethane in 100mL of diethyl ether. I'm using an excess of bromoethane as i don't want any magnesium leftover to react with the p-chlorophenyl acetonitrile we'll be using later. Now we slowly drip in the bromoethane solution and it'll start reacting with the magnesium to make ethyl magnesium bromide, our grignard reagent. I have a whole video on grignard reagents which i've linked the video description. Apologies for the cooling tubing flexing into the video. The cold water going through it changes its rigidity. Anyway, after all the bromoethane is added and making sure that the magnesium is fully reacted, we now fill our addition funnel with a solution of 25g of p-chlorophenyl acetonitrile in 200mL of ether and slowly drip it in. The ethyl magnesium bromide should be reacting with the nitrile group on our p-chlorophenyl acetonitrile to yield an imine that we'll later hydrolyze. After the solution is completely added, we let it sit to react for a couple of hours. Now we get a large 1L flask containing a few hundred grams of ice and add in our reaction mixture. This will hydrolyze the reaction products and hopefully produce our target ketone. Be careful as even though it should be ice cold there can be hotspots where the ether boils out. Now the mixture contains a lot of insoluble magnesium hydroxides and bromides that will make this hard to filter. so to destroy them as well as force the hydrolysis reaction forward we add in 100mL of hydrochloric acid. This should react away all the alkaline products. Let me turn off stirring, and there we go, looks good. Now we use a separatory funnel to remove the bottom aqueous layer and retain the upper organic layer. We now transfer the organic layer into a distillation apparatus over a water bath and gently distill off the diethyl ether as well as any unreacted bromoethane. I hope it goes without saying that this whole experiment should be performed in a fume hood as bromoethane is carcinogenic and i have no idea how toxic p-chlorophenyl acetonitrile is. And there is our residue containing our target (p-chlorophenyl) 2-Butanone. Looks like it needs more washing. So we add it to 50mL of water in a separatory funnel and on top we also add 50mL of toluene. Then we give it a shake and let it settle. After removing the water layer we collect our toluene layer containing our product. Now you might be wondering why I used toluene, well that's because we're going to setup a dean-stark apparatus to dry the product. I have another video in the video description where i explain the use of the dean-stark apparatus but basically, some solvents like toluene form azeotropes with water that phase separate on cooling. The design of the dean stark apparatus allows the return of the organic solvent and removal of the water. You can dry solvents this way or in my case, dry substances dissolved in the solvent as well. And here we are, a dried solution of our product in toluene. Now for the second step of the pyrimethamine synthesis. We somehow need to add on this pyrimidine structure. Fortunately, 2-cyanoguanidine pretty much has the whole thing preassembled for us. So to use it, We add in 14g of 2-cyanoguanidine. Now we setup a distillation apparatus and distill off the toluene. Eventually, we should have just a mixture of our ketone and the 2-cyanoguanidine. Now we increase the temperature further until the internal temperature of the mixture is 200 celsius. We can actually leave the apparatus as-is, we don't need to rearrange or remove anything as this reacts. What's happening, or what should be happening, is the 2-cyanoguanidine should be reacting with the ketone compound to form our final pyrimethamine. While this does seem rather unusual, this reaction was performed on many similar ketones in the literature. There is a whole paper all about using this type of reaction to make pyrimidine containing drugs. So it doesn't seem to be a far stretch to extend it to ours. Anyway, according to the literature this should be left for a full day so i'll come back to this tomorrow. And here we are, and this is where things start going very badly. This does not look good. It seems to have solidified into a hard mass of tar. Generally tar is a bad sign. I tried to dissolve the mass in sodium hydroxide solution and ether like i did when i previously made pyrimethamine but it wouldn't dissolve. I then tried water and toluene and that seemed to work much better. At first i thought everything was going well since i got the unique three layer separation i did with pyrimethamine originally. I then proceeded to filter and wash the solids with water and diethyl ether. Here is the product, the color and texture doesn't look right. Although it might just be contaminants. I then proceeded to purify the product by boiling with ethanol. And this is where it fails. Pyrimethamine easily dissolves in hot ethanol. But here it's barely dissolving at all. Whatever this is, it's unlikely it's pyrimethamine. So I filtered it again and sent a sample of the solid for Nuclear Magnetic Spectroscopy analysis. And this is the spectrum of our final product. For comparison, this is the known spectrum of pyrimethamine. They look nothing alike. This looks like the spectrum for ethanol. While I would expect some ethanol contamination, i see very little of any other product. I think this stuff is polymerized melamine. A decomposition product of 2-cyanoguanidine when heated to high temperatures. Polymerized melamine doesn't dissolve very well in the chloroform NMR solvent so it doesn't show up in the NMR spectrum. So it looks like we failed, miserably. The chemistry itself seems sound from the existing literature. I think the problem is a matter of reaction conditions. Maybe i need to heat for less time or more time or do a better job of removing water from the reaction as it forms. Perhaps the reaction temperature needs some adjustment. Perhaps i did make some pyrimethamine but the huge amount of polymerized melamine totally dominated the product and whatever pyrimethamine i had was washed out. Another issue might be a much simpler chemical one. We could simply be reacting the aromatic halide on the p-chlorophenyl 2-butanone with the nucleophilic amine groups on the 2-cyanoguanidine. While aromatic halides are much less susceptible to this reaction than say alkyl halides, perhaps at these high temperatures this reaction goes anyway. This in turn leads to what we top level scientists call a conglomeration of reactants and alternative products. It's a highly scientific term for when the resultant products are too complex to analyze. And we usually abbreviate this term as crap. In this case i have made nothing but crap. You know now that I think about it, I can see why the general literature procedure for making pyrimethamine is this three step process. I'm sure they thought of the two step process since the methods were already well-known decades ago. But the three step process seems more robust. It was robust enough that I, an amaetur chemist using homemade chemicals of questionable purity, was able to do it in my basement. I'll be honest though i think i'm going to abandon this project. I wanted to do it for completeness of my pyrimethamine project but i think the general public has moved on to other issues that occupy the collective consciousness. While I think I could get this to work eventually, or at least ascertain the exact reason why it failed, I think our time is better spent on more rewarding projects like making alkali metals, or converting alcohol into gasoline. So that's what i've been doing this past month. Thanks for watching this failure. And once again please support our sponsor Air. We could all use some Air. Life is better with Air. Special thank you to all of my supporters on patreon for making these science videos possible with their donations and their direction. If you are not currently a patron, but like to support the continued production of science videos like this one, then check out my patreon page here or in the video description. I really appreciate any and all support.
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