Mexiletine is an antiarrhythmic drug that is prescribed to patients with certain heart conditions. The patients take either 200 or 250 mg tablets and as the drug has a half-life of 10–12 h, they take two tablets per day.
The 200 and 250 mg tablets are the same price. Previously they were 6c each. Now, for some reason, they are $1.65 each and some patients can’t even find them at this price. These patients have had to forgo their mexiletine and experience much of the discomfort of their ailment. This new price is around $7 per gram. If we could produce mexiletine for $2 per gram and sell it at $4 per gram, we might be able to help these patients and make a profit at the same time.
Synthesis of Mexiletine.
A simple three-step synthesis is used to arrive at Mexiletine.
Synthesis of Mexiletine.
A simple three-step synthesis is used to arrive at Mexiletine.
Synthesis of Mexiletine
The start material, which is the sodium salt of 2,6-xylenol, can be got at easily enough. Sigma-Aldrich sell 2,6‑xylenol in a 10 Kg container for US$524. But there are several other well published methods to prepare 2,6‑xylenol, most of which use phenol as a start material. One method reacts phenol with methanol using Al2O3 and MgO as catalysts.
Chloroacetone is the most difficult. It is somewhat more expensive; Sigma-Aldrich offer 500 g of it for US$205, which is about 10x their price for 2,6‑xylenol. However, it can be prepared by the chlorination of acetone. One method uses CuCl2 and acetone, both of which are cheap enough, but multi-chlorinated side products are common meaning that much effort in distillations and disposals are necessary in order to purify the chloroacetone prepared this way.
The hydroxylamine is not expensive, but it should be noted that it comes as a solution in water as the freebase quickly degrades.
The final step, a hydrogenation, requires hydrogen gas and a catalyst. The catalyst can be re-used for each batch, but the Parr hydrogenator can be a great expense, especially one that can hold 2–5 L.
Chloroacetone is the most difficult. It is somewhat more expensive; Sigma-Aldrich offer 500 g of it for US$205, which is about 10x their price for 2,6‑xylenol. However, it can be prepared by the chlorination of acetone. One method uses CuCl2 and acetone, both of which are cheap enough, but multi-chlorinated side products are common meaning that much effort in distillations and disposals are necessary in order to purify the chloroacetone prepared this way.
The hydroxylamine is not expensive, but it should be noted that it comes as a solution in water as the freebase quickly degrades.
The final step, a hydrogenation, requires hydrogen gas and a catalyst. The catalyst can be re-used for each batch, but the Parr hydrogenator can be a great expense, especially one that can hold 2–5 L.
Another drug which is really considered to be more of an orphan than mexiletine is thiola. Thiola is also known as tiopronin and is used to treat cystinuria. Only about 7000 people worldwide suffer from cystinuria: a condition where the patients develop kidney stones that are pure cysteine.
Cystinuria patients require three tablets of either 250 or 300 mg of thiola per day. Previously these tablets were $1 each but now they are $30 each. This new price is around $120 per gram.
Synthesis of Thiola.
A simple three-step synthesis has been used to arrive at Thiola (tiopronin) and was published in the Chinese Journal of Modern Applied Pharmacy. α-Bromopropionyl chloride and glycine were used as start materials．The mercapto group was introduced by exposure to thioacetic acid, followed by removal of the acetyl group.
Synthesis of Thiola.
A simple three-step synthesis has been used to arrive at Thiola (tiopronin) and was published in the Chinese Journal of Modern Applied Pharmacy. α-Bromopropionyl chloride and glycine were used as start materials．The mercapto group was introduced by exposure to thioacetic acid, followed by removal of the acetyl group.
Chinese synthesis of Thiola
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The glycine is, of course, an amino acid and is freely available from natural sources.
The α-bromopropionyl chloride is obtained by treating 2-bromopropionic acid with thionyl chloride. I have seen Sigma-Aldrich quote a price of US$282 for 1 Kg of 2-bromopropionic acid. That is 28c per gram but I imagine that larger quantities could be found for purchase for even less per gram.
Thioacetic acid can be prepared by the reaction of acetic anhydride with hydrogen sulphide in the presence of a catalytic amount of acetyl chloride or acetyl bromide. I have seen Sigma-Aldrich quote a price of US$848 for 5 Kg of thioacetic acid. That is 17c per gram but I imagine that larger quantities could be found for purchase for even less per gram.
The deprotection step is done here using ammonia. I imagine that its ammonia dissolved in water. There are other options to deacylate a thiol that can be tried if this one proves to be inconvenient.
The α-bromopropionyl chloride is obtained by treating 2-bromopropionic acid with thionyl chloride. I have seen Sigma-Aldrich quote a price of US$282 for 1 Kg of 2-bromopropionic acid. That is 28c per gram but I imagine that larger quantities could be found for purchase for even less per gram.
Thioacetic acid can be prepared by the reaction of acetic anhydride with hydrogen sulphide in the presence of a catalytic amount of acetyl chloride or acetyl bromide. I have seen Sigma-Aldrich quote a price of US$848 for 5 Kg of thioacetic acid. That is 17c per gram but I imagine that larger quantities could be found for purchase for even less per gram.
The deprotection step is done here using ammonia. I imagine that its ammonia dissolved in water. There are other options to deacylate a thiol that can be tried if this one proves to be inconvenient.
