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Synthesis of Muscimole

Muscimole can be found in the mushroom species Amanita muscaria (fly agaric). It is a powerful drug (e.g., 10 mg for oral dose) but its synthesis is rather difficult. I feel that there are better drugs that can be made much more easily and cheaply, so I have only included two formulas for the drug. The first formula uses ibotenic acid for a starting material. To make ibotenic acid requires more work than to make muscimole, but ibotenic acid can be purchased from many suppliers at a lower cost than to synthesize muscimole. Ibotenic acid is stocked by Aldrich, Sigma, Chemical Dynamics, Regis Chemical Reagents, etc. Look in Chemical Sources for more suppliers and then call for the best price, as sometimes there is a large price difference. Ibotenic is not a psychedelic (not a useful one anyway), so you could purchase it without alerting the DEA. The last I heard, muscimole is not illegal either, so you may be able to order that through the mail also.

Muscimole from Ibotenic Acid. Reflux ibotenic acid in 10 times its weight of water.

Muscimole. CA, 65, 2266 (1966). Dissolve 626 g of 2-(2-nitrovinyl)-furan in 3.1 liters of 48% HBr and 6.25 liters glacial acetic acid, then heat on steam bath for 9 hours. Concentrate by evaporating in vacuo to 3 liters. Add 3 liters of water, boil and add decolorizing carbon, filter hot, cool, and filter again. Extract the filtrate with 2 liters of chloroform using small portions.

Add residue to the precipitate and recrystallize with benzene-cyclo-hexane to get intermediate. 44 g of the above intermediate is added to 440 ml coned sulfuric acid and add 80 g of CrO3 (that has been added to 80 ml of water) dropwise over three hours while maintaining a temp of 15-20C. Pour onto 800 g of ice and extract the aqueous solution with three 500 ml portions of ether. Evaporate the ether in a vacuum to get 3-Br-isoxazole-5-COOH and recrystallize from benzene-toluene to purify. Dissolve 30 g of this above product in 500 ml methanol along with 27 g of KOH and stir for 2 hours at 140C. Cool and add l.5 liters of water and extract with three 1.5 liter portions of ether. If you encounter much color, you should boil for a short time with a small amount of decolorizing carbon, then filter hot and acidify with small portions of concentrated HCl acid. Filter cool and recrystallize with benzene to get 3-methoxy-isoxazole-5-COOH. Dissolve 5.2 g of this last compound with 100 ml of 3% HCl acid in methanol and reflux for 3 hours. Evaporate in vacuo and recrystallize the residue with petroleum ether. Add 0.8 g of the recrystallized product with stirring to 40 ml of aqueous ammonia (have a density of .90) and stir for 30 min at room temp. Filter and wash with cold water, then dry, to get 500 mg of product, which is a carboxamide. Dissolve 37.8 g of NaBH4 in 100 ml of diglyme and 32 ml BF3 etherate in diglyme, then add to 4.6 g of the carboxamide above in 100 ml of tetrahydrofuran and reflux for 48 hours. Add hydrogen chloride (HCl acid), evaporate in vacuo and dissolve the residue in water. Basify with 50% KOH and extract with ether, dry, filter, evaporate in vacuo to get intermediate. One g of this intermediate is added to 10 ml of glacial acetic acid and 4.5 g of HBr and reflux for 1 hour. Evaporate to get muscimole. As you can see, this is a long, drawn out process that is not worthwhile in cost or yield. I figured that, for the price of the chemicals, you could buy 4 or 5 times as much ibotenic acid and save your self days of hard work, plus gain much more product than the formula could ever give. There are lots of different formulas, but the result is the same.

Reference: "Recreational Drugs" by Professor Buzz