Lysergic acid diethylamine

Blaho K, Merigian K, and Wingery S (1997) Clinical pharmacology of lysergic acid diethylamine Case reports and review of the treatment of intoxication. American Journal of Therapeutics 4 211-221. 

Application of GC/MS to Studies on the Metabolism of Dependence Causing Drugs. Lysergic Acid Diethylamine (LSD) and Amphetamines Koenshu - lyo Masu Kenkyukai 4 75-82 (1979) CA 92 192081w... 

Lysergic acid diethylamine (LSD) was first synthesized by Dr. Albert Hofftiaan, a Swiss chemist, in 1938. 

LSD from Lysergic Acid. This is based on the formula taken from CA, 50, 10803d (1956). Dissolve 5.5 g of dry lysergic acid in 125 ml of acetonitrile that has been cooled to -10° and cool further to -20° with an external freezing mixture. Add 8.8 g of trifluoroacetic anhydride in 75 ml of acetonitrile (this solution must be cooled to -20° before the addition). Be careful making this addition, so as not to raise the temp, etc. Let stand at -20° until all the lysergic add dissolves (about 1V2 hours). Add 7.6 g of diethylamine (or analog) in 150 ml of acetonitrile and allow to set at room temp in darkness for 2 hours. Evaporate in vacuo to get the LSD, which can be separated from the iso-LSD as above. 

Method A. A slurry of 3.15 g d-lysergic acid monohydrate (monohydrate means dry) and 7.3 g of diethylamine (or 0.1 mole of similar amine) in 150 ml of pure chloroform is heated to reflux. After the lysergic acid is dissolved (a few min) cool the mixture down to where reflux has stopped by removing the heat. Before the mixture cools any further 2 ml of phosphorous oxychloride is added at such a rate as to give reflux (about 2 min). After addition, reflux for 4-5 min further until an amber-colored solution results. Cool to room temp and wash the mixture with 200 ml of 1 M ammonium hydroxide. The chloroform solution was dried with MgSC>4 (this would have to be after separation), filtered, and concentrated by evaporation in vacuo under a temp of 38° (at no time let the temp go over 40°). The last traces of solvent are removed at 2-5 mm. Dissolve the residue in a minimum amount of methanol and acidify with freshly prepared solution of 20% maleic acid in methanol (not aqueous) to precipitate the LSD in its maleate form. Filter the fluffy white needles, wash with cold methanol and air dry to get 2.2 g of LSD that requires no further purification. 

The present invention is characterised in that the azides of d or cZ,Z-lysergic acid or d or cZ, Z-iso-lysergic acid or mixtures of these azides are caused to react with diethylamine and the diethylamides of lysergic acid separated from the reaction products. 

About 1.64 g. of potassium d-lysergic acid hydrate are suspended in about 25 mL. of anhydrous hexane. To the suspension is added a solution of 0.8 g. of sulfur trioxide dissolved in 25 mL. of acetonitrile, the addition being carried out with the reagents maintained at about 5° C., and with sufficient stirring. To the mixture is added a solution of about 1.82 g. of diethylamine dissolved in 25 mL. of ether. 

Rgts Trifluoroacetic acid anhydride Diethylamine Acetonitrile Product d-iso-Lysergic acid diethylamide Ref. Pioch 1956... 

Rgts Propanephosphoric acid anhydride, Diethylamine, Triethylamine Product cZ-Lysergic acid diethylamide Ref Galen 1998... 

The d-iso-fysergic add azide is dissolved in 100 mL of ether. 1 mL of diethylamine is added to the solution and placed in the dark for 24 hours. The solution is evaporated to leave a residue of d-iso-lysergic acid diethylamide. 

Starting Molecule d-/so-Lysergic acid azide Reagent Diethylamine... 

Starting Molecule anhydrous Lysergic acid Reagents Phosgene Diethylamine... 

A solution of 1.1 grams of diethylamine is dissolved in 14 mL of ether with stirring and poured into the solution. Allow to set for five minutes. The solution is then extracted three times with 100 mL of water. The aqueous extracts are combined and saturated with salt. The solution is then extracted three times with 100 mL of ethylene dichloride or appropriate solvent. The solvent is then evaporated to leave a residue of d-iso-lysergic acid diethylamide and d-lysergic acid diethylamide. 

The lysergic acid molecule is the key to all known methods of LSD production. The common thread that all the synthetic routes to LSD share is that the path they travel starts with the naturally occurring alkaloids, the amide linkage is lopped off to give lysergic acid, and then the lysergic acid is reacted with diethylamine to give LSD shown below ... 

This simple and easy reaction is done as follows In a flask wrapped in a single layer of foil are placed 1 gram iso- lysergic acid pyrazole, and 20 ml diethylamine. Diethylamine is a definite do not purchase item. Easy directions for its synthesis are given in this chapter. The two ingredients are swirled until mixed, then allowed to stand at room temperature for about a day. 

The addition of phosgene should bring the lysergic acid suspension into solution. Continue the stirring in the cold and dark for half an hour, then add a previously-cooled solution of 7 grams diethylamine in 100 ml dimethlyformamide. Continue stirring in the cold for half an hour, then allow the flask to warm to room temperature while stirring for a couple of hours. 

The reaction to produce LSD from the acid chloride is then a very simple one. A very standard and time tested procedure would be to mix about 1.5 ml of diethylamine into 50 ml of chloroform for this one half gram example recipe. Then slowly and with stirring the approximately one half gram of lysergic acid halide obtained from the preceeding recipe should be added in small portions to the diethylamine in chloroform. It would be best if the Lysergic acid halide was in solution when it is added to the reaction mixture. We know it dissolves into naptha or hexane, so that is one solvent choice. It probably dissolves into chloroform as well. Once all the lysergic acid... 

They next proceeded to heat this mixture at 195 to 200 °C for a prolonged period of time. For benzyl amine they heated for 8 hours, and for cyclohexylamine they heated for 60 hours. They never tried diethylamine in the experimental results published in Chem Abstracts, but I would think that 24 to 60 hours should be enough for diethylamine. It s not as reactive as benzylamine, but it should be pretty similar to cyclohexylamine. The temperatures used are below the critical temperature of diethylamine, so if the natural lysergic acid holds up to the heat, this method would be the winner of the simplest, best, and highest yielding recipe contest. There is no mention in the Patent as to whether the lysergic acid should be the baked dry form. There is water formed as the result of the reaction anyway, so it seems that small amounts of water carried in from the lysergic acid would be OK. 

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