Lysergic Acid Morpholide

The ethylene dichloride extracts are combined and are evaporated in vacuo leaving a residual syrup comprising, a mixture of the diethyl amides of d-lysergic and d-isolysergic acids. 

The syrup is dissolved in a mixture of 60 mL. of benzene and 20 mL. of chloroform and the solution is passed over a chromatographic column of 150 g. of basic alumina. The chromatogram is developed with the same solvent mixture. The more rapidly moving of the two blue fluorescing bands consists of the diethylamide of d-lysergic acid. About 2 liters of solvent mixture are required to elute the first band. The eluate is treated with a sufficient amount of tartaric acid to convert the amide to the tartrate salt, and the salt is isolated by evaporating the solution to a low volume to cause separation of the tartrate salt of the diethylamide of d-lysergic acid. 

The diethylamide of rf-isolysergic acid is recovered by eluting it from the alumina column with chloroform, and evaporating the chloroform eluate. 

The residual syrup containing the two /-(+)-propanol amides of d,Z-lysergic acid is treated with methanol and excess maleic acid to convert the two amides into their maleate salts. The mixture of amide maleates is precipitated from the methanol solution by the addition of ethyl ether, and the precipitated mixture is filtered off and dried in air. Source Garbrecht 1956 

The following examples more specifically illustrate the preparation of the novel amides of lysergic acid which are included within the scope of the invention. 

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The residual sjrrup comprising J-lysergic acid morpholide is dissolved in 25 mL. of methanol, the solution is acidified with excess maleic acid, and is diluted with ether to incipient turbidity. The mixture is allowed to stand in a refrigerator for several hours, whereupon off-white, needle-like crystals of d-lysergic acid morpholide acid maleate are formed and precipitate from the solution. 

From the crystallization mother liquors, after concentration, neutralization, and re-extraction with ethylene dichloride, there can be obtained about 0.8 g. of amorphous d-isolysergic acid morpholide. This material can be isomerized to d-lysergic acid morpholide by the procedure disclosed by Smith and Timmis in J. Chem. Soc. 139, II, 1168 (1936). 

The maleate salt is dissolved in a minimum volume of water and neutralized with sodium carbonate. The resulting mixture is extracted with three 100 mL. portions of chloroform, the combined chloroform extracts are dried with sodium sulfate, are filtered, and are evaporated to dryness in vacuo. The residue is taken up in a small volume of benzene and cooled, whereupon crystals of <7-lysergic acid morpholide are formed. 

The combined filtrate and washings from the isolation of d-lysergic acid morpholide acid maleate are evaporated to dryness. The acid maleate salt of rf-isolysergic acid morpholide contained in the residue is dissolved in water, is converted to the corresponding free base by treatment with sodium carbonate and is extracted with chloroform as set forth hereinabove. The chloroform solution containing the free... 

Gogerty, J.H. Dille, JJVI. Pharmacology of ci-Lysergic Acid Morpholide (LSM). J. Pharmacol Exp. Then (1957) 120 340-348... 

Product d d-iso-Lysergic acid morpholide Reference (Garbrecht 1956)... 

LSD (4.126) is a rather structure-specific compound. Only the (+)-isomer is active, and alkylamides other than the diethyl derivative, including some cyclic analogs (the pyrro-lidide and morpholide analogs), have very low activity. Lysergic acid does contain the... 

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