Amides of Lysergic Acid

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. 

The above procedure yields about 1.5 g. of crystals which melt indefinitely with decomposition on a Fisher John block at about 195° C. 

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). 

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Amides often have pronounced physiological activity acetaminophen, a common pain reliever, and the diethyl amide of lysergic acid (LSD), a hallucinogen, are two ex-... 

A new efficient method for the direct amidation of /-lysergic acid was used to prepare a variety of lysergamides. A pharmacological evaluation of these compounds, their di- and tetrahydro derivatives, and derivatives bearing substituents in the indole portion of the molecule showed that, in general, only 9,10-dihydrolysergamides of primary amines possess activity comparable to the potent emetic activity of the components of dihydroergotoxine. 

A further process, which is used on a technical scale and which, like the azide method, had its origin in the SANDOZ laboratories, employs lysergic acid chloride hydrochloride as the activated form (146, 92). Furthermore, the method developed in peptide chemistry, using N,N -carbonyldiimidazole as condensation agent (147), may be used to produce acid amides of lysergic acid and dihydrolysergic acid (148). 

The Garbrecht Synthesis Preparation of Amides of Lysergic Acid... 

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

Garbrecht, W.L. Preparation of Amides of Lysergic Acid US Patent 2,774,763 (1956)... 

Hofmann worked during the 1940s with synthetic amides of lysergic acid and prepared a series, one of which was the diethylamide with absolutely unexpected hallndnogenic effects. He has described this in his laboratory journal for 19 April 1943. The effective dose is only 25-100 micrograms. 

Much more complex are the thousands of alkaloids that include an indole (or 2,3-dihydroindole) sub-unit and in each of these one can discern the tryptamine nnit of the biosynthetic precursor tryptophan strychnine (33.3.2) (Strychnos nux vomica), vincristine (33.7) (Catharanthus roseus), and the antipsychotic and antihypertensive reserpine (Rauwolfia serpentina) are examples. A group of amides of lysergic acid, for example, ergotamine, occur in ergot fnngi (e.g. Claviceps purpurea), the remainder of the molecule comprising proline, phenylalanine and alanine nnits. Lysergic acid diethylamide is the notorious LSD. 

Figure 1 Key intermediate and enzymes from the first committed step in ergot alkaloid biosynthesis through the synthesis of lysergic acid. Simple amides of lysergic acid and ergopeptines are covered in Figs 2 and 3, respectively. Abbreviations DMAPP = dimethylallyl pyrophosphate DMAT = dimethylallyl tryptophan AdoMet = S-adenosyl-methionine.

Mother Nature s bounty is then squirreled off to the lab site for the biochemical phase of the process - the isolation of the lysergic alkaloids. Here one or more of a series of alkaloids are freed from the very complex plant matrix and hopefully isolated in a pure form. These alkaloids all have one thing in common - they are amides of lysergic acid. See the structures of the major naturally occurring amides pictured below ... 

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