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US Patent 4524208

Sauer; Gerhard, et. al. Jun. 18, 1985

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A process for preparing lysergic acid esters of the formula R'COOR wherein R is alkyl of up to 3 carbon atoms, comprises reacting corresponding lysergic acid or isolysergic acid amides with corresponding alcohols at temperatures of 0 deg. to 65 deg. C. for 2 to 30 hours in the presence of an acid at a pH value of 0-1.


It is an object of the present invention to provide a process that produces the desired lysergic acid esters in the pure state in a high yield, e.g., typically at least about 80 molar % of theory.

It has now been found surprisingly that it is possible to convert lysergic acid and/or isolysergic acid amides, in the presence of an inorganic or organic acid, into the natural lysergic acid ester of 8.beta.-configuration, in a smooth reaction, there additionally occurring in case of the isolysergic acid amide reactant, a surprising isomerization to the lysergic acid ester. The yields are practically quantitative.


In order to conduct the process, a lysergic acid amide or isolysergic acid amide or a mixture of both is dissolved in the corresponding alcohol, e.g., methanol, ethanol, n-propanol, or isopropanol. Generally, amounts of the amide relative to the alcohol are 1-10 parts by weight, i.e., usually an excess of alcohol is utilized. Suitable acids include for example sulfuric acid, hydrochloric acid, perchloric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc., or an acid in the form of an acidic ion exchange resin, e.g., sulfonic acids like RSO(3) H, wherein R is the resin residue.

The acid is added to the alcohol solution in a quantity so that the pH value of the reaction solution is about 0-1. The reaction is carried out at 0 deg. to the boiling temperature of the reaction mixture, generally up to 65 deg. C.; suitably, the temperature range is 20 deg. -55 deg. C. The reaction temperature is maintained for a relatively long period of time. Depending on the acid concentration and reaction temperature the reaction period is 2 hours, usually at most 30 hours and, in the normal case, is completed after about 16 hours. Preferably, the reaction is conducted under anhydrous conditions.

Subsequently the reaction mixture is worked up by using known methods, such as washing, extraction, precipitation, crystallization, etc. Acid salts of the amides can equivalently be used as starting materials, e.g., the hydrochloride, tartrate, hydrogen maleate, methane sulphonate and hydrogen phosphate.


Example 1

A suspension is prepared from 5.0 g of isolysergic acid amide in 80 ml of anhydrous methanol; the mixture is cooled to about -50 deg. C. and, under agitation, 40 ml of a 13N solution of hydrogen chloride in anhydrous methanol is added thereto. The clear solution is allowed to warm up to room temperature and further stirred overnight. The primary amount of the thus-formed ester hydrochloride is thus crystallized. By cooling in an ice bath and adding ethyl acetate, the crystallization is completed, and the precipitate is vacuum-filtered.

Yield: 5.2 g (84% of theory) of lysergic acid methyl ester, hydrochloride.

alpha(D) =+94 deg. (0.5% in methanol).

Example 2

Starting with 5.0 g of lysergic acid amide, lysergic acid methyl ester is obtained as the hydrochloride in an 86% yield according to Example 1.

alpha(D) =+94 deg. (0.5% in methanol).

Example 3

A mixture of 2.5 g of lysergic acid amide and 2.5 g of isolysergic acid amide in 500 ml of methanol is heated with 100 g of p-toluenesulfonic acid for 4 hours to 50 deg. C. Then half of the solvent is removed by distillation, the residue is poured into a mixture of 200 ml of concentrated ammonia and ice, and extracted with methylene chloride. The organic phase is dried with sodium sulfate and evaporated, thus obtaining after crystallization from ethanol 4.45 g (81% by theory) of lysergic acid methyl ester. alpha(D) =+68 deg. (0.5% in chloroform).

Now, Tetrahedron Letters No. 8, pp 4171-4174, 1977.

"Trimethylaluminum reacts with a secondary amine in a 1:1 ratio at room temperature in methylene chloride with evolution of methane to give dimethylaluminum amides. ... Addition of an ester to dimethylaluminum amide, followed by gentle warming at 25-41 degrees for 5 to 48 hours produces the carboximide in high yield."

"In a typical experiment 0.8 ml (2.0 mmol) of a 2.5 M solution of trimethylaluminum in hexane was slowly added at room temperature to a solution of 2.0 mmol of amine in 5 ml of dry methylene chloride under nitrogen. The mixture was stirred at room temperature for 15 min and 2.0 mmol of ester was added. The misture was warmed at 25-41 degrees under nitrogen until TLC indicated that the reaction had gone to completion. The reaction was carefully quenched with dilute HCL and extracted with methylene chloride. The organic extract was dried (MgSO4) and concentrated to afford the carboxamide which could be recrystallized, if necessary."

Does the above sound like a feasible synthesis for LSD starting from a mixture of lysergic/isolysergic amide (from Morning Glories ,HBW or whathaveyou), conversion of the lysergic amides to the methyl ester then conversion to the diethylamide by way of trimethylaluminum diethylamide?

Another method of reacting lysergic acid methyl ester with amines, exemplified for 2-aminobutanol. Should work with diethylamine, too.

Collection Czechoslov. Chem. Commun. Vol. 22 (1957)

Condensation of the d-Lysergic acid-methylester with (+)-2-Aminobutanol-(1)

The mixture of 1.60 g of d-Lysergic acid-methylester with a content of 12% of crystalbound benzene.[SMP. 168-170 under decomposition, aD(20) +84 (c=0.52, Chloroform) for the crystal solvent-free substance] and 1.33 g (+)-2-Aminobutanol-(1) was heated in a pipe -which was closed by melting it- in nitrogen-atmosphere and without direct light for 3 hours in an oil-bath at 135-140 C.

The viscose dark-green coloured reaction mixture was dissolved in 70 ml of Chloroform-Ethanol (9:1) and the bases were extracted with 1 % tartaric acid solution (about 500 ml) from the solution. (until the extract gave no positive Keller-reaction to ergot-alkaloids) The united aqueous extracts were filtered after a little amount of Carboraffin was added. The salts were free-based with 100 ml 1N NaHCO3 and after the addition of 100 mg NaCl the bases were extracted into ether in 10% ethanol. The united ether extracts (about 1500 ml) were dried (K2CO3) and freed from the solvent by vacuum distillation.

The amorphous hardly coloured sediment weighed 940 mg (55%)

In the semiquantative paper chromatography evaluation of the raw product, besides a little amount of decomposition products and unused d-lysergic acid-methylester, the (+)-Butanolamide-(2) of d-and-l-Isolysergic acid (I and II) and the (+)-Butanolamide-(2) of d- and l-lysergic acid (III and IV) was found in the proportion of about 35:35:15:15.

The solution of the mixture (940 mg) in a little amount of chloroform was added to a column of 25g of Aluminium oxide and the (+)-Butanolamide-(2) of the isolysergic acids (I and II) were eluted first only with chloroform and then with chloroform with 0.5% and 1% ethanol. The first extracts were accumulated at the derivate of the l-Isolysergic acid, the last at the derivate of the d-iso compound (620 mg).

After the separation of a little extract which included all 4 (+)-Butanolamides (about 10 mg), the elution was continued under the use of chloroform with 2% and finally with 5% ethanol. This way, a mixture of the d- and-l-Lysergic acid derivates was received. (190 mg). The first extracts were accumulated at the d-Lysergic acid-(+)-butanolamide -(2), the last at the l-lysergic acid derivate.

Yield: roughly 95,000 µg of the d-lysergic acid (+)-butanolamide-(2). The course of separation was observed with UV-light - in which the Lysergic acid derivates fluoresced blue - and paper chromatography.