U.S. Patent 2,438,259; Patented Mar. 23, 1948.

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Arthur Stoll and Albert Hofmann, Basel, Switzerland, assignors Sandoz Ltd., Fribourg, Switzerland, a Swiss firm.

No Drawing. Application April 28, 1944, Serial No. 533,264. In Switzerland April 30, 1943

1 Claim. (CI. 260--236)

The present invention relates to new d-lysergic acid dialkylamides which are valuable therapeutic products and to a process for their preparation.

It has been found that by condensing azides of d- or d,l-lysergic acid respectively or of d- or d,l-isolysergic acid respectively or mixtures of these compounds with diakylamines, d-lysergic acid dialkylamides are obtained, which products have not yet become known hitherto. The alkyl groups present in the dialkylamines used according to the present invention can either be identical or different and may be of saturated or unsaturated character. Such amines are for instance dimethylamine, diethylamine, dipropylamine, dibutylamine, diamylamine, methyl-ethylamine, ethyl-allylamine, butyl-amylamine, etc.

The new d-lysergic acid amides are distinguished from the known natural and synthetic ergot alkaloids and from the d-lysergic acid amides described in our U. S. Patent No. 2,090,430 by their powerful specific action on the central nervous system.

The condensation of the d-lysergic acid- or d-isolysergic acid azides with the dialkylamines is carried out in the presence of an inert organic solvent and preferably at room temperature. During the reaction taking place between the azides and the dialkylamine generally mixtures of different dialkylamides will be obtained. This can, for instance, be seen in the following illustrative example showing the reaction of d-lysergic acid azide with diethylamine. During the interaction of these compounds a mixture will be obtained consisting of d-lysergic acid diethylamide and of d-isolysergic acid diethylamide, from which mixture the d-lysergic acid derivative will be separated. By using as a starting product d-isolysergic acid azide and diethylamine a mixture of d-lysergic acid diethylamide and of d-isolysergic acid diethylamide will be obtained, this mixture being subsequently separated into its constituents. Finally by starting from racemic lysergic acid azide or racemic isolysergic acid azide, mixtures consisting of d,l-lysergic acid diethylamide and d,l-isolysergic acid diethylamide will be obtained, from which the d-lysergic acid diethyl amide can be separated in a suitable manner, e.g., in form of its tartaric acid salt.

The following examples, without being limitative, illustrate the present invention, the parts being by weight.

Example 1

3 parts of d-isolysergic acid hydrazide are transformed in the usual way in a hydrochloric acid solution by a treatment with sodium nitrite at 0 degrees C. into the azide, and, after neutralization of the acid solution with sodium bicarbonate, the azide thus formed is shaken out by means of 300 parts ethyl ether. The ethereal solution is then dried with freshly calcinated potassium carbonate and treated with 3 parts of diethylamine. The solution is allowed to stand, preferably in the dark and at room temperature, for 24 hours with repeated shaking. The ether is then evaporated in vacuo, the residue triturated with 30 parts of water and filtered by suction. The dark amorphous product thus obtained possesses a specific rotation of [alpha]20/D=about+100 degrees (in pyridine) and consists essentially of a mixture of nearly equal parts of d-lysergic acid diethylamide and d-isolysergic acid diethylamide.

The separation of both isomers can be carried out for instance by the so-called chromatographic adsorption method. For this purpose the mixture is dissolved in chloroform containing about 0.5% of ethanol and is passed through a column of aluminium oxide of 60 cm. length and 4 cm. radius and the chromatogram developed with the same solvent. The dark impurities pass rapidly into the filtrate. Then follows a bright zone, which has a blue appearance in ultra-violet light and which contains the d-lysergic acid diethylamide. From this fraction 1.0 to 1.3 parts of this product will be obtained.

A further slowly passing portion of the solution contains the d-isolysergic acid diethylamide. By evaporating this chloroform fraction and crystallizing the residue from acetone, 0.8 to 1.2 parts of a compound crystallizing in beautiful prisms of melting point 182 degrees C. (corr.) under decomposition is obtained, this compound being the pure d-isolysergic acid diethylamide. Its specific rotation is [alpha]20/D=+217 degrees (c=0.4 in pyridine). Elementary analysis has given the following values: C 74.41; H 7.48; N 13.27%. The calculated values for d-isolysergic acid diethylamide, i.e., C20H25ON3 are C 74.25; H 7.79; N 13.00%.

The d-isolysergic acid diethylamide can be transformed into d-lysergic acid diethylamide by using the methods known for the ergot alkaloids. By allowing the solution of the iso- compound to stand in dilute alcoholic potassium hydroxide, a mixture of about equal parts lysergic acid and isolysergic acid compounds will be produced after a short time. The d-lysergic acid diethylamide can then be separated from the mixture in the manner described above.

The amorphous d-lysergic acid diethylamide, which can be separated by the chromatographic method, crystallizes, by dissolving it in a small amount of acetone and diluting this solution with ethyl ether, in bundles of needles. From benzene pointed prisms will be obtained, that melt under decomposition at 80-85 degrees C. (corr.). The new compound is difficulty soluble in water, but very soluble in methanol and ethanol. It possesses the specific rotation of [alpha]20/D=+30 degrees (c=0.4 in pyridine). Elementary analysis gives the following values: C 73.50; H 7.81; N 12.92%. For d-lysergic acid diethyl amide, C20H25ON3, the calculated values are C 74.25; H 7.79; N 13.00%.

By dissolving one equivalent of the base with one equivalent of d-tartaric acid in a small quantity of methanol the neutral tartrate of d-lysergic acid diethylamide crystallizes out in form of bundles of needles. The salt is very easily soluble in water and melts indistinctly and under decomposition at 200 degrees C. (corr.).

Example 2

An ethereal solution of d-lysergic acid azide, prepared in the usual manner from 3 parts of d-lysergic acid hydrazide, is treated with 3 parts of diethylamine and allowed to stand for 24 hours in the dark and at room temperature with occasional shaking. The isolation of the compound thus produced is carried out in the manner described in the Example 1. The first separation by means of the chromatographic adsorption yields 1.3 to 1.7 parts of d-lysergic acid diethylamide and about 0.5 to 0.8 part of d-isolysergic acid diethylamide.

Example 3

3 parts of racemic isolysergic acid hydrazide are transformed in the usual manner into the respective azide and the formed compound is precipitated by means of an excess of a sodium bicarbonate solution in the form of voluminous yellowish flocks, which are separated by suction and immediately introduced at -5 degrees C. into a solution of 3 parts of diethyl amine in 30 parts of ethanol. The azide readily dissolves in the solution which becomes brown and is then heated slowly to 30 degrees C. The solution is maintained at this temperature for 1 hour, whereupon the solvent is evaporated in vacuo. The sticky residue is triturated with 30 parts of water and filtered. The raw condensation product amounting to about 2.8 parts consists of racemic isolysergic acid diethylamide and of racemic lysergic acid diethylamide and is separated by the chromatographic method in the manner described in Example 1. During the chromatographic separation two zones are obtained which are colored, in ultra-violet light, in brilliant blue shades. The more rapidly passing zone contains the racemic lysergic acid diethylamide, whereas the slower passing zone consists of racemic isolysergic acid diethylamide.

From the racemic lysergic acid diethylamide the d-lysergic acid diethylamide can be separated by transforming the same for instance into its neutral tartaric acid salt. For this purpose 3.2 parts of racemic lysergic acid diethylamide (1/100 mol.) are dissolved in 6 parts of methanol and added to a solution of 0.75 part of d-tartaric acid (1/200 mol.) in 2 parts of methanol.

On inoculation with d-lysergic acid diethylamide tartrate this compound crystallizes out in nearly colorless bundles of needles. Yield 1.0 to 1.2 parts. The properties of the compound thus obtained are identical with those described in Example 1 for the neutral d-tartaric acid salt of d-lysergic acid diethylamide.

What we claim is:

The crystalline d-lysergic acid diethylamide which crystallizes from benzene in prisms melting with decomposition at 80-85 degrees C., which is difficulty soluble in water but easily soluble in methanol and in ethanol, which possesses the specific rotation [alpha]20/D=+30 degrees (c=0.4 in pyridine) and which corresponds to the formula C20H25ON3.





The following references are of record in the file of this patent:


Number Name Date
2,090,430 Stoll et al. Aug.17, 1937
2,265,207 Stoll et al. Dec. 9, 1941
2,265,217 Stoll et al. Dec. 9, 1941



Preparation for Lysergic Acid Amides:

United States Patent 2,736,728

Patented February 28, 1956

Richard P. Pioch, Indianapolis, Indiana, assignor, to Eli Lilly and Co., Indianapolis, Indiana, a corporation of Indiana. No drawing. Application December 6, 1954, Serial No. 473,443. 10 Claims.

This invention relates to the preparation of lysergic acid amides and to a novel intermediate compound useful in the preparation of said amides.

Although only a few natural and synthetic amides of lysergic acid are known, they possess a number of different and useful pharmacologic properties. Especially useful is ergonovine, the N-(1(+)-1-hydroxyisopropyl) amide of d-lysergic acid, which is employed commercially as an oxytocic agent.

Attempts to prepare lysergic acid amides amides by the usual methods of preparing amides, such as reacting an amine with lysergic acid chloride or with ester of lysergic acid, have been unsuccessful. United States Patents No. 2,090,429 and No. 2,090,430, describe processes of preparing lysergic acid amides and, although these processes are effective to accomplish the desired conversion of lysergic acid to one of its amides, they are not without certain disadvantages.

By my invention I have provided a simple and convenient method of preparing lysergic acid amides, which comprises reacting lysergic acid with trifluoroacetic anhydride to produce a mixed anhydride of lysergic and trifluoroacetic acids, and when reacting the mixed anhydride with a nitrogenous base having at least one hydrogen linked to nitrogen. The resulting amide of lysergic acid is isolated from the reaction mixture by conventional means.

The reaction of the lysergic and the trifluoroacetic anhydride is a low temperature reaction, that is, it must be carried out at a temperature below about 0 degrees C. The presently preferred temperature range is about -15 C. to about -20 C. This range is sufficiently high to permit the reaction to proceed at a desirably fast rate, but yet provides an adequate safeguard against a too rapid temperature and consequent excessive decomposition of the mixed anhydride.

The reaction is carried out in a suitable dispersing agent, that is, one which is inert with respect to the reactants. The lysergic acid is relatively insoluble in dispersants suitable for carrying out the reaction, so it is suspended in the dispersant.

Two gallons of trifluoroacetic anhydride are required per mol. of lysergic acid for the rapid and complete conversion of the lysergic acid into the mixed anhydride. It appears that one molecule of the anhydride associates with or favors an ionic adduct with one molecule of the lysergic which contains a basic nitrogen atom and that it is the adduct which reacts with a second molecule of trifluoroacetic anhydride to form the mixed anhydride along with one molecule of trifluoroacetic acid. The conversion of the lysergic acid to the mixed anhydride occurs within a relatively short time, but to insure a complete conversion the reaction is allowed to proceed for about one to three hours.

The mixed anhydride of lysergic and trifluoroacetic acids is relatively unstable, especially at room temperature and above, and must be stored at a low temperature. This temperature instability of the mixed anhydride makes it desirable that it be converted into a lysergic acid amide without unnecessary delay. The mixed anhydride itself, since it contains a lysergic acid group, also can exist in the reaction mixture in large part as an ionic adduct with trifluoroacetic anhydride or trifluoroacetic acid. It is important for maximum yield of product that the lysergic acid employed in the reaction be dry. It is most convenient to dry the acid by heating it at about 105-110 degrees C. in a vacuum of about 1 mm. of mercury or less for a few hours, although any other customary means of drying can be used.

The conversion of the mixed anhydride into an amide by reacting the anhydride with the nitrogenous base, such as an amino compound, can be carried out at room temperature or below. Most conveniently the reaction is carried out by adding the cold solution of the mixed anhydride to the amino compound or a solution thereof which is at about room temperature. Because of the acidic components present in the reaction mixture of the mixed anhydride, about five mols or equivalents of the amino compound are required per mole or equivalent of mixed anhydride for maximal conversion of the mixed anhydride to the amide. Preferably a slight excess over the five mols is employed to insure complete utilization of the mixed anhydride. If desired, a basic substance capable of neutralizing the acid components present in the reaction mixture, but incapable of interfering with the reaction, can be utilized. A strongly basic tertiary amine is an example of such a substance. In such case, about one equivalent of amino compound to be converted to a lysergic acid amide, as well as any unconverted lysergic acid, can be removed from the reaction mixture and can be re-employed in other conversions.

A preferred method for carrying out the process of this invention is as follows:

Dry lysergic acid is suspended in a suitable vehicle as acetonitrile, and the suspension is cooled to about -15 C. or -20 C. To the suspension is then added slowly a solution of about two equivalents of trifluoroacetic anhydride dissolved in acetonitrile and previously cooled to about -20 degrees C. The mixture is maintained in a low temperature for about one to three hours to insure the completion of the formation of the mixed anhydride of lysergic and trifluoroacetic acids.

The solution of the mixed anhydride is then added to about five equivalents of the amino compound which is to be reacted with the mixed anhydride. The amino compound need not be previously dissolved in a solvent, although it is usually convenient to use a solvent. The reaction is carried out with the amino compound or solution of amino compound at about room temperature or below. The reaction mixture is allowed to stand at room temperature for one or two hours, preferably in the dark, and the solvent is then removed by evaporation in vacuo at a temperature which desirably is not greatly in excess of room temperature. The viscous residue, consisting of the amide together with excess amine and amine salts, is taken up in a mixture of chloroform and water. The water is separated and the chloroform solution which contains the amide is washed several times with water to remove excesss amine and the various amine salts formed in the reaction, including that of any unconverted lysergic acid. The chloroform solution is then dried and evaporated, leaving a residue of lysergic acid amide. The amide so obtained can be purified by any conventional procedure.

Dispersants suitable for the purpose of this invention are those which are liquids at the low temperatures employed for the reaction and are of such an inert nature that they will not react preferentially to the lysergic acid with trifluoroacetic anhydride. Among suitable dispersants are acetonitrile, dimethylformamide, propionitrile, and the like. Additional suitable agents will readily be apparent from the foregoing enumeration. Of those listed above, acetonitrile is preferred since it is non-reactive and mobile at the temperature used, and is relatively volatile and hence readily separable from the reaction mixture by evaporation in vacuo.

A wide variety of nitrogenous bases such as amino compounds can be reacted with the mixed anhydride to form a lysergic acid amide. As previously stated, the amino compound must contain a hydrogen atom attached to nitrogen to permit amide formation. Illustrative amino compounds which can be reacted are ammonia, hydrazine, primary amines such as glycine, ethanolamine, diglycylglycine, norephedrine, aminopropanol, butanolamine, diethylamine, ephedrine, and the like.

When an alkanolamine such as ethanolamine or aminopropanol is reacted with the mixed anhydride of lysergic and trifluoroacetic acids, the reaction product contains not only the desired hydroxy amide but also, to a minor extent, some amino ester. These two isometric substances arise because of the bi-functional nature of the reacting alkanolamine. Ordinarily the amino ester amounts to no more than 25-30 percent of the total amount of reaction product, but in cases where the amino group is esterically hindered, the proportion of amino ester will be increased. The amino ester can readily be converted to the desired hydroxy amide, and the over-all yield of the latter increased by treating the amino ester, or the mixture of amide and ester with alcoholic alkali to cause the rearrangement of the amino ester to the desired hydroxy amide. Most conveniently the conversion is carried out by dissolving the amino ester or mixture containing the amino ester in a minimum amount of alcohol and adding to the mixture a twofold amound of 4 N alcoholic potassium hydroxide solution. The mixture is allowed to stand at room temperature for several hours, the alkali is neutralized with acid, and the lysergic acid amide is then isolated and purified.

It should be understood that, as used herein, the term "lysergic acid" is used generically as inclusive of any or all of the four possible stereoisomers having the basic lysergic acid structure. Isomers of the lysergic acid series can be separated or interconverted by means known to the art.

This invention is further illustrated in the following specific examples.

[Example One]

Preparation of the mixed anhydride of lysergic and trifluoroacetic acids:

5.36 g. of d-lysergic acid are suspended in 125 ml. of acetonitrile and the suspension is cooled to about -20 degrees C. To this suspension is added a cold (-20 degrees C.) solution of 8.82 g. of trifluoroacetic anhydride in 75 ml. of acetonitrile. The mixture is allowed to stand at -20 degrees C. for about 1 1/2 hours during which time the suspended material dissolves, and the d-lysergic acid is converted to the mixed anhydride of lysergic and trifluoroacetic acids. The mixed anhydride can be separated in the form of an oil by evaporating the solvent in vacuo at a temperature below about 0 degrees centigrade.

[Example Two]

Preparation of d-lysergic and N,N-diethyl amide:

A solution of the mixed anhydride of lysergic acid and trifluoroacetic acid in 200 ml. of acetonitrile is obtained by reacting 5.36 g. d-lysergic acid and 8.82 g. trifluoroacetic anhydride in accordance with the procedure of example one. The acetonitrile solution containing mixed anhydride is added to 150 ml. of acetonitrile containing 7.6 g. of diethylamine. The mixture is held in the dark at room temperature for about two hours. The acetonitrile is evaporated in vacuo leaving a residue which comprises the "normal" and "iso" forms of d-lysergic acid N,N-diethyl amide together with some lysergic acid, the diethylamine salt of trifluoroacetic acid and like by-products. The residue is dissolved in a mixture of 150 ml. of chloroform and 20 ml. of ice water. The chloroform layer is separated, and the aqueous layer is extracted with four 50 ml. portions of chloroform. The chloroform extracts are combined and are washed four times with about 50 ml. portions of cold water in order to remove residual amounts of amine salts. The chloroform layer is then dried over anhydrous sodium sulfate, and the chloroform is evaporated in vacuo. A solid residue of 3.45 gm. comprising the "normal" and "iso" forms of d-lysergic acid N,N-diethylamide is obtained. This material is dissolved in 160 ml. of a 3-to-1 mixture of benzene and chloroform, and is chromatographed over 240 g. of basic alumia. As the chromatogram is developed with the same solvent, two blue fluroescing zones appear on the alumina column. The more rapidly moving zone is d-lysergic acid N,N-diethylamide which is eluted with about 3000 ml. of the same solvent as above, the course of the elution being followed by watching the downward movement of the more rapidly moving blue fluorescing zone. The eluate is treated with tartaric acid to form the acid tartrate of d-lysergic acid N,N-diethyl amide which is isolated. The acid tartrate of d-lysergic acid N,N-diethyl amide melts with decomposition at about 190-196 degrees centigrade.

The di-iso-lysergic acid N,N-diethyl amide which remains absorbed on the alumia column as the second fluroescent zone is removed from the column by elution with chloroform. The "iso" form of the amide is recovered by evaporating the chloroform eluate to dryness in vacuo.

[Example Three]

Preparation of d-lysergic acid N-diethylaminoethyl amide:

A solution of the mixed anhydride of lysergic acid and trifluoroacetic acid is prepared from 2.68 g. of d-lysergic acid and 4.4 g. of trifluoroacetic acid anhydride in 100 ml. of acetonitrile by the method of Example One. This solution is added to 6:03 g. of diethylaminoethylamine. The reaction mixture is kept in the dark at room temperature for 1 1/2 hours. The acetonitrile is evaporated, and the residue treated with chloroform and water as described in Example Two. The residue treated comprising d-iso- lysergic acid N-diethylaminoethyl amide is dissolved in several ml. of ethyl acetate, and the solution is cooled to about 0 degrees centigrade, whereupon di-iso-lysergic acid N-diethylaminoethyl amide separates in crystalline form. The crystalline material is filtered off, and the filtrate reduced in volume to obtain an additional amount of crystalline amide. Recrystallization from ethyl acetate of the combined fractions of crystalline material yields d-iso-lysergic acid N-diethylaminoethyl amide melting at about 157-158 degrees centigrade. The optical rotation is as follows:

[x] d^26 = + 372 degrees (c. = 1.3 in pyridine)