From Hoffman's LSD patent:
U.S. Patent 2,438,259; Patented Mar. 23, 1948.
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.
)