236 lines
15 KiB
Plaintext
236 lines
15 KiB
Plaintext
Making LSD In The Laboratory
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To make synthetic acid, you need a basic understanding of chemistry
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and access to a lab. Since I don't quite understand all the chemical hocus-
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pocus, I'm going to cop out and quote you the patent for it. If you don't
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understand chemistry, just skip this recipe and go on to the next one for
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acid, it's much simpler.
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Preparation for Lysergic Acid Amides:
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United States Patent Office 2,736,728
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Patented February 28, 1956
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Richard P. Pioch, Indianapolis, Indiana, assignor, to Eli Lilly and Co.,
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Indianapolis, Indiana, a corporation of Indiana.
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No drawing. Application December 6, 1954, Serial No. 473,443. 10 Claims.
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(Cl. 260-285.5)
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This invention relates to the preparation of lysergic acid amides and
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to a novel intermediate compound useful in the preparation of said amides.
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Although only a few natural and synthetic amides of lysergic acid
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are known, they possess a number of different and useful pharmacologic
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properties. Especially useful is ergonovine, the N-(1(+)-1-hydroxyisopropyl)
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amide of d-lysergic acid, which is employed commercially as an oxytocic agent.
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Attempts to prepare lysergic acid amides amides by the usual methods
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of preparing amides, such as reacting an amine with lysergic acid chloride or
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with ester of lysergic acid, have been unsuccessful. United States Patents No.
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2,090,429 and No. 2,090,430, describe processes of preparing lysergic acid
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amides and, although these processes are effective to accomplish the desired
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conversion of lysergic acid to one of its amides, they are not without certain
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disadvantages.
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By my invention I have provided a simple and convenient method of
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preparing lysergic acid amides, which comprises reacting lysergic acid with
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trifluoroacetic anhydride to produce a mixed anhydride of lysergic and
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trifluoroacetic acids, and when reacting the mixed anhydride with a
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nitrogenous base having at least one hydrogen linked to nitrogen. The
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resulting amide of lysergic acid is isolated from the reaction mixture by
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conventional means.
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The reaction of the lysergic and the trifluoroacetic anhydride is a
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low temperature reaction, that is, it must be carried out at a temperature
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below about 0 degrees C. The presently preferred temperature range is about
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-15 C. to about -20 C. This range is sufficiently high to permit the reaction
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to proceed at a desirably fast rate, but yet provides an adequate safeguard
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against a too rapid temperature and consequent excessive decomposition of the
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mixed anhydride.
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The reaction is carried out in a suitable dispersing agent, that is,
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one which is inert with respect to the reactants. The lysergic acid is
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relatively insoluble in dispersants suitable for carrying out the reaction, so
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it is suspended in the dispersant.
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Two gallons of trifluoroacetic anhydride are required per mol. of
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lysergic acid for the rapid and complete conversion of the lysergic acid into
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the mixed anhydride. It appears that one molecule of the anhydride associates
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with or favors an ionic adduct with one molecule of the lysergic which
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contains a basic nitrogen atom and that it is the adduct which reacts with a
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second molecule of trifluoroacetic anhydride to form the mixed anhydride along
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with one molecule of trifluoroacetic acid. The conversion of the lysergic
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acid to the mixed anhydride occurs within a relatively short time, but to
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insure a complete conversion the reaction is allowed to proceed for about one
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to three hours.
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The mixed anhydride of lysergic and trifluoroacetic acids is
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relatively unstable, especially at room temperature and above, and must be
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stored at a low temperature. This temperature instability of the mixed
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anhydride makes it desirable that it be converted into a lysergic acid amide
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without unnecessary delay. The mixed anhydride itself, since it contains a
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lysergic acid group, also can exist in the reaction mixture in large part as
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an ionic adduct with trifluoroacetic anhydride or trifluoroacetic acid. It is
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important for maximum yield of product that the lysergic acid employed in the
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reaction be dry. It is most convenient to dry the acid by heating it at about
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105-110 degrees C. in a vacuum of about 1 mm. of mercury or less for a few
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hours, although any other customary means of drying can be used.
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The conversion of the mixed anhydride into an amide by reacting the
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anhydride with the nitrogenous base, such as an amino compound, can be
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carried out at room temperature or below. Most conveniently the reaction is
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carried out by adding the cold solution of the mixed anhydride to the amino
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compound or a solution thereof which is at about room temperature. Because of
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the acidic components present in the reaction mixture of the mixed anhydride,
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about five mols or equivalents of the amino compound are required per mole or
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equivalent of mixed anhydride for maximal conversion of the mixed anhydride to
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the amide. Preferably a slight excess over the five mols is employed to insure
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complete utilization of the mixed anhydride. If desired, a basic substance
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capable of neutralizing the acid components present in the reaction mixture,
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but incapable of interfering with the reaction, can be utilized. A strongly
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basic tertiary amine is an example of such a substance. In such case, about
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one equivalent of amino compound to be converted to a lysergic acid amide, as
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well as any unconverted lysergic acid, can be removed from the reaction
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mixture and can be re-employed in other conversions.
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A preferred method for carrying out the process of this invention is
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as follows:
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Dry lysergic acid is suspended in a suitable vehicle as acetonitrile,
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and the suspension is cooled to about -15 C. or -20 C. To the suspension is
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then added slowly a solution of about two equivalents of trifluoroacetic
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anhydride dissolved in acetonitrile and previously cooled to about -20 degrees
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C. The mixture is maintained in a low temperature for about one to three
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hours to insure the completion of the formation of the mixed anhydride of
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lysergic and trifluoroacetic acids.
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The solution of the mixed anhydride is then added to about five
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equivalents of the amino compound which is to be reacted with the mixed
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anhydride. The amino compound need not be previously dissolved in a solvent,
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although it is usually convenient to use a solvent. The reaction is carried
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out with the amino compound or solution of amino compound at about room
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temperature or below. The reaction mixture is allowed to stand at room
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temperature for one or two hours, preferably in the dark, and the solvent is
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then removed by evaporation in vacuo at a temperature which desirably is not
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greatly in excess of room temperature. The viscous residue, consisting of the
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amide together with excess amine and amine salts, is taken up in a mixture of
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chloroform and water. The water is separated and the chloroform solution which
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contains the amide is washed several times with water to remove excesss amine
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and the various amine salts formed in the reaction, including that of any
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unconverted lysergic acid. The chloroform solution is then dried and
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evaporated, leaving a residue of lysergic acid amide. The amide so obtained
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can be purified by any conventional procedure.
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Dispersants suitable for the purpose of this invention are those which
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are liquids at the low temperatures employed for the reaction and are of such
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an inert nature that they will not react preferentially to the lysergic acid
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with trifluoroacetic anhydride. Among suitable dispersants are acetonitrile,
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dimethylformamide, propionitrile, and the like. Additional suitable agents
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will readily be apparent from the foregoing enumeration. Of those listed
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above, acetonitrile is preferred since it is non-reactive and mobile at the
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temperature used, and is relatively volatile and hence readily separable from
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the reaction mixture by evaporation in vacuo.
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A wide variety of nitrogenous bases such as amino compounds can be
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reacted with the mixed anhydride to form a lysergic acid amide. As previously
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stated, the amino compound must contain a hydrogen atom attached to nitrogen
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to permit amide formation. Illustrative amino compounds which can be reacted
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are ammonia, hydrazine, primary amines such as glycine, ethanolamine,
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diglycylglycine, norephedrine, aminopropanol, butanolamine, diethylamine,
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ephedrine, and the like.
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When an alkanolamine such as ethanolamine or aminopropanol is reacted
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with the mixed anhydride of lysergic and trifluoroacetic acids, the reaction
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product contains not only the desired hydroxy amide but also, to a minor
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extent, some amino ester. These two isometric substances arise because of the
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bi-functional nature of the reacting alkanolamine. Ordinarily the amino ester
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amounts to no more than 25-30 percent of the total amount of reaction product,
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but in cases where the amino group is esterically hindered, the proportion of
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amino ester will be increased. The amino ester can readily be converted to the
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desired hydroxy amide, and the over-all yield of the latter increased by
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treating the amino ester, or the mixture of amide and ester with alcoholic
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alkali to cause the rearrangement of the amino ester to the desired hydroxy
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amide. Most conveniently the conversion is carried out by dissolving the amino
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ester or mixture containing the amino ester in a minimum amount of alcohol and
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adding to the mixture a twofold amound of 4 N alcoholic potassium hydroxide
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solution. The mixture is allowed to stand at room temperature for several
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hours, the alkali is neutralized with acid, and the lysergic acid amide is
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then isolated and purified.
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It should be understood that, as used herein, the term "lysergic acid"
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is used generically as inclusive of any or all of the four possible
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stereoisomers having the basic lysergic acid structure. Isomers of the
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lysergic acid series can be separated or interconverted by means known to the
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art.
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This invention is further illustrated in the following specific
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examples.
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[Example One]
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Preparation of the mixed anhydride of lysergic and trifluoroacetic
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acids:
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5.36 g. of d-lysergic acid are suspended in 125 ml. of acetonitrile
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and the suspension is cooled to about -20 degrees C. To this suspension is
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added a cold (-20 degrees C.) solution of 8.82 g. of trifluoroacetic anhydride
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in 75 ml. of acetonitrile. The mixture is allowed to stand at -20 degrees C.
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for about 1 1/2 hours during which time the suspended material dissolves, and
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the d-lysergic acid is converted to the mixed anhydride of lysergic and
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trifluoroacetic acids. The mixed anhydride can be separated in the form of an
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oil by evaporating the solvent in vacuo at a temperature below about 0 degrees
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centigrade.
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[Example Two]
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Preparation of d-lysergic and N,N-diethyl amide:
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A solution of the mixed anhydride of lysergic acid and trifluoroacetic
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acid in 200 ml. of acetonitrile is obtained by reacting 5.36 g. d-lysergic
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acid and 8.82 g. trifluoroacetic anhydride in accordance with the procedure of
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example one. The acetonitrile solution containing mixed anhydride is added to
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150 ml. of acetonitrile containing 7.6 g. of diethylamine. The mixture is held
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in the dark at room temperature for about two hours. The acetonitrile is
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evaporated in vacuo leaving a residue which comprises the "normal" and "iso"
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forms of d-lysergic acid N,N-diethyl amide together with some lysergic acid,
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the diethylamine salt of trifluoroacetic acid and like by-products. The
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residue is dissolved in a mixture of 150 ml. of chloroform and 20 ml. of
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ice water. The chloroform layer is separated, and the aqueous layer is
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extracted with four 50 ml. portions of chloroform. The chloroform extracts
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are combined and are washed four times with about 50 ml. portions of
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cold water in order to remove residual amounts of amine salts. The chloroform
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layer is then dried over anhydrous sodium sulfate, and the chloroform is
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evaporated in vacuo. A solid residue of 3.45 gm. comprising the "normal" and
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"iso" forms of d-lysergic acid N,N-diethylamide is obtained. This material
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is dissolved in 160 ml. of a 3-to-1 mixture of benzene and chloroform, and
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is chromatographed over 240 g. of basic alumia. As the chromatogram is
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developed with the same solvent, two blue fluroescing zones appear on the
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alumina column. The more rapidly moving zone is d-lysergic acid
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N,N-diethylamide which is eluted with about 3000 ml. of the same solvent as
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above, the course of the elution being followed by watching the downward
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movement of the more rapidly moving blue fluorescing zone. The eluate is
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treated with tartaric acid to form the acid tartrate of d-lysergic acid
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N,N-diethyl amide which is isolated. The acid tartrate of d-lysergic acid
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N,N-diethyl amide melts with decomposition at about 190-196 degrees
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centigrade.
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The di-iso-lysergic acid N,N-diethyl amide which remains absorbed on
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the alumia column as the second fluroescent zone is removed from the column
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by elution with chloroform. The "iso" form of the amide is recovered by
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evaporating the chloroform eluate to dryness in vacuo.
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[Example Three]
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Preparation of d-lysergic acid N-diethylaminoethyl amide:
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A solution of the mixed anhydride of lysergic acid and
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trifluoroacetic acid is prepared from 2.68 g. of d-lysergic acid and 4.4 g. of
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trifluoroacetic acid anhydride in 100 ml. of acetonitrile by the method of
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Example One. This solution is added to 6:03 g. of diethylaminoethylamine.
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The reaction mixture is kept in the dark at room temperature for 1 1/2 hours.
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The acetonitrile is evaporated, and the residue treated with chloroform and
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water as described in Example Two. The residue treated comprising d-iso-
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lysergic acid N-diethylaminoethyl amide is dissolved in several ml. of ethyl
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acetate, and the solution is cooled to about 0 degrees centigrade, whereupon
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di-iso-lysergic acid N-diethylaminoethyl amide separates in crystalline form.
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The crystalline material is filtered off, and the filtrate reduced in volume
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to obtain an additional amount of crystalline amide. Recrystallization from
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ethyl acetate of the combined fractions of crystalline material yields
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d-iso-lysergic acid N-diethylaminoethyl amide melting at about 157-158 degrees
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centigrade. The optical rotation is as follows:
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26
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[x] d = + 372 degrees (c. = 1.3 in pyridine)
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There has been in the last few years a great deal of discussion about
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the correct treatment for victims of bad LSD trips. When an individual does go
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into a panic on acid, it is an extremely delicate situation. Although it has
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been said that tranquilizers, such as thorazine, will help to calm the person
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down, be very careful, as certain drugs react violently with tranquilizers
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(STP). My advice in a situation of that sort is just to attempt to create an
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atmosphere of reassurance and sympathy. In no circumstances, except real
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uncontrollable panic, should a person on acid be taken to a city hospital. If
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you want a really freaky experience, spend a couple of hours at any city
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hospital and watch the people die in the halls!
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Talk to the person on acid and remind him that he is under the
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influence of acid. Try to calm him down. Even a change of environment can
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effectively reverse a bad trip.
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*************************************************
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