LSD Synthesis
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from "Psychedelic Guide to the Preparation of the Eucharist" by Robert
Brown, 1967.
Preparatory arrangements:
Starting material may be any lysergic acid derivative, from ergot on
rye grain or from culture, or morning glory seeds or from synthetic
sources. Preparation #1 uses any amide, or lysergic acid as starting
material. Preparations #2 and #3 must start with lysergic acid only,
prepared from the amides as follows:
10 g of any lysergic acid amide from various natural sources dissolved
in 200 ml of methanolic KOH solution and the methanol removed
immediately in vacuo. The residue is treated with 200 ml of an 8%
aqueous solution of KOH and the mixture heated on a steam bath for one
hour. A stream of nitrogen gas is passed through the flask during
heating and the evolved NH3 gas may be titrated is HCl to follow the
reaction. The alkaline solution is made neutral to congo red with
tartaric acid, filtered, cleaned by extraction with ether, the aqueous
solution filtered and eva****ated. Digest with MeOH to remove some of
the coloured material from the crystals of lysergic acid.
Arrange the lighting in the lab similarly to that of a dark room. Use
photographic red and yellow safety lights, as lysergic acid
derivatives are decomposed when light is present. Rubber gloves must
be worn due to the highly poisonous nature of ergot alkaloids. A hair
drier, or, better, a flash eva****ator, is necessary to speed up steps
where eva****ation is necessary.
Preparation #1
Step I. Use Yellow light
Place one volume of powdered ergot alkaloid material in a tiny
roundbottom flask and add two volumes of anhydrous hydrazine. An
alternate procedure uses a sealed tube in which the reagents are
heated at 112 C. The mixture is refluxed (or heated) for 30 minutes.
Add 1.5 volumes of H2O and boil 15 minutes. On cooling in the
refrigerator, isolysergic acid hydrazide is crystallised.
Step II. Use Red light
Chill all reagents and have ice handy. Dissolve 2.82 g hydrazine
rapidly in 100 ml 0.1 N ice-cold HCl using an ice bath to keep the
reaction vessel at 0 C. 100 ml ice-cold 0.1 N NaNO2 is added and after
2 to 3 minutes vigorous stirring, 130 ml more HCl is added dropwise
with vigorous stirring again in an ice bath. After 5 minutes,
neutralise the solution with NaHCO3 saturated sol. and extract with
ether. Remove the aqueous solution and try to dissolve the gummy
substance in ether. Adjust the ether solution by adding 3 g
diethylamine per 300 ml ether extract. Allow to stand in the dark,
gradually warming up to 20 C over a period of 24 hours. Eva****ate in
vacuum and treat as indicated in the purification section for
conversion of iso-lysergic amides to lysergic acid amides.
Preparation #2
Step I. Use Yellow light
5.36 g of d-lysergic acid are suspended in 125 ml of acetonitrile and
the suspension cooled to about -20 C in a bath of acetone cooled with
dry ice. To the suspension is added a cold (-20 C) solution of 8.82 g
of trifluoroacetic anhydride in 75 ml of acetonitrile. The mixture is
allowed to stand at -20 C for about 1.5 hours during which 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 eva****ating the
solvent in vacuo at a temperature below 0 C, but this is not
necessary. Everything must be kept anhydrous.
Step II. Use Yellow light
The solution of mixed anhydrides in acetonitrile from Step I is added
to 150 ml of a second solution of acetonitrile containing 7.6 g of
diethylamine. The mixture is held in the dark at room temperature for
about 2 hours. The acetonitrile is eva****ated in vacuo, leaving a
residue of LSD-25 plus other impurities. The residue is dissolved in
150 ml of chloroform and 20 ml of ice water. The chloroform layer is
removed and the aqueous layer is extracted with several ****tions of
chloroform. The chloroform ****tions are combined and in turn washed
with four 50 ml ****tions of ice-cold water. The chloroform solution is
then dried over anhydrous Na2SO4 and eva****ated in vacuo.
Preparation #3
This procedure gives good yield and is very fast with little iso-
lysergic acid being formed (its effect are mildly unpleasant).
However, the stoichometry must be exact or yields will drop.
Step I. Use White light
Sulfur trioxide is produced in anhydrous state by carefully
decomposing anhydrous ferric sulfate at approximately 480 C. Store
under anhydrous conditions.
Step II. Use White light
A carefully dried 22 litre RB flask fitted with an ice bath,
condenser, dropping funnel and mechanical stirrer is charged with 10
to 11 litres of dimethylformamide (freshly distilled under reduced
pressure). The condenser and dropping funnel are both protected
against atmospheric moisture. 2 lb of sulfur trioxide (Sulfan B) are
introduced dropwise, very cautiously stirring, during 4 to 5 hours.
The temperature is kept at 0-5 C throughout the addition. After the
addition is complete, the mixture is stirred for 1-2 hours until some
separated, crystalline sulfur trioxide-dimethylformamide complex has
dissolved. The reagent is transferred to an air- tight automatic
pipette for convenient dispensing, and kept in the cold. Although the
reagent, which is colourless, may change from yellow to red, its
efficiency remains unimpaired for three to four months in cold
storage. An aliquot is dissolved in water and titrated with standard
NaOH to a phenolphthalein end point.
Step III. Use Red light
A solution of 7.15 g of d-lysergic acid mono hydrate (25 mmol) and
1.06 g of lithium hydroxide hydrate (25 mmol) in 200 ml of MeOH is
prepared. The solvent is distilled on the steam bath under reduced
pressure. the residue of glass-like lithium lysergate is dissolved in
400 ml of anhydrous dimethyl formamide. From this solution about 200
ml of the dimethyl formamide is distilled off at 15 ml pressure
through a 12 inch helices packed column. the resulting anhydrous
solution of lithium lysergate left behind is cooled to 0 C and, with
stirring, treated rapidly with 500 ml of SO3-DMF solution (1.00
molar). The mixture is stirred in the cold for 10 minutes and then
9.14 g (125.0 mmol) of diethylamine is added. The stirring and cooling
are continued for 10 minutes longer, when 400 ml of water is added to
decompose the reaction complex. After mixing thoroughly, 200 ml of
saturated aqueous saline solution is added. The amide product is
isolated by repeated extraction with 500 ml ****tions of ethylene
dichloride. the combined extract is dried and then concentrated to a
syrup under reduced pressure. Do not heat up the syrup during
concentration. the LSD may crystallise out, but the crystals and the
mother liquor may be chromatographed according to the instructions on
purification.
Purification of LSD-25
The material obtained by any of these three preparations may contain
both lysergic acid and iso-lysergic acid amides. Preparation #1
contains mostly iso-lysergic diethylamide and must be converted prior
to separation. For this material, go to Step II first.
Step I. Use darkroom and follow with a long wave UV
The material is dissolved in a 3:1 mixture of benzene and chloroform.
Pack the chromatography column with a slurry of basic alumina in
benzene so that a 1 inch column is six inches long. Drain the solvent
to the top of the alumina column and carefully add an aliquot of the
LSD-solvent solution containing 50 ml of solvent and 1 g LSD. Run this
through the column, following the fastest moving fluorescent band.
After it has been collected, strip the remaining material from the
column by wa****ng with MeOH. Use the UV light sparingly to prevent
excessive damage to the compounds. Eva****ate the second fraction in
vacuo and set aside for Step II. The fraction containing the pure LSD
is concentrated in vacuo and the syrup will crystallise slowly. This
material may be converted to the tartrate by tartaric acid and the LSD
tartrate conveniently crystallised. MP 190-196 C.
Step II. Use Red light
Dissolve the residue derived from the methanol stripping of the column
in a minimum amount of alcohol. Add twice that volume of 4 N alcoholic
KOH solution and allow the mixture to stand at room temperature for
several hours. Neutralise with dilute HCl, make slightly basic with
NH4OH and extract with chloroform or ethylene dichloride as in
preparations #1 or #2. Eva****ate in vacuo and chromatograph as in the
previous step.
Note: Lysergic acid compounds are unstable to heat, light and oxygen.
In any form it helps to add ascorbic acid as an anti- oxidant, keeping
the container tightly closed, light-tight with aluminum foil, and in a
refrigerator.
Created 9/15/2000 12:53:31
Modified 9/15/2000 12:57:01 Leda version 1.4.3
http://leda.lycaeum.org/?ID=8774
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