LSD-25 Synthesis

Contents
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LSD-25 Synthesis from "Psychedelic Guide to the Preparation of the
Eucharist"
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 evaporated. 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 evaporator, is necessary to speed up steps where
evaporation 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. Evaporate 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 evaporating 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 evaporated 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 portions of chloroform.
The chloroform portions are combined and in turn washed with four 50 ml
portions of ice-cold water. The chloroform solution is then dried over
anhydrous Na2SO4 and evaporated 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 portions 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 washing with MeOH. Use the UV
light sparingly to prevent excessive damage to the compounds. Evaporate
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. Evaporate in vacuo and chromatograph as in the
previous step.

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.

Synthesis of d-LSD maleate or tartrate from lysergic acid with POCl3

Ref:

Johnson, Ary, Teiger, Kassel. "Emetic Activity of Reduced Lysergamides."
Journal of Medicinal Chemistry. 16(5):532-537. 1973.

Related:

Huang, Marona-Lewicka, Pfaff, Nichols. "Drug Discrimination and Receptor
Binding Studies of N-Isopropyl Lysergamide Derivates." Pharmacology,
Biochmistry and Behavior. 47(3):667-673, 1994.

Oberlender, Pfaff, Johnson, Huang, Nichols. "Stereoselective LSD-like
Activity in d-Lysergic Acid Amides of (R)- and (S)-2-Aminobutane."
Journal of Medicinal Chemistry. 35(2):203-211, 1992.

Hoffman-AJ, Nichols. "Synthesis and LSD-like Descriminative Stimulus
Properties in a Series of N(6)-alkyl Norlysergic Acid N,N-Diethylamide
Derivates." Journal of Medicinal Chemistry. 28:1252-1255, 1985.

NOTE: JMC 35(2):203-211 has some amazing stereoviews of LSD which might
interest non-chemists who like to cross their eyes.

Under reduced light (or red light) a stirred solution of 3.15g (11 mmol)
of d-lysergic acid monohydrate and 4.45g (99 mmol) of diethylamine was
brought to reflux by heating. Heat was removed, and reflux was
maintained by the addition of 2ml (3.4g, 22mmol) of phosphorous
oxychloride (POCl3) over a 2 minute period. The mixture was then
refluxed for an additional 4-5 mins until an amber-colored solution
resulted. The solution was brought to room temperature and was washed
with 200ml of 1M NH4OH. The CHCl3 solution was dried (MgSO4), filtered,
and concentrated under vacuum (not allowing the solution to exceed 40
degrees C). The last traces of the solvent were removed at 2-5 mm. The
viscious residue was dissolved in a minimum amount of MeOH and acidified
with a freshly prepared 20% solution of maleic acid in MeOH.
Crystallization occured spontaneously. The needles were filtered, washed
with cold MeOH and air-dried. Yield was 66% after further purification
by column chromatography over alumina (Brockman) and elution with 3:1
benzene-chloroform. The chromatography takes appx 8-9 hours.
Alternatively, it can be crystallized as the (+)-tartrate from MeOH.
After crystallizing from cold MeOH, it is diluted with ethyl acetate,
filtered and the the crystals are washed with ethyl acetate.

This procedure also works for primary amines and small dialkyl amines.
LSD, however, probably remains the most worthwhile product. Other
interesting amines might be the N-ethyl-N-propyl derivative (LEP) and
the morpholide (LSM-775). 75ug of the morpholide have been reported to
have been as effective as 50ug of d-LSD but with 45 min onset (vs 1
hour) and a 1 hour peak (vs 4 hours). The procedure would probably work
well for LEP, but yields would be reduced for the morpholide. Other
N(20)-alkyl-lysergic acid derivatives tend to be more than 10 times less
potent than LSD if not effectively inactive. N(6)-ethyl- (and -allyl-
and -propyl-) derivates of LSD may be more active than LSD itself, but
synthetic routes to these chemicals presently start with LSD and yields
would probably inhibit their appearance on the illicit market. (N(6) is
the other nitrogen on the ring structure in addition to the N(1)
pyrrole/indole nitrogen). Derivatives of LSD (besides LSA/LA-111 and
lysergic acid) are not scheduled, but would be prosecutable under the
designer drugs act after testimony from a DEA agent that _in their
opinion_ the defendant was planning to distribute them.

--
"In consciousness dwells the wondrous,
with it man attains the realm beyond the material,
and the Peyote tells us,
where to find it."