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This file is a part of the 1999 Hyperreal Drug Archives Snapshot.
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INTRODUCTION
Okay, this is going to be as easy at it gets. There are a few other
synths out there which appear to have more "detailed" instructions to
them, but they are still nothing approaching a "cookbook" and they leave
off important information and when you get right down to it are still much
more difficult. While there aren't any "detailed" instructions for this
synthetic route, all of the synthesis routes to make d-LSD will probably
require the equivalent of a Batchelor's degree (4-year college) in
chemistry anyway. There are no "easy" synths of LSD. TANSTAAFL.
WARNING: This synthesis is almost certainly hazardous to your heath and
safety. The mere possession of precursors and chemicals may get
you into legal trouble (e.g. POCl3 is used to create nerve gas and
export is controlled). The chemicals themselves are toxic. The
synthesis is dangerous (e.g. adding POCl3 too fast and generating
too much heat). The usual disclaimers apply, including a warning
that while nothing inaccurate has been intentionally introduced
into this file, there are no guarantees against typos, etc -- you
are expected to familiarize yourself with the primary literature if
you're actually psychotic enough to try to make this...
PRECURSOR MATERIAL
A source of lysergic acid is required. Most LSD is probably synthesized
from 'diverted' sources of ergotamine or ergonovine (lysergic acid
propanolaminde), both of which are used medically or in veterinary med.
Bromocriptine is also a novel possible starting material. Other
possibilities in this vein might include ergocristine, ergocryptine,
ergosine, or ergocornine. Hydergine is another possible source, although
the 9,10 double bond would need to be synthesized. There are also plant
sources of lysergic acid amides, including morning glories (_ipomea
violacea_ and other members of _convolvulaceae_), hawaiian baby woodrose
(_argyreia nervosa_), and ergot fungus (_claviceps purpurea_).
It is unlikely that anyone actually uses c. pupurea as starting material
for LSD synthesis. Most likely diverted ergotamine or ergonovine is used
by hydrolizing it to give lysergic acid. HBWR or MG seeds would probably
be used before attempting c. pupurea cultivation.
SYNTHESIS of d-LSD maleate or tartrate from lysergic acid with POCl3
Primary 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 7.23g (99 mmol) of diethylamine in 150ml
of CHCl3 was brought to reflux by heating. Heat was removed, and
2ml (3.4g, 22mmol) of phosphorous oxychloride (POCl3) was added over a 2
minute period at a rate just sufficient to maintain reflux, being careful
not to exceed this rate. 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(1)-acetyl-LSD (ALD-52) is
equimolar potent with LSD (90% as potent as LSD by weight) and can be
obtained by acetic anhydride acetylation of lysergic acid, followed by
preparation of the diethylamide (or vice versa). N(1)-methyl-LSD (MLD) is
also roughly as potent as LSD. But for both of these the synthesis
introduces needless complications, lower yields and no benefit either
pharmacologically or legally -- although for some reason ALD-52 still
apparently makes an appearance on the market from time to time.
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 in the USA
under the designer drugs act after testimony from a DEA agent that _in
their opinion_ the defendant was planning to distribute them.
Now, as "The Mysterious Mister Magneto" posted to alt.drugs.psychedelics,
"for shits and giggles," here's the synthesis of N(6)-allyl-LSD from Hoffman
and Nichols, 1985 (good luck!!! -- and beware of typos!):
(9)
323 mg (1 mM) of LSD was dissolved in 10 ml of chloroform. This was
diluted with 70 ml reagent carbon tetrachloride and was added, over
1h, to a refluxing solution of 440 mg (4.15 mM) of BrCN in 30 ml of
CCl4. The reaction wa stirred under a nitrogen atmosphere with
external heat provided by an oil bath held at 110 C. After the
addition was complete, reflux was continued for 6 h. The mixture was
allowed to cool and was washed once with 30 ml of 1% aqueous tartaric
acid. Following concentration of the organic solution by rotary vacuum
evaporation, the residue was partitioned between dichloromethane (2 x
35 ml) and 50 ml of 1% tartaric acid solution. The organic layer was
dried in the dark over anhydrous sodium sulfate. Filtration and
solvent removal afforded a purple residue that was passed over 5 g of
neutral alumina and eluted with 9:1 chloroform-methanol. This crude
material was then purified by centrifugal chromatography
(chromatotron) using 2-mm plate of neutral alumina (Merck 1092) and
elution with dichloromethane. An ammonia atmosphere was maintained by
bubbling nitrogen gas through concentrated ammonium hydroxide and
continuously purging the chromatotron chamber. The use of silica gel
for this purification gave a blue product and a lower overall
recovery. The product band eluted from the plate was concentrated
under vacuum in the dark and was recrystallized from ethyl acetate or
2-propanol: yield 237 mg (71%); mp 190-191 C (i-PrOH)
(8)
A mixture of 334 mg (1mM) of (9), 3.0 ml of glacial acetic acid, 0.6
ml of water, and 0.60 g of powdered zinc was stirred together under a
nitrogen atmosphere for 4 h, with external heating provided by an oil
bath held at 130 C. The reaction flask was then placed in an ice bath,
and 3 ml of water an a sufficient quantity of concentrated ammonium
hydroxide were added to make the contents strongly alkaline. The basic
suspension was extracted with 5 x 10 ml of dichloromethane. The
combined organic extract was then dried (Na2SO4), filtered, reduced by
rotary evaporation, and dried under high vacuum to yield 295 mg of a
tan solid that was one major spot by TLC (silica; 8:2)
chloroform-methanol). Purification by centrifugal chromatography over
alumina, elution with 9:1 chloroform-methanol under ammonia vapor, and
concentration of the eluate band gave a solid that was recrystallized
from ethyl acetate-hexanes to yield 190 mg (61%) of tan crystals, mp
196-198 C.
(6)
A mixture of 66 mg of (8) (0.21 mmol), 48 mg of anhydrous potassium
carbonate (0.35 mmol), and allyl bromide (0.24 mmol) in 2 ml of
freshly distilled DMF in a small amber vial was stirred under N2 at
room temperature. The reaction was monitored by TLC (silica; 9:1
CHCl3-MeOH) at 1-h intervals to determine reaction completion. When
the starting material (8) had been consumed, the solvent was stripped
from the reaction under high vacuum. The resulting residue was
extracted with chloroform (5 x 5ml), dried (Na2SO4), and reduced by
rotary evaporation to yield the product, usually as a white solid.
Centrifugal chromatography over a 1-mm alumina plate and elution with
methylene chloride under ammonia atmosphere led to the separation of
two blue, highly fluorescent fast-moving bands. The first band eluted
from the plate was the major component and was concentrated, dissolved
in a minimum of hot benzene, filtered, and cooled. Hexane was added
when necessary to induce crystallization to yield 67 mg (88%) of
N(6)-allyl LSD mp 88-90 C
Now, do the math on the yields. If you don't screw anything up the
final yield is 38% of the d-LSD that you started with, for roughly the
same gain in potency, or less.