Introduction
LSD is, without a doubt, the king of hallucinogens. It is rather
difficult to make by total synthesis, but with the right starting
materials (lysergic
acid, ergotamine) it is as easy to produce as your average THC or
amphetamine. I call it the king because of the awesome potency, the
usual hallucinogenic
dose being about 100 to 400 micrograms orally. The amphetamine DOM
(STP), which is 100 times more powerful than mescaline, requires a dose
of 5 milligrams.
This gives one gram of LSD the potential to contain 4,000 to 10,000
doses. With an average of about 6,000 doses per gram, the street value
(based on $5 a
hit) of one gram of LSD is $30,000.
LSD Synthesis
As with the rest of this book, I will deal only with the synthetic
manufacture of drugs (LSD included). If you want to grow the ergot
alkaloids that
begin the total synthesis of LSD, then you will have to go to the Merck
Index and look up the references to the operation. Michael V. Smith's
book,
Psychedelic Chemistry, has a section on growing Claviceps purpurea,
which yield ergot compounds. This section is very complete and
informative, but I think
that you should also look up the dangers of growing this fungus before
doing it, as it causes a type of gangrene that can kill you (not to
mention making
your arms and legs fall off) upon contamination of your body. As Mr.
Smith's book states, this fungus is very temperamental, hard to obtain,
even harder to
grow and diffficult to work with. Smith's book gives many references and
many formulas that you will not see here, but which are of great
interest in the
making of all hallucinogens (not just LSD). This does not make my book
incomplete. On the contrary, I have given more than enough information
to make every
major type of drug.
My book is not intended to cut in on Smith's book sales. It is
intended to give you information and formulas that Smith's book lacks.
Where he gives
many different types of formulas, I give only the fast, simple and high
yielding formulas. Also, you will not see the same formula in both his
and my book,
unless it is a general method and not specific. What his book lacks, my
book gives (equipment, methods, basic chemistry, a wider variety of
types of
different classes of drugs, glossary terms, easier to understand
wordage, how to buy and make precursors, etc.). What my book lacks, his
book gives (more
variety of hallucinogenic formulas, cultivation of pot and ergot, tests
for activity, etc.). I feel it would be a good idea to buy his book and
try some of
these harder formulas after learning the basics and practicing some of
the formulas from my book, for complete understanding first.
Forgive me for wandering from the subject of LSD synthesis. As this
first chapter of formulas is for psychedelics, I felt it necessary to
explain the
difference of the only other book of this type. If you are sharp, and
have carefully read my chapter on buying precursors, you should be able
to get
lysergic acid from a supplier. Be warned, that the DEA must be informed
of the purchase by the supplier, according to laws requiring them to do
so.
Lysergic acid can be made. Following is the general method to give you a
very good idea of the procedure and chemicals involved.
Synthesis of Lysergic Acid
By reacting N-benzoyl-3-(B-carboxyethyl)-dihydroindole (see JCS, 3158 (1931)
for the preparation of this compound) with thionyl chloride, followed
by aluminum chloride gives
1-benzoyl-5-keto-1,2,2a,3,4,5-hexahydrobenzindole. This is then
brominated to give the 4-bromo-derivative, which is converted to
the ketol-ketone by reacting with methylamine acetone ethylene ketol.
This is then hydrolized by acid to yield the diketone and treated with
sodium methoxide
to convert it to the tetracyclic ketone. Acetylate and reduce this
ketone with sodium borohydride to get the alcohol, which is converted to
the hydrochloride
form, as usual.
The above hydrochloride is treated with thionyl chloride in liquid
sulfur dioxide, to produce an amorphous chloride hydro chloride, which
is converted
to the nitrile with sodium cyanide in liquid hydrogen cyanide.
Methanolysis then gives the ester of the nitrile. Alkaline hydrolysis of
this last compound,
followed by catalytic dehydrogenation in water using a deactivated Raney
Nickle catalyst (see JOC. 13, 455 1948) gives dl-lysergic acid.
Total Synthesis Of Lysergic Acid
This is the easiest way to totally synthesize lysergic acid. There
are other ways, but after reviewing other methods, I found this to be
superior. It is
quite complicated and it takes good modern equipment.
JACS, 78, 3087 (1956). 3-Indolepropionic acid, 94.5 g (0.5
mole) is dissolved in 600 ml of water containing 20 g of NaOH. The
solution is mixed
with 100 g of Raney Nickle catalyst and hydrogenated at room temp in a
steel bomb at about 3,500 psi until the uptake of hydrogen stops (about
20-30 hours).
Filter off the catalyst and wash it with a little water to remove the
product that is clinging to it. Add 85 ml of concd HCl acid to the
filtrate, and cool.
If your reduction is incomplete, you will now have unreacted starting
material separate, and this must be removed by filtration. Benzoylate
the filtrate
(the Schotten and Baumann method is preferable), using 210 ml of 12 N
NaOH 180 ml of benzoyl chloride. Keep the solution alkaline throughout
the benzoylation,
and keep the temp below 40°C by cooling. When the benzoyl chloride is
fully reacted, the reaction mixture is cooled and acidified with 300 ml
of HCl acid.
Filter the crude product by filtration, wash with water, and extract
with four 1 liter portions of hot water. Separate, and crystallize the
resulting syrupy
product from a few volumes of methanol. Filter and wash with a little
cold methanol to get a little over 100 g that melts at 151-153°. This is
l-Benzoyl-3-beta-carboxyethyl-2,3-dihydroindole. This can be purchased
to eliminate this step.
1-Benzoyl-5-keto-1,2,2a,3,4,5,-hexahydrobenzindole. 118 g of the
above product (1-benzoyl-3-B-carboxyethyl-2,3-dihydroindole) is mixed
with 200 ml of
pure thionyl chloride. This solution is allowed to stand for 30 min,
then it is warmed gently for 15-21 min on a steam bath. Excess thionyl
chloride is
completely evaporated with the temp maintained between 22-26°C in vacuo.
The crude acid chloride is dissolved in dry carbon disulfate. This
solution is
added, in a thin stream, to a well stirred suspension of 240 g of
aluminum chloride in 1750 ml of carbon disulfate in a 5,000 cc flask.
Note: this must be
done under a fume hood. A complex will separate and bog down the
stirring device. Heat this mixture under reflux with stirring for 1
hour. Decompose this
mixture by adding 500 g of ice, 250 ml of concd HCl acid, and 500 ml of
water, all while good stirring is continued. Cooling of this operation
is affected
by periodic distillation of the carbon disulfate in vacuo. After the
decomposition is complete, any remaining carbon disulfate is removed
completely in
vacuo, and the product is extracted with 2 liters of benzene. The
extract is washed well with 500 ml of 2 N NaOH in three portions, and
then with water.
Dry (with the usual magnesium sulfate), and evaporate to a small volume
in vacuo. Add this small volume to several portions of ether to get the
ketone to
crystallize (add slowly), and filter, then wash with ether to get 85 g
of pure title product, mp: 146-147°C.
1-Benzoyl-4-bromo-5-keto-1,2,2a,3,4,5-hexahydrobenzindole. A solution
of the above indole (305 g) in 2,200 ml of glacial acetic acid is
warmed to 40°C.
While the reaction is illuminated with a 250 watt bulb, 352 g of
pyridine hydrobromide perbromide is added in portions, over 5 min with
shaking. The
solution is then heated to 60° and is held between there and 55°C for 30
min. Treat the mixture with carbon, and evaporate to a small volume in
vacuo. The
residue is taken up with 2,200 ml of chloroform, and wash this solution
with several portions of water, dry as above, and concentrate in vacuo.
Crystallize
the residue from 2,200 ml of 50% acetic acid and 50% ether to get 270 g
of title product that melts at 180.5-181.5°C. Another crop can be
obtained from
concentrating the fltrates. Yield: 30 g of less pure product.
1-Benzoyl-2,2a,3,4-tetrahydro-4-methyl-2-methyl-1,3-dioxolan-2-yl-methyl-aminobenzindol-5-(1H)one.
A solution of the last indole product above (270 g)
and 307 g of methylaminoacetone ethylene ketol in 4,500 ml of dry
benzene is refluxed for 21 hours under a slow stream of nitrogen. The
mixture is cooled
and 151 g of methylaminoacetone ethylene ketol hydrobromide is filtered
off. The filtrate is washed with ice water, then extracted with 2.5
liters of cold
dilute HCl acid containing 150 ml of the concd acid. The acid extracts
are immediately added to an excess of ice cold dilute NaOH. Extract with
1 1iter of
chloroform, dry over magnesium sulfate, treat with carbon and
concentrate by evaporation in vacuo. The residual ketol-ketone is
crystallized from acetone
to yield 220 g, mp: 135-136°C.
5-Keto-4-N-methyl-N-acetonylamino-1,2,2a,3,4,5-hexahydrobenzindole.
20 g of the above product is dissolved in a mixture of 250 ml of concd
HCl acid and
250 ml of water, and the solution is kept under nitrogen for 5 days at
37°. Cool the mixture, treat with carbon, filter, and concentrate the
filtrate in
vacuo to a small volume. Treat the residue with an excess of sodium
bicarbonate, extract with cold chloroform, and remove the chloroform by
evaporation in
vacuo at room temp. The crude diketone is powdered, slurried with 75 ml
of benzene-ether, and filtered. Yield: 9.8 g, mp: 105-107°C.
9-keto-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo-(4,3)isoquinoline.
25 g of the above product is mixed with 550 ml of absolute ethanol. Stir
this
mixture under nitrogen and cool to -15° with an external freezing
mixture. Sodium methoxide is added (17 g) and the mixture is stirred for
10 min at
-10 to -12°. Cool to -25°, and the product is filtered and washed (while
still in the funnel) with cold ethanol and ether. Without exposure to
air the
crude ketone is immediately slurried with a little ice water and
filtered. Wash with ice water, ethanol, then ether (all cold) to yield
16 g of product
melting at 145-147°.
4-Acetyl-9-keto-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo-4,3-quinoline.
24 g of the last product is added to 80 ml of cold acetic anhydride.
The
mixture is held at 25° for about 5 min, then thoroughly cooled,
filtered, and the product (a solid) washed with ether to yield 20.5 g,
mp: 169-170°.
A second crop is obtained by concentrating the mother liquor by
evaporation.
A mixture of the last product (1.0 g) and 10 g of palladium carbon
(5%), in 35 ml of xylene, is heated under reflux for 4 hours. The
catalyst is
filtered and extracted with hot methanol and chloroform. The combined
extract filtrates and the initial filtrate are combined and evaporated
in vacuo. The
residue is recrystallized from water to give 0.6 g of a monohydrate
product that melts at 255-256°. This product is called
4-acetyl-4,5,5a,6-tetrahydro-9-hydroxy-7-methylindolo-(4,3fg)-quinolinium
hydroxide
betaine.
4-Acetyl-9-hydroxy-7-methyl-4,5,5a,6,7,8,9,10-octahydroindolo-(4,3fg)-quinoline.
1 g of the above betaine in a mixture of 20 ml of ethanol and 5 ml of
water, is treated with 0.08 g of sodium borohydride, and this solution
is refluxed for 10 min and kept at 25° for 1 hour after the reflux is
finished. The
solvent is distilled off, and the residue is taken up in a mixture of
chloroform and water. The chloroform solution is separated, dried as
above, and then
the solvent is distilled off. The residue is recrystallized from a
nitromethane-ethyl acetate mixture to yield 0.2 g (21%), mp 193-196°.
Not only is this a
small scale, but it is a poor yield, requiring you to perform it several
times to get enough product to perform the next step. When you have
more than
enough, convert the product into its hydrochloride form by dissolving in
dry methanol and precipitating with dry hydrogen chloride.
4-acetyl-9-chloro-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo-(4,3fg)-quinoline
hydrochloride. 3.1 g of the above product in its hydrochloride form is
dissolved in 75 ml of liquid sulfur dioxide contained in a glass lined,
high pressure bomb, or autoclave. Thionyl chloride (1.2 ml) is added and
the vessel
is sealed and kept at 25° for 6 hours. Vent the vessel carefully and
remove the mixture. Evaporate the sulfur dioxide while keeping the
volume of the
solution constant by the slow addition of dry ether. The amorphous
chloro hydrochloride is filtered, washed with ether (dry) and dried by
evaporating in
vacuo to give 3.5 g of product, mp:130-135°.
4-Acetyl-9-cyano-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo-(4,3fg)-quinoline.
40 g of dry, powdered sodium cyanide, is added to ice cold liquid
hydrogen
cyanide and stirred gently with ice bath cooling. Speed up the stirring,
continue the cooling, and add 7.5 g of the amorphous product directly
above.
Continue stirring for 30 min, then the hydrogen cyanide is distilled
under enough reduced pressure to keep it coming over the condenser at a
temp below
10-12°. The residue is mixed with chloroform and ice water, and the
resulting mixture is filtered. The organic layer of the filtrate is
separated and the
aqueous layer is extracted with two separate portions of chloroform. The
combined extracts (this would include the separated chloroform, as
usual) are dried
over magnesium sulfate, decolorized, and the solvent removed by
distillation in vacuo. Crystallize the product in ethyl acetate. Yield:
3.3 g, mp: 173-174°.
Recrystallize again for extra purity.
9-Carbomethoxy-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo-(4,3fg)-quinoline.
1 g of the last product is mixed with 15 ml of methanol and 0.25 ml of
water.
With external (ice bath) cooling add 2 ml of concd sulfuric acid slowly.
Seal this solution in a high pressure bomb with a glass liner (or in a
glass tube
taking safety precautions in case of explosion) with a nitrogen
atmosphere, and heat at 100° for 23-24 hours. Note: I have seen a big
pressure cooker (like
gramma cans peas with) work for some of these bomb procedures. I do not
recommend it, but here is how to do it right, if you feel you must. Use
only the
great big heavy duty models, in excellent condition, set the pop off
(relief valve) for near maximum position; never, ever tamper or modify
this valve to
get more pressure. Put the product in a glass beaker, put it in the
cooker, flush with nitrogen, heat and stay in a different house during
the reaction.
Carefully turn off heat, notice or record pressure gauge after time has
elapsed. Wait until pressure drops noticeably, bleed off remaining
pressure and get
product.
Treat the mixture with decolorizing carbon and then evaporate in
vacuo to 10 ml. Pour onto a mixture of 30 ml of chloroform, ice, and 10 g
of sodium
bicarbonate. Separate the chloroform layer, and extract the aqueous
phase with three 10 ml portions of chloroform. The combined chloroforms
are dried,
evaporated to dryness in vacuo, and the product is crystallized from
benzene to give 1/2 g of product that melts at 159-160°. You may purify
more by
recrystallizing from ethyl acetate. This is not very much product. As
with the procedure 4 steps back, you will have to perform this step over
and over.
If you try to double or triple the amounts given, you may get more
product, but you will hurt the yield.
dl-Lysergic acid. 3.9 g of the last product is mixed with 78 ml of
1.5% potassium hydroxide solution. Reflux for 30 min under nitrogen. 8.5
g of hydrogen
sodium arsonate, and Raney Nickle (16 g wet), that has previously been
deactivated by boiling in xylene suspension (see JOC, 455 (1948) to
deactivate), is
added and the mixture is refluxed and stirred under a nitrogen
atmosphere for 20 hours. The solution is treated with carbon, and the
crude lysergic acid is
precipitated by neutralization to pH 5.6, and then filter it off and
wash with water. Yield: 1.04 g. A second crop is obtained in the usual
manner (0.15 g).
Purify by dissolving in dilute ammonium hydroxide, treat with
decolorizing carbon, and reprecipitate with carbon dioxide to get a mp
of 242-243°. You may
be able to get an analytical or laboratory consultant to make one of
these products near the final step, thereby eliminating the need to go
through all of
the steps as described. This will save you much time, but as these
people are highly trained, their time will be costly.
Lysergic acid can be made from many ergot derivatives by hydrolysis
of these compounds. These compounds include ergonovine, ergotamine,
ergokryptine,
ergosine, methysergide, ergine, and a few others. Total synthesis of
these compounds is impractical, as lysergic acid is made before the
alkaloid. You
could stop the operation as soon as you reach lysergic acid, otherwise
you will have to hydrolyze as described below. There are many analogs of
these
alkaloids that end with the ine suffix. These are not as suspicious as
the former because they lead to an inactive iso-LSD. They will look like
this: the
ergotamine isomer = ergotaminine, the ergonovine isomer = ergonovinine,
etc. These analogs are easily converted to the active forms or they may
be used
exactly as the non-iso versions to give the iso-LSD, which is converted
very easily to LSD as also described below.
Lysergic Acid From Ergot Alkaloids.
Dissolve 20 g of the alkaloid (use any of the above or one of its
isomers or a combination) in 200 ml of 1 M methanolic KOH solution (this
is made by
dissolving 14 g of KOH in 250 ml of dry methanol) in a 1 1iter
evaporation flask (heavy walled construction). Evaporate the methanol
off. Add 400 ml of
8% aqueous (water) KOH solution to the residue and boil for one hour
under a slow stream of nitrogen that is allowed to flow through a small
orifice for
exhausting purposes. Cool, acidify with dilute sulfuric acid, and shake
in a separatory funnel with 1 1iter of dry ether. Separate the lower
aqueous layer
and filter it with vacuum assist. Wash the precipitate with 20 ml of
dilute sulfuric acid. This is lysergic acid; store as described later in
this chapter.
There remains a small amount of lysergic acid in the filtrate
solution. Remove it by basifying the solution with sodium carbonate, and
then bubbling CO2
through it. Filter it off and add it to the other lysergic acid. Now you
will need to precipitate the iso-lysergic acid out and convert it. If
you did not
use any iso-alkaloid then you will have very little iso-lysergic acid,
but it is still worth converting. If you used iso-alkaloid, this is a
must.
Precipitate the iso-lysergic acid by adding some 10% HNO3, filter,
add more portions until no more precipitate forms. Convert it to
lysergic acid by
adding 3 ml of 10% KOH per every 0.1 g of iso-lysergic acid, heat on
steam bath for 1 hour under a nitrogen atmosphere. Precipitate the
changed lysergic
acid by acidifying with glacial acetic acid. The total yield of this
entire operation (including the iso change) is a little under 10 grams.
As stated
earlier, you may use only iso-alkaloid in the hydrolysis step above to
get iso-lysergic acid which can be used in the synthesis of LSD to get
iso-LSD,
which can be changed to the active LSD as described later. Note: iso-LSD
is not active.
Some sources say that lysergic acid does not need to be purifed. I
feel that everything should be purified. In the event that something
should go wrong
with the formula, you can immediately rule out impurities as the cause.
Also, impurities create unwanted byproducts which can be poisonous,
creating dangers
for the drug user. Purification of lysergic acid is very easy. Dissolve
the acid in dilute ammonium hydroxide, treat with decolorizing carbon,
reprecipitate
(after filtering off and washing product from the carbon) with carbon
dioxide.
Convert iso-LSD to LSD. Add 50 ml of ethanol and 5 ml of 4 N KOH per
every gram of iso-LSD. Let this mixture stand for 2 hours at room temp.
Evaporate
in vacuo to get the LSD.
Separate iso-LSD from LSD. Dissolve the residue of the mixture of
LSDs from the end of the formula in 120 ml of benzene and 40 ml of
chloroform. Add
tartaric or maleic acid to precipitate the LSD, filter off, add a little
ether and put in refrigerator for several days to get a little more
LSD, which is
filtered off and added to the rest. Evaporate the filtrate in vacuo to
get the iso-LSD and convert as above.
LSD from Lysergic Acid. This is based on the formula taken from CA,
50, 10803d (1956) Dissolve 5.5 g of dry lysergic acid in 125 ml of
acetonitrile that
has been cooled to -10° and cool further to -20° with an external
freezing mixture. Add 8.8 g of trifluoroacetic anhydride in 75 ml of
acetonitrile (this
solution must be cooled to -20° before the addition). Be careful making
this addition, so as not to raise the temp, etc. Let stand at -20° until
all the
lysergic acid dissolves (about 1/2 hours). Add 7.6 g of diethylamine (or
analog) in 150 ml of acetonitrile and allow to set at room temp in
darkness for 2
hours. Evaporate in vacuo to get the LSD, which can be separated from
the iso-LSD as above.
LSD From Lysergic Acid
This is taken from CA, 57, 5979 (1962). It is designed by Hofmann to
give 1-methyl-D-lysergic acid, and is modified to give LSD and iso-LSD.
Dissolve
0.54 g of lysergic acid in 10 ml of freshly distilled phosphorous
oxychloride, stir 0.42 g of powdered, fresh phosphorous pentachloride.
Allow to stand at
room temp for 2 min, then at 90° for 2 min, then evaporate in vacuo.
Extract the residue with hexane to give lysergic acid chloride
hydrochloride. To save
time you may extract the reaction mixture without evaporating. Add 2.5 g
of the hydrochloride to a cooled solution of 7 ml of diethylamine (or
analog) in
25 ml of methylene chloride that is cooled to 0° Note This solution is
cooled to 0° before the addition. With stirring add 13.75 ml of dry
pyridine and
stir for 30 min with cooling to keep the temp at 0° or a little below.
Warm to room temp and continue the stirring for 90 min. Evaporate in
vacuo to get
the LSDs. Separate as already described.
LSD From Lysergic Acid Monohydrate
This is, in my opinion, the best of all the methods. It was designed
to be used to experiment with different types of amines, so if you would
like to
substitute diethylamine with another amine this would be the best bet.
It also gives good yields (50% or better) and is very easy. The
reference that gives
it (JMC, 16, 532 (1973)), also gives potency data for many lysergamides
and many of their formulas. The reading is good, interesting,
informative, and the
method given below gives no useful amount of iso-LSD, so separation of
that product is not necessary. Both method A and B were from JMC, 16,
532.
Method A. A slurry of 3.15 g d-lysergic acid monohydrate (monohydrate
means dry) and 7.3 g of diethylamine (or 0.1 mole of similar amine) in
150 ml of
pure chloroform is heated to reflux. After the lysergic acid is
dissolved (a few min) cool the mixture down to where reflux has stopped
by removing the
heat. Before the mixture cools any further 2 ml of phosphorous
oxychloride is added at such a rate as to give reflux (about 2 min).
After addition, reflux
for 4-5 min further until an amber-colored solution results. Cool to
room temp and wash the mixture with 200 ml of 1 M ammonium hydroxide.
The chloroform
solution was dried with MgSO4 (this would have to be after separation),
filtered, and concentrated by evaporation in vacuo under a temp of 38°
(at no time
let the temp go over 40°). The last traces of solvent are removed at 2-5
mm. Dissolve the residue in a minimum amount of methanol and acidify
with freshly
prepared solution of 20% maleic acid in methanol (not aqueous) to
precipitate the LSD in its maleate form. Filter the fluffy white
needles, wash with cold
methanol and air dry to get 2.2 g of LSD that requires no further
purification.
Method B. This is proven to be more effective for using substituted
amines. Mix the following slurry; 3.15 g of dry d-lysergic acid in 150
ml of
chloroform and reflux in a 3 necked flask. As soon as you have the
reflux adjusted add 7.3 g of diethylamine (or 0.1 mole of analog) in 25
ml of chloroform
and at the same time, from another addition funnel mounted in the
opposite neck of the flask, add 2 ml of phosphorous oxychloride so that
both the
additions begin at the same time. The additions should be timed so that
they both finish after 2-3 min. Keep at reflux with gentle heating for
another
3-5 min until a clear amber-colored solution results. Cool thesolution
to room temp and finish the work up, as in method A directly above, to
get 2 g of
LSD maleate. As in method A, this method gives very little or no
iso-LSD, so don't worry about removing that.
Lysergic Acid Monohydrate
I put this formula in this book specifically for the two methods (A
and B) directly above, however, lysergic acid monohydrate can be used on
any of the
LSD formulas with possible success. I feel this may be easier than the
first method given at the beginning of this chapter.
Dissolve 175 g of KOH in 1,750 ml of water in a flask of 5 liters
volume equipped with a reflux condenser and a gas inlet tube. If a
stirring device is
not required, it should be removed and the open neck stoppered. Heat the
mixture to 80° under a stream of nitrogen and add 500 g of ergotamine
tartrate.
Hold the temp at 80° for 2 1/2 hours with bubbling from the nitrogen
filled gas inlet tube. Pour the mixture into a 5 gallon polyethylene
bucket (made from
the same material as a plastic gas can) filled with about 6 liters of
ice. Put the bucket in a cooling mixture to cool below 10°. Neutralize
the mixture by
adding cold dilute sulfuric acid to a congo red end point (pH 4.2).
Lysergic acid and potassium sulphate will be seen to precipitate. Let
stand for 2-3
hours in the 5-10° cooling mixture. Filter with vacuum assist, and let
vacuo suck as dry as possible. Break up the filter cake and put in a 2
liter beaker.
Make a solution from 150 ml of liquid ammonia and 2.5 liters of very
cold dry denatured ethanol and add to the reaction mixture. Stir for 1
hour and filter.
Keep the fltrate and treat the filter cake to 1/2 the ammonia ethanol
mixture as above. This second extract is filtered and the cake is washed
with 250 ml
of the ammoniacal ethanol mixture. Combine the fitrates, and evaporate
to total dryness with a strong vacuum and gently heating. Do not heat at
too high of
a temp. Scrape the product from the vacuum vessel and put into a mortar.
Mix 113 ml of methanol with 38 ml of water, and rinse the rest of the
residue from
the evaporation vessel and dump into the mortar with the rest of the
product. The slurry in the mortar is ground up well and filtered. Wash
the flter cake
with 150 ml of cold water and use vacuum to suck dry for 1 hour. Break
up the filter cake and dry at 80-85° under a high vacuum to get about
65-75 g of
cream-white to gray-white powder. This is lysergic acid monohydrate.
I think that if you dry the lysergic acid (obtained from the ergot
alkaloids by hydrolysis as described earlier) it will also work in
methods A and B.
This is how you dry lysergic acid: dry under high vacuum at 140-145° for
2-3 hours.
LSD From Ergot Alkaloids
This was invented by Hofmann and is a superior method because you may
proceed from the ergot alkaloids to LSD without isolating the lysergic
acid. CA, 57, 12568 (1962).
Add 1.2 g of ergotamine hydrochloride to 4 ml of anhydrous hydrazine
and heat 1 hour at 90°. Add 20 ml of water and evaporate in vacuo, to
get
d-iso-lysergic acid hydrazine. 1 g of the lysergic hydrazine is powdered
well and added to 40 ml of 0.1 N (ice cold) HC1 acid. To this, cooled
to 0°, is
added 4 ml of 1 N Na nitrite, with good stirring. Over 2-3 min, add 40
ml of 0.1 N HC1 acid to get pH to 5. Let stand for 5 min, basify with 1 N
NaHCO3,
extract with 100 ml of ether, and then with 50 ml of ether. Wash the
ether layer with water and dry, then evaporate in vacuo at 10°. Dissolve
the resulting
yellow azide in about 5 ml of diethylamine at 0° and then heat in a
metal bomb at 60° for 1 hour. If a bomb is unavailable you may get by
with heating for
3-4 hours at 45° in a vented flask under a nitrogen atmosphere. Also, I
would flush the bomb with nitrogen before sealing and heating. Remove
heat after
time elapses and let stand (after bleeding off pressure for bomb method)
for 2 hours and evaporate in vacuo to get 0.7 g of LSD and 0.15 g of
iso-LSD. The
iso-LSD will not do anything (good or bad) if consumed, so you may leave
it in with the LSD. You may also separate it and convert it to LSD as
in the
formulas ahove.
LSD From Lysergic Acid JOC, 24, 368 (1959)
This is a simple method that gives good yields of LSD with very
little (if any) iso-LSD. You will be required to purchase sulfur
trioxide from Allied
Chemical and Dye Corp (ask for Sulfan B, or SO3), but this is not a
suspicious chemical so ordering is not a problem.
Sulfur trioxide-Dimethylformamide complex (SO3-DMF). This is a
reagent required for this method of LSD production. A completely dry 22
liter flask
(round bottom) in an ice cooling bath is fitted with a condenser,
stirring device, addition funnel, then is filled with 10-11 liters of
DMF
(dimethylformamide) that has been freshly distilled under reduced
vacuum. Use drying tubes to protect the reaction from all moisture
(including atmospheric
moisture). 2 pounds of sulfur trioxide (SO3) are then added, with a
great deal of caution, over 4-5 hours with stirring, dropwise. The temp
must be held
between 0°-5° during this addition. Stir for 1-2 hours after the
addition until some separated, crystalline SO3-DMF complex has
dissolved. Store in the
dark in a suitable vessel, in a refrigerator for not more than 3 months.
Upon storage, the complex will turn yellow and then orange. This is
normal. As
long as it is less than 3-4 months, it is still good. This mixture gives
a molarity of 1 (1 M) and can be made using 1/2 or 1/4 of the amounts
above to
scale down the version, still giving a 1 M solution.
Lysergic Acid Diethylamide. A solution of 7.1 g of lysergic acid
monohydrate. As with any of the formulas calling for the monohydrate,
you may substitute
dry or anhydrous lysergic acid in place of the lysergic acid monohydrate
by using a smaller amount of the dry lysergic acid. I have found that
dividing the
amount of the monohydrate by the constant of 1.1 gives a close amount of
dry lysergic to use, e.g., 7.1 divided by 1.1 = 6.5 g, to substitute in
the formula.
Likewise, the monohydrate can be figured into a formula calling for dry
lysergic, 6.5 times 1.1 = 7.1 g. Also, if a formula does not specify if
the lysergic
acid is to be dry, e.g., add 0.54 g of d-lysergic acid, then always use
dry or monohydrate as any water will kill the yield. Dry as stated
above. As a
general rule dry your lysergic acid as soon as you plan to use it
(because it collects H2O from air). 1 g of lithium hydroxide hydrate in
200 ml of methanol
is prepared. Distill off the solvent (methanol) on a low temp steam bath
under reduced pressure, or evaporate under vacuum. The resulting
glass-like
lithium lysergate residue, is dissolved in 400 ml dry dimethylformamide
(DMF). 200 ml of this DMF is distilled off with 15 mm pressure through a
12 inch
helices-packed fractional column. Cool the resulting solution to 0°, and
with stirring, quickly add the SO3-DMF solution (50 ml of 1 M). The
mixture is
stirred with cooling for 10 min and 125.0 mmol. of the desired amine is
added (that would be 9.05 g of diethylamine). The stirring and cooling
are continued
for 10 min after the amine addition, and then the reaction is decomposed
by adding 400 ml of water. After stirring thoroughly the reaction
mixture is
treated with a saturated solution of NaCl. Table salt and water are fine
for this if the salt is not iodized. Use 200 ml of the saturated
solution on the
reaction mixture. Extract the amide (LSD) with repeated portions of
ethylene dichloride. Test for completeness of extraction with Van Urk
test or hold
extract under black light briefly and look for fluorescence as compared
with non-extracted ethylene dichloride, or use any indole test. The
combined
extracts are dried (with MgSO4 as usual), and then evaporated under
vacuo to a syrup. Keep the temp below at least room temp. Dissolve the
residue in about
60 ml of dry methanol, acidify with solid maleic acid, treat to
turbidity with dry ether, and refrigerate for 3-6 hours to get colorless
soft needles of
LSD maleate which are filtered from the mother liquor. More crystals may
be obtained by evaporating the mother liquor in a cool, dark place
under vacuum.
Things To Remember When Working With Ergot Alkaloids, Lysergic Acid, And LSD
These compounds are very sensitive and even unstable. This means that
the following steps must be taken to keep from ruining your compound or
yield.
- Always use red or yellow photographic dark room light bulbs during any step of LSD manufacture. Direct sunlight, electric filament, or fluorescent light bulbs (etc.) will hurt the above compounds. Dark room bulbs are cheap and are a must.
- Keep all forms of H2O out of the reaction. Thoroughly dry all the glass ware to be used. Use a drying tube filled with anhydrous MgSO4 (calcium chloride reacts with amines in an unfavorable way and should not be used). I can't be there to hold your hand and guide you through every step, so unless the formula says to add water, the drying tube should be in use, and after the water addition is over, the drying tube goes back on. This way the reaction is always protected even if it does not need to be. Better safe than sorry. Also, if you're not sure if you should use dry reagents, use dry reagents anyway. Also dry the lysergic acid (as described above) and any other precursors in whatever drying process required for that compound before use. Dry the finished LSD or even any intermediate along the way after you have completed the product. Likewise, dry an intermediate that you may have purchased from a chemical supplier.
- Keep oxidizing agents from these items. Even the oxygen in the
air can oxidize some of these compounds. The formula states that during
some of the
reactions above, an inert gas (nitrogen) must be used for an atmosphere
inside the reaction vessel. Nitrogen can be obtained in small bottles
(tanks) at a
very reasonable fee, without any questions asked. Make sure you use a
regulator and introduce a slow stream into the vessel by way of a gas
inlet tube or
an equivalent. Always flush the vessel before putting any reagents into
it (flush the air out with nitrogen). I would use a nitrogen atmosphere
from the
very beginning of the formula to the very end, even if the formula did
not specify its use. Very few of the above formulas call for a nitrogen
atmosphere
during evaporation, but I feel this may be bad for yield and or potency.
LSD has many doses per gram, and if you lose 1/2 g because you were too
cheap to
use three dollars worth of nitrogen, you have lost about 2,000 doses at
$5 a dose = $10,000 of LSD wasted. Better safe than sorry? Also, any
precursors you
make or buy should be stored in a nitrogen atmosphere, as should LSD.
This can be done by poking a gas inlet tube into the vessel trust above
or a little
below the substance) flushing the air out with a moderate stream of
nitrogen then quickly reinstall the cap or stopper.
The best way to store LSD is by producing it in the maleate form. This not only makes it resistant to oxidation, but it purifies it, too. Use the procedure above (JOC, 24, 368, or CA, 57, 5979) when you get to the last dry-and-evaporate-in-vacuo step, then treat the residue as specified. - Never subject these compounds to excessive heat, or any type of temperature warmer than the inside of your refrigerator. Even LSD maleate will decompose in excess heat, so store in a refrigerator. Keep evaporation procedures cooled. This will slow the evaporation process down, but that is better than losing the product. Some of the above formulas require heat for a reaction. This is Ok, but do not exceed the temp stated at any time and never heat longer than needed. Also, nitrogen atmospheres are used during heating operation.
Substituents
LSD analogs (lysergic acid amides) can be prepared by substituting
amines in place of diethylamine. The potency usually drops anywhere from
33% to 75%
depending on the substituent. Diethylamine is highly suspicious, and the
substituent will produce a lysergamide that is most likely legal, as
legislation
has only singled out lysergic acid diethylamide. Little work has been
done on the potency of substituted Iysergamides, so a little
experimentation by you
may be in order. Personally, I would like to try substituting a potent
phenethylamine or phenylisopropylamine such as DOM (STP) or
4-bromo-2,5-dimethoxyamphetamine. If I could get a government grant, or
maybe a grant from a major pharmaceutical corporation, like Upjohn or
Lilly, then
I could play around with such experiments.
The following substituents give lysergamides with potencies as
indicated in doses per gram (remember that LSD gives about 6,000 to
9,000 doses):
| Ethylpropylamine | 2,000 to 5,000 |
| Morpholide | 600 to 2,000 |
| Methylpropylamine | 600 to 1,000 |
| Dipropylamine | 600 to 1,000 |
| Methylethylamine | 400 to 600 |
| Dimethylamine | 300 to 400 |
| Pyrrolidide | 300 to 400 |
As a point of reference, DOM (STP) is one of the most powerful
amphetamines, at 200 doses per gram. At $5 a line, its value is about 5
times 200 = $1,000
a gram. For more info see JMC, 16, 532 (1973).
Claviceps purpurea is not the only place to get d-lysergic amides.
The plant group of Convolvulacea has been found to posses lysergic acid
amides such
as ergine and several others. These Convolvulacea type of plants do not
cause the dreaded St. Anthony's fire, as does claviceps purpurea, and as
a matter
of fact, they are hallucinogenic if eaten in large doses. Care must be
taken that the seeds have not been treated with poison to discourage
usage as a mind
alterant, or treated with methyl mercury to prevent spoilage.
When these seeds are to be used for LSD syntheses, make sure to clean
off the white layer that surrounds them by singeing or mild burning.
Also, ask for
Hawaiian Rose Wood, as these are the only ones that contain an
appreciable amount of lysergic related compounds. These compounds must
be extracted as below,
hydrolyzed (like ergotamine) as above, and then used in any of the
formulas that require d-lysergic acid or possibly used directly in the
Hofmann hydrazine
method; CA, 57, 12568 (1962). These seeds have very little amide, so you
can plan on quite a lot of work in the extraction step. According to A.
Hoffer and
H. Osmond, the most amide plentiful species (Woodrose) has a minute 3 to
6 mg of amide per every gram of seed. This means that if you extract
very thoroughly,
you will require a little over 200 g of seeds to get 1 g of amide, which
will be reduced further after hydrolysis to give you about 0.5 g of
usable
d-lysergic acid. Extract as follows.
Pulverize the seeds in a clean blender until they are a fine powder.
Put this powder into a beaker, add 1 1iter of petroleum ether to every
900 to 1000g
of powdered seeds, stopper the beaker to prevent evaporation and let set
for 3 days. Filter off the petroleum ether and let evaporate to make
sure no amides
were extracted (there should not be much, if any) from the ether. Add 1
1iter of methanol (dry is best) and let soak for 4 days with vigorous
shaking, now
and then. Filter off the methanol and evaporate it under vacuo (vacuum
speeds the process). In the meantime, add 500 ml of fresh methanol to
the powder and
extract it again for 3 or 4 days.
Filter as before and extract again with about 300 ml of methanol. Combine the residues of all extractions and hydrolyze.
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