=============================================================================
                              LSD Synthesis Notes
=============================================================================
 
     This text was originally published in 1967 as The 
Psychedelic Guide to Preparation Eucharist by Robert E. Brown

               Synthes of LSD-25

Preparatory arrangements

     Starting material may be any lysergic acid derivative,from 
Claviceps purpures(ergot) on rye grain or from culture,from 
Ipomea (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 is dissolved in 200ml of mathanoic KOH solution and the 
methanol removed immediately in vacuum. The residue is treated 
with 200ml of an 8% aqueous solution of KOH and the mixture 
heated on a steam bath for one hour. A stream of N2 gas is 
passed through the flask during heating and the evolved NH3 in 
the gas stream may be titrated in HCL to follow the reaction. 
The alkaline solution is made neutral to congo red with tartaric 
acid,filtered,cleaned by extracting with ether, the aqueous 
solution filtered and evaporated. Digest with MeOH to remove 
some of the colored material from the crystals of lysergic acid.
     Arrange the lighting in the laboratory similarly to that of 
a darkroom. Use photographic red and yellow safety lights since 
lysergic acid derivatives are decomposed by light. A weak, long 
wave ultraviolet source is conveniently made from the purple 
glass filter used in the 1950 ford dash lighting system. A small 
tungsten bulb will provide enough light.
     Have plenty of aluminum foil handy to cover reagents and 
products when light is present. Rubber gloves must be worn due 
to the highly poisonous nature of ergot alkaloids. A hair dryer, 
or, much 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 degrees C. The mixture is 
refluxed (or heated) for 30 minutes. With an open condenser, 
keep an inert atmosphere on the reaction. Add 1.5 volumes H2O 
and boil 15 minutes. On cooling in the refrigerator, isolysergic 
acid hydrazide is crystallized.

Step II -Use Red Light
     Chill all reagents and have ice handy. Dissolve 2,82 g of 
the hydrazide rapidly in 100ml 0.1 N ice-cold HCL using an ice 
bath to keep the reaction vessel at o degrees. 100ml ice-cold 
0.1 N NaNO2 is added and after 2 to 3 minutes vigorous stirring, 
130ml more HCL is added dropwise with vigorous stirring again in 
an ice bath. After 5 minutes, neutralize 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 39ml 
ether extract. Allow to stand in dark, gradually warming up to 
20 degrees 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 125ml of 
actonitrile and the suspension cooled to about minus 20 degrees 
C in a bath of acetone cooled with dry ice. To the suspension is 
added a cold -20 degrees C solution of 8.82 g of trifluoroacetic 
anhydride in 75ml of acetonitrile. The mixture is allowed to 
stand at -20 degrees C for about 1 1/2 hours during which time 
the suspended material dissolves, and the d-lysergic acid is 
converted to the mixture anhydride of lysergic and 
trifluoroacetic acids. The mixed anhydride can be separated in 
the form of an oil by evaporating the solvent in vacuum at a 
temperature below about 0 degrees C.Everything must be kept 
anhydrous.

Step II - Use Red Light
     The solution of mixed anhydrides in acetonitrile from Step 
I  is added to 150ml 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 
vacuum, leaving a residue of LSD-25 plus other impurities. The 
residue is dissolved in 150ml of chloroform and 20ml 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 50ml portions 
of ice-water. The chloroform solution is then dried over 
anhydrous Na2SO4 and evaporated in vacuum.

PREPARATION # 3
     The following procedure gives good yield and is very fast 
with little iso-lysergic acid being produced, however, the 
stoichometry must be exact or yields will drop.

Step I - Use White Light
     Sulfur trioxide id produced in an anhydrous state by 
carefully decomposing anhydrous ferric sulfate at approximately 
480 degrees C. Store under anhydrous conditions.

Step II - Use White Light
     A carefully dried 22 liter RB flask fitted with an ice 
bath,condenser, dropping funnel and mechanical stirrer is 
charged with 10 to 11 liters of dimethyformamide (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 with stirring, during 4 to 5 hours. The temperature 
is kept at 0-5 degrees 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 colorless may change 
to yellow and red, its efficiency remains unimpaired for three 
to four months in cold storage. An aliguot 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 L 
of MeOH is prepared. The solution is distilled on the steam bath 
under reduced pressure. The residue of glass-like lithium 
lysergate is dissolved in 400ml of anhydrous dimethyl formamide. 
From this solution about 200ml of the dimethyl formamide id 
distilled off at 15mm pressure through a 12- inch helices packed 
column. The resulting anhydrous solution of lithium lysergate 
left behind is cooled to 0 degrees and, with stirring, treated 
rapidly with 500ml 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 400ml of water is added to 
decompose the reaction complex. After mixing thoroughly, 200ml 
of saturated aqueous saline solution is added. The amide product 
is isolated by repeated extraction with 500ml portions of 
ethylene dicloride. The combined extract is dried and then 
concentrated to a syrup under reduced pressure. Do not heat the 
syrup during concentration. The LSD may crystallize 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 Long Wave UV
     The material is dissolved in a three to one mixture of 
benzene in chloroform. Pack a chromatography column with a 
slurry of basic alumina in benzene so that a one-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 50ml of solvent and 1 g LSD. Run this solution 
through the column, following the fastest moving blue 
fluorescent band. After it has been collected, strip the 
remaining material from the column by washing with MeOH. Use the 
UV light sparingly during this procedure to prevent excessive 
damage to the compounds. Evaporate the second fraction in vacuum 
and set aside for Step II. The fraction containing the pure LSD 
is concentrated in vacuum and the syrup will crystallize slowly. 
This material may be converted to the tartaric acid and the LSD 
tartrate conveniently crystallized. MP 190-196 Degrees 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. Neutralize with dilute HCl, 
make slightly basic with NH4OH and extract with chloroform or 
ethylene dicloride as in preparations #1 or #2. Evaporate in 
vacuum and chromatograph as in the previous step.

Salvage
     Neutralize all leftover solutions and residues with NaHCO3 
and evaporate in vacuum to low volume. Extract with ammoniacal 
chloroform and evaporate the extract to dryness. This residue 
may be run through the whole process again and more LSD will be 
produced.

Storage and use
     Lysergic acid compounds (among them LSD) 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 refrigerator.
     Packaging for use presents many possibilities, partially 
due to the incredibly small dosage involved. First a bio-assay 
of the solvent is made, then it may be measured by the volume of 
the solvent it is in. The solvent may be evaporated onto a 
weighed, calculated amount of some inactive powder such as 
chalk. sugar or baking soda. This bulky powder may be easily 
encapsulated in weightable portions. It is advantageous to add a 
trace of dry ascorbic acid to the dried powders. Sugar cubes 
offer a handy but extremely notorious method of dispensing. 
Other methods are without number, here being offered just a few 
occasionally used by the criminal element. Gelatin capsules are 
coated with the liquid solution and the capsules filled with an 
inert substance. Decoys such as this inert mixture might include 
a trace of brown color, a trace of quinine for fluorescence, and 
a trace of some relatively non-toxic compound which nearly 
mimicas the infra-red spectrum of LSD. For transport, a smuggler 
might evaporate a considerable amount onto a pocket handkerchief 
or onto a sheet of paper, providing the solution was properly 
decolorized before such treatment. These underhanded methods are 
used by criminals to avoid punitive action by law enforcement 
enthusiasts.
     One gram of pure LSD, if used in a truly enlightened, 
careful manner can be the door to a magnificent experience to 
nearly 3,000 individuals. Used furtively and in ignorance, the 
same amount may bring terrible confusion and abject terror to 
nearly one-third of these.

                         BIBLIOGRAPHY

Chem. Abstracts 44, 10740
Chem. Abstracts 38, 1499 c
Chem. Abstracts 41, 2450 d
J O C 24, 368 & 370
J B C 104, 547
Patent application serial # 473, 443 by Eli Lilly Co. Dec. 6, 1954

=============================================================================


               Ergot Culture and Extraction
               of Lysergic Acid Derivatives

Claviceps purpures (Ergot) must first be isolated as a pure 
culture or obtained from a maintained collection of pure culture 
stocks.
The culture is revitalized and prepared for inoculating a large 
culture by growing as a small surface culture on the medium 
described below for two weeks at ph 4.

               Sucrose...........  100  g
               Chick pea meal....   50  g
               Ca (NO3)2.........  1.0  g   Make up to 1 liter
               KH2PO4............  0.25 g   and adjust to ph 4
               MgSO4.............  0.25 g   with citric acid and
               KCL............... 0.125 g   ammonia.Autoclave to
               FeSO4-7H2o........ 8.34 mg   sterilize.
               ZnSO4-7H2o........ 3.44 mg

     Great care must be taken not to eontaminate the 
culture,since Claviceps is a parasite and is taken over by any 
number of more vigorous strains of saprophytic fungi and 
bacteria.
     Inoculate a number of large surface ferments in gallon jugs 
containing the above media, using the smaller culture by 
homogenizing it and using portions of it under sterile 
conditions.
     Prior to inoculation, make an aerator by ramming a large 
glass tube full of cotton,fitting one hole stoppers to the 
ends,attaching glass tubing,and attaching a stopper to fit the 
jugs with a vent tube to be extended to a flask containing a 
dilute solution of hypochlorite. Put the stoppers,tubing and 
filter in a paper bag stapled shut, and autoclave it. After 
inoculation, carefully place the assembled aerator on the jug 
and force air through it into the solution.
     Maintain aeration at 25 degrees in the absence of bright 
lights. After ten days, adjust the culture to 1 % ethanol using 
95% ethanol (under sterile conditions), after which, growth is 
maintained under these conditions for 14 more days.
     The culture is made acidic with tartaric and is homogenized 
in a blender at maturity. After an hour, NH4OH is added to 
adjust the ph to 9.0 and the solution is extracted with benzene 
or chloroform isobutanol mixture. Extract with alcoholic 
tartaric acid and evaporate in a vacume to dryness. Recover the 
free base as needed by making the tartrate basic with ammonia to 
ph 9.0 and extracting with chloroform. Evaporate the chloroform 
in a vacume. Protect the base from light, heat, moisture and 
air.

Extraction: Cultured ergot,ergot sclerotia,Morning glory seeds

Equipment:  Blender
            Separatory funnel
            Chromatography column
            Flash evaporator ( or hair dryer)
            Long wave UV lamp

     Reduce the material to a fine powder in a blender. if moist 
or wet, dry first, preferably in a vacume. Pack the powder in a 
large chromatography column as a slurry with ligroine or lighter 
fluid. Soak overnight and drip (percolate) slowly until the 
solvent is grease free. This takes about 5 oz./oz. of seeds, but 
less on ergot. When the fats are thus removed, an ammoniacal 
chloroform solution is washed slowly through. Prepare this 
solution by shaking 100ml con  NH4OH in 900ml chloroform. The 
bottom chloroform layer is drawn off with the help of a 
separatory funnel. This chloroform wash should be dripped slowly 
through as soon as the ligroine fraction shows no grease film 
when evaporated in a watch glass. Collect and save the 
chloroform extract untilit doesn't fluoresce on evaporation of a 
drop on a watch glass. Evaporate this solution using a hair 
drier or even better, a flash evaporator. Wash the residue with 
a 3 % tartaric acid solution. Color the 3% tartaric solution 
with an acid-base indicator and estimate the number of moles of 
alkaloid present by titrating with this acid. Most of the 
residue should be dissolved or suspended. Transfer the solution 
to a separatory funnel,washing the evaporating vessel with extra 
acid. Make basic with NaHCO3 solution. Add equal volume of 
CHCL3. Shake thoroughly, let stand and remove the bottom layer. 
Extract again with chloroform. Reduce the combined chloroform 
extracts to a solid as before. Scrape the solid up with 
stainless steel spatula. This powder can be used directly to 
make the hydrazide. Ascorbic acid is usually used as a 
preserving agent.

                         BIBLIOGRAPHY

Chem. Abstracts 57,  13021
Chem. Abstracts 60,  11345

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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...

=============================================================================

From: chrle@mursuky.campus.mci.net

As a public service to alt.drugs I have posted the following with some
comments by myself. The following is a good example of the credo: A
handful of refs does not a chemist make. I found this on one of the
drug info sites (hyperreal, paranoia, sputnik.. not sure which one it
was). I've number the lines for commenting.

LSD Synthesis
-------------

1. Under reduced light (or red light) a stirred solution of 3.15g
   (11mmol)

2. of d-lysergic acid monohydrate and 4.45g (99 mmol) of diethylamine
   was

3. brought to reflux by heating.  Heat was removed, and reflux was
   maintained

4. by the addition of 2ml (3.4g, 22mmol) of phosphorous oxychloride
   (POCl3)

5. over a 2 minute period. The mixture was then refluxed for an
   additional

6. 4-5 mins until an amber-colored solution resulted.  The solution
   was

7. brought to room temperature and was washed with 200ml of 1M NH4OH.

8. The CHCl3 solution was dried (MgSO4), filtered, and concentrated
   under vacuum

9. (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.


Comments:
Line 1: suppose to be a refluxing slurry according to ref (Johnson,
Ary, Teiger, Kassel. "Emetic Activity of Reduced Lysergamides."Journal
of Medicinal Chemistry.  16(5):532-537.  1973.) Method B

Line 2: The 3.25g of d-lysergic acid monohydrate is suppose to be
dissolved in 150ml of CHCl3. 96mmol of diethylamine is supposed to be
used and 96mmol of this is ~7.1g, not 4.45g...(where's a good periodic
chart when you need one?). The 7.1g of diethylamine is supposed to be
dissolved in 25ml of CHCl3.

Line 3-4: To the 3.25g of d-lysergic acid monohydrate dissolved in
150ml of CHCl3 that is undergoing reflux is added the
diethylamine/CHCl3 solution and 2 ml of POCl3. These
are added simultaneously from separate dropping funnels over 2-3
minutes. Method B

Line 8: The CHCl3 is dried... What? Yes, it's dried but this is the
first time that the procedure that was given in this "how to" even
makes mention of it! Of course, all of this is made very clear in the
ref (Johnson, Ary, Teiger, Kassel.  "Emetic Activity of Reduced
Lysergamides."Journal of Medicinal Chemistry.  16(5):532-537.  1973.

It's pretty clear that this "how to" was posted by someone with little
or no chemical expertise who had a couple of refs in hand, ran to the
local college library, photocopied the papers, typed up this mess and
posted it for the benefit (ha!) of others. 

So, do you still want to attempt a synthesis of LSD? Yes? Well get the
refs and get the whole story. A few chemistry classes wouldn't hurt
either.

============================================================================= 

Making LSD In The Laboratory
----------------------------

        To make synthetic acid, you need a basic understanding of chemistry
and access to a lab. Since I don't quite understand all the chemical hocus-
pocus, I'm going to cop out and quote you the patent for it. If you don't
understand chemistry, just skip this recipe and go on to the next one for
acid, it's much simpler.

Preparation for Lysergic Acid Amides:

United States Patent 2,736,728
Patented February 28, 1956

Richard P. Pioch, Indianapolis, Indiana, assignor, 
to Eli Lilly and Co., Indianapolis, Indiana, a corporation of Indiana.
No drawing. Application December 6, 1954, Serial No. 473,443. 10 Claims.

        This invention relates to the preparation of lysergic acid amides and
to a novel intermediate compound useful in the preparation of said amides.
        Although only a few natural and synthetic amides of lysergic acid
are known, they possess a number of different and useful pharmacologic
properties. Especially useful is ergonovine, the N-(1(+)-1-hydroxyisopropyl)
amide of d-lysergic acid, which is employed commercially as an oxytocic agent.
        Attempts to prepare lysergic acid amides amides by the usual methods
of preparing amides, such as reacting an amine with lysergic acid chloride or
with ester of lysergic acid, have been unsuccessful. United States Patents No.
2,090,429 and No. 2,090,430, describe processes of preparing lysergic acid
amides and, although these processes are effective to accomplish the desired
conversion of lysergic acid to one of its amides, they are not without certain
disadvantages.
        By my invention I have provided a simple and convenient method of
preparing lysergic acid amides, which comprises reacting lysergic acid with
trifluoroacetic anhydride to produce a mixed anhydride of lysergic and
trifluoroacetic acids, and when reacting the mixed anhydride with a
nitrogenous base having at least one hydrogen linked to nitrogen. The
resulting amide of lysergic acid is isolated from the reaction mixture by
conventional means.
        The reaction of the lysergic and the trifluoroacetic anhydride is a
low temperature reaction, that is, it must be carried out at a temperature
below about 0 degrees C. The presently preferred temperature range is about
-15 C. to about -20 C. This range is sufficiently high to permit the reaction 
to proceed at a desirably fast rate, but yet provides an adequate safeguard
against a too rapid temperature and consequent excessive decomposition of the 
mixed anhydride.
        The reaction is carried out in a suitable dispersing agent, that is,
one which is inert with respect to the reactants. The lysergic acid is
relatively insoluble in dispersants suitable for carrying out the reaction, so
it is suspended in the dispersant.
        Two gallons of trifluoroacetic anhydride are required per mol. of
lysergic acid for the rapid and complete conversion of the lysergic acid into
the mixed anhydride. It appears that one molecule of the anhydride associates
with or favors an ionic adduct with one molecule of the lysergic which
contains a basic nitrogen atom and that it is the adduct which reacts with a
second molecule of trifluoroacetic anhydride to form the mixed anhydride along
with one molecule of trifluoroacetic acid. The conversion of the lysergic
acid to the mixed anhydride occurs within a relatively short time, but to
insure a complete conversion the reaction is allowed to proceed for about one
to three hours.
        The mixed anhydride of lysergic and trifluoroacetic acids is
relatively unstable, especially at room temperature and above, and must be
stored at a low temperature. This temperature instability of the mixed
anhydride makes it desirable that it be converted into a lysergic acid amide
without unnecessary delay. The mixed anhydride itself, since it contains a
lysergic acid group, also can exist in the reaction mixture in large part as

an ionic adduct with trifluoroacetic anhydride or trifluoroacetic acid. It is
important for maximum yield of product that the lysergic acid employed in the
reaction be dry. It is most convenient to dry the acid by heating it at about
105-110 degrees C. in a vacuum of about 1 mm. of mercury or less for a few
hours, although any other customary means of drying can be used.
        The conversion of the mixed anhydride into an amide by reacting the
anhydride with the nitrogenous base, such as an amino compound, can be
carried out at room temperature or below. Most conveniently the reaction is
carried out by adding the cold solution of the mixed anhydride to the amino
compound or a solution thereof which is at about room temperature. Because of
the acidic components present in the reaction mixture of the mixed anhydride,
about five mols or equivalents of the amino compound are required per mole or
equivalent of mixed anhydride for maximal conversion of the mixed anhydride to
the amide. Preferably a slight excess over the five mols is employed to insure
complete utilization of the mixed anhydride. If desired, a basic substance
capable of neutralizing the acid components present in the reaction mixture,
but incapable of interfering with the reaction, can be utilized. A strongly
basic tertiary amine is an example of such a substance. In such case, about
one equivalent of amino compound to be converted to a lysergic acid amide, as
well as any unconverted lysergic acid, can be removed from the reaction
mixture and can be re-employed in other conversions.
        A preferred method for carrying out the process of this invention is
as follows:
        Dry lysergic acid is suspended in a suitable vehicle as acetonitrile,
and the suspension is cooled to about -15 C. or -20 C. To the suspension is
then added slowly a solution of about two equivalents of trifluoroacetic 
anhydride dissolved in acetonitrile and previously cooled to about -20 degrees
C. The mixture is maintained in a low temperature for about one to three
hours to insure the completion of the formation of the mixed anhydride of
lysergic and trifluoroacetic acids.
        The solution of the mixed anhydride is then added to about five
equivalents of the amino compound which is to be reacted with the mixed 
anhydride. The amino compound need not be previously dissolved in a solvent,
although it is usually convenient to  use a solvent. The reaction is carried
out with the amino compound or solution of amino compound at about room
temperature or below. The reaction mixture is allowed to stand at room
temperature for one or two hours, preferably in the dark, and the solvent is
then removed by evaporation in vacuo at a temperature which desirably is not
greatly in excess of room temperature. The viscous residue, consisting of the
amide together with excess amine and amine salts, is taken up in a mixture of
chloroform and water. The water is separated and the chloroform solution which
contains the amide is washed several times with water to remove excesss amine
and the various amine salts formed in the reaction, including that of any 
unconverted lysergic acid. The chloroform solution is then dried and
evaporated, leaving a residue of lysergic acid amide. The amide so obtained 
can be purified by any conventional procedure.
        Dispersants suitable for the purpose of this invention are those which
are liquids at the low temperatures employed for the reaction and are of such
an inert nature that they will not react preferentially to the lysergic acid
with trifluoroacetic anhydride. Among suitable dispersants are acetonitrile,
dimethylformamide, propionitrile, and the like. Additional suitable agents 
will readily be apparent from the foregoing enumeration. Of those listed 
above, acetonitrile is preferred since it is non-reactive and mobile at the
temperature used, and is relatively volatile and hence readily separable from
the reaction mixture by evaporation in vacuo.
        A wide variety of nitrogenous bases such as amino compounds can be
reacted with the mixed anhydride to form a lysergic acid amide. As previously
stated, the amino compound must contain a hydrogen atom attached to nitrogen
to permit amide formation. Illustrative amino compounds which can be reacted
are ammonia, hydrazine, primary amines such as glycine, ethanolamine,
diglycylglycine, norephedrine, aminopropanol, butanolamine, diethylamine,
ephedrine, and the like.
        When an alkanolamine such as ethanolamine or aminopropanol is reacted 
with the mixed anhydride of lysergic and trifluoroacetic acids, the reaction
product contains not only the desired hydroxy amide but also, to a minor
extent, some amino ester. These two isometric substances arise because of the
bi-functional nature of the reacting alkanolamine. Ordinarily the amino ester
amounts to no more than 25-30 percent of the total amount of reaction product,
but in cases where the amino group is esterically hindered, the proportion of
amino ester will be increased. The amino ester can readily be converted to the
desired hydroxy amide, and the over-all yield of the latter increased by 
treating the amino ester, or the mixture of amide and ester with alcoholic
alkali to cause the rearrangement of the amino ester to the desired hydroxy
amide. Most conveniently the conversion is carried out by dissolving the amino
ester or mixture containing the amino ester in a minimum amount of alcohol and
adding to the mixture a twofold amound of 4 N alcoholic potassium hydroxide
solution. The mixture is allowed to stand at room temperature for several
hours, the alkali is neutralized with acid, and the lysergic acid amide is
then isolated and purified.
        It should be understood that, as used herein, the term "lysergic acid"
is used generically  as inclusive of any or all of the four possible
stereoisomers having the basic lysergic acid structure. Isomers of the
lysergic acid series can be separated or interconverted by means known to the
art.
        This invention is further illustrated in the following specific
examples.

[Example One]
        Preparation of the mixed anhydride of lysergic and trifluoroacetic
acids:
        5.36 g. of d-lysergic acid are suspended in 125 ml. of acetonitrile
and the suspension is cooled to about -20 degrees C. To this suspension  is 
added a cold (-20 degrees C.) solution of 8.82 g. of trifluoroacetic anhydride
in 75 ml. of acetonitrile. The mixture is allowed to stand at -20 degrees C.
for about 1 1/2 hours during which time 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 about 0 degrees
centigrade.

[Example Two]
        Preparation of d-lysergic and N,N-diethyl amide:
        A solution of the mixed anhydride of lysergic acid and trifluoroacetic
acid in 200 ml. of acetonitrile is obtained by reacting 5.36 g. d-lysergic
acid and 8.82 g. trifluoroacetic anhydride in accordance with the procedure of
example one. The acetonitrile solution containing mixed anhydride is added to
150 ml. of acetonitrile containing 7.6 g. of diethylamine. The mixture is held
in the dark at room temperature for about two hours. The acetonitrile is
evaporated in vacuo leaving a residue which comprises the "normal" and "iso"
forms of d-lysergic acid N,N-diethyl amide together with some lysergic acid,
the diethylamine salt of trifluoroacetic acid and like by-products. The
residue is dissolved in a mixture of 150 ml. of chloroform and 20 ml. of
ice water. The chloroform layer is separated, and the aqueous layer is
extracted with four 50 ml. portions of chloroform. The chloroform extracts
are combined and are washed four times with about 50 ml. portions of 
cold water in order to remove residual amounts of amine salts. The chloroform 
layer is then dried over anhydrous sodium sulfate, and the chloroform is  
evaporated in vacuo. A solid residue of 3.45 gm. comprising the "normal" and
"iso" forms of d-lysergic acid N,N-diethylamide is obtained. This material
is dissolved in 160 ml. of a 3-to-1 mixture of benzene and chloroform, and
is chromatographed over 240 g. of basic alumia. As the chromatogram is
developed with the same solvent, two blue fluroescing zones appear on the
alumina column. The more rapidly moving zone is d-lysergic acid
N,N-diethylamide which is eluted with about 3000 ml. of the same solvent as
above, the course of the elution being followed by watching the downward
movement of the more rapidly moving blue fluorescing zone. The eluate is
treated with tartaric acid to form the acid tartrate of d-lysergic acid
N,N-diethyl amide which is isolated. The acid tartrate of d-lysergic acid
N,N-diethyl amide melts with decomposition at about 190-196 degrees
centigrade.
        The di-iso-lysergic acid N,N-diethyl amide which remains absorbed on
the alumia column as the second fluroescent zone is removed from the column
by elution with chloroform. The "iso" form of the amide is recovered by
evaporating the chloroform eluate to dryness in vacuo.

[Example Three]
        Preparation of d-lysergic acid N-diethylaminoethyl amide:
        A solution of the mixed anhydride of lysergic acid and
trifluoroacetic acid is prepared from 2.68 g. of d-lysergic acid and 4.4 g. of
trifluoroacetic acid anhydride in 100 ml. of acetonitrile by the method of
Example One. This solution is added to 6:03 g. of diethylaminoethylamine.
The reaction mixture is kept in the dark at room temperature for 1 1/2 hours.
The acetonitrile is evaporated, and the residue treated with chloroform and
water as described in Example Two. The residue treated comprising d-iso-
lysergic acid N-diethylaminoethyl amide is dissolved in several ml. of ethyl
acetate, and the solution is cooled to about 0 degrees centigrade, whereupon 
di-iso-lysergic acid N-diethylaminoethyl amide separates in crystalline form. 
The crystalline material is filtered off, and the filtrate reduced in volume
to obtain an additional amount of crystalline amide. Recrystallization from
ethyl acetate of the combined fractions of crystalline material yields
d-iso-lysergic acid N-diethylaminoethyl amide melting at about 157-158 degrees
centigrade. The optical rotation is as follows:
        26
   [x] d  = + 372 degrees (c. = 1.3 in pyridine)


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From: aankrom@blackfoot.ucs.indiana.edu (aankrom)
Subject: Re: How to Make LSD File 2
Date: Mon, 4 Apr 1994 18:56:10 GMT

When I saw the subjects relating to the synthesis of LSD, I knew the
information would be outdated. It's humourous to see people who think 
they're in the know giving out information that was outdated even in the 70's.
Lysergic acid amides are commonly made by a simple and efficient procedure
using POCl3 and the desired amine in CHCl3 solution. I doubt that this
procedure is used by the majority of clandestine chemists, but since I 
don't know any, I wouldn't know. By the description of the procedure,
it's simple and uses relatively safe reagents. (I have a reference, but
not handy...) And you won't find it in any obvious places even in the 
most recent Merck because LSD is not the product of focus in the article.
This is why I doubt that unsavvy clandestine chemists would be using this
procedure. But according to the article, the method has a broad scope
and has been used by Nichols and Oberlender for some other lysergic acid
amides. (The article in question regards 9,10 saturated derivatives 
tested for emetic properties.) It's time to stop turning to those stupid
"how to make your very own drug" guides and learn how to read real chemsitry
literature. If you can't, don't bother... 
 Even the synthesis of lysergic acid is outdated. Rebek has described 
an extremely elegant synthesis of methyl lysergate from L-tryptophan 
which gives only the natural isomer of lysergic acid. It's still a 
several step procedure, but most of the reagents are fairly common and the
yields are greatly improved over past syntheses.
 This brings me to an interesting side-note. Several years ago, analogues
of LSD that were 2 and 3 times as potent as LSD were synthesized. These
went largely unnoticed and would most likely prove of little interest 
to clandestine chemists because LSD was the precursor used and the loss
in synthesis outweighed the gain in potency. But using Rebek's synthesis,
one could simply alter the procedure slightly and intorduce the groups
that make the compounds more potent. When the 6N-methyl group is replaced
by ethyl or allyl, it becomes 2 and 3 times as potent respectively.
I am posting this for general information. I may post references if I
decide it would be prudent. Requests will be ignored and I ask you not to
send e-mail requesting references. But if you just want to chat about them
and maybe speculate on subjective effects or other avenues of substitution...
I don't know if I'll ever see the day that research in this area is open 
and legal, but I'd love to...

Anthony

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From: aankrom@blackfoot.ucs.indiana.edu (aankrom)
Subject: References as promised...
Date: Thu, 7 Apr 1994 14:41:27 GMT

 OK. The references that I mentioned, here they come...

"Synthesis of Ergot Alkaloids from Tryptophan"
  J Rebek Jr., et al, JACS 106, 1813 (1984)

"A New Synthesis of Lysergic Acid"
  eidem., Tet Lett 859 (1983)
(and refs. therein.)

"Emetic Activity of Reduced Lysergamides"
  FN Johnson et al, JMC 16, 532 (1973)
 (Lysergamides using s-amine and POCl3)

I still feel like making a disclaimer that I am not encouraging this 
information to be used to synthesize illegal compounds, but for 
personal enlightenment. It's time to pull chem-wannabe's out of the
Dark Ages! 

Anthony

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