Drugs
Drugs
Drugs
arteries, partial paralysis, etc. The death rate among intravenous addicts
is extremely high (a recent English study found the rate for smack heads
thirty times higher than for a control group) and the best that can be said
for these drugs is that they are a rather expensive and unreliable way of
committing suicide.
Medical Use of Psychedelics
It is often said that psychedelics have no recognized medical use.
Anyone who examines the technical literature with even a modicum of
critical competence realizes that this is true simply because there has
been virtually no adequate research. Psychedelics clearly have tremendous
potential in medicine (e.g., psychotherapy, antidepressants, appetite
stimulators, analgesics, aphrodisiacs, etc.) as well as in biology and
psychology. Psychotherapy is the most obvious area of application, and
though many studies have been done, very few deserved publication. Careful
selection of subjects, adequate controls, and careful followups are
uncommon, and the techniques used usually border on the idiotic. For
example, the use of LSD in the treatment of alcoholism: Four different
studies reported in 1969 found, in contrast to other work, that LSD was of
no use in the treatment of alcoholism. These four studies shared the
following characteristics: 1) there was little or no preparation for the
drug experience, and a large dose was given the first time; 2) the drug was
given in a hospital setting; 3) the patient had to trip alone, and had no
one present whom he loved or trusted; 4) there was little or no effort to
use psychotherapy before, during, or after the drug experience; 5) perhaps
the most important, the LSD was given only once. Since all five of these
conditions are contrary to what experience has shown to be the most
effective ways of using psychedelics, the negative results of the studies
are hardly surprising. To varying degrees, such inadequacies are present in
most medical research with psychedelics, and progress in this area can be
expected to be very slow, especially in view of the legal hindrances due to
neanderthaloid legislators.
For a recent discussion of the potential value of LSD psychotherapy
and the relative lack of adverse side effects, see Psych. Bulletin
79,341(1973). Above all, see Stanislav Grof's definitive study REALMS OF
THE HUMAN UNCONSCIOUS (1976).
Synthetic Us. Organic
Many people believe that organic or natural psychedelics such as
peyote, magic mushrooms and marijuana are safer or produce better trips
than synthetic compounds. This is almost certainly false, since any plant
material contains hundreds of compounds, many of which have a definite
toxicity, but few of which have psychedelic properties (they tend to make
you sick, not stoned). The various impurities or the additives (e.g.,
amphetamine, belladonna, strychnine) sometimes found in synthetic
preparations are probably no more toxic than many of the compounds found in
the psychedelic plants, and like these compounds, such additives or
impurities probably have relatively little effect on the trip.
There is a great deal of superstition regarding purification of
psychedelics. Actually, any impurities which may be present as a result of
synthetic procedures will almost certainly be without any effect on the
trip. If there are 200 micrograms of LSD in a tablet, there could only be
200 micrograms of impurities present even if the LSD was originally only
50% pure (assuming nothing else has been added), and few compounds will
produce a significant effect until a hundred to a thousand times this
amount has been ingested. Even mescaline, which has a rather specific
psychedelic effect, requires about a thousand times this amount. It is
possible that iso-LSD may block LSD effects somewhat and inhibit the cosmic
trips that can result from high doses; this is however unproven.
Nevertheless, the prime reasons for a lack of cosmicity are undoubtedly low
doses and the development of tolerance. A single exposure to LSD or other
psychedelics may produce an adaptation or tolerance that lasts the rest of
your life (seeing the ocean for the first time is not a repeatable
experience). Furthermore, as seems to be the case with the active chemical
(THC) and its inhibitor (CBD) in marijuana,the presence of the inhibitor
may sometimes result in a more pleasant experience. Only careful studies in
which varying amounts of iso-LSD are added to LSD will decide the issue.
Trip Differences
If a psychedelic is taken several days in succession, some degree
of tolerance (failure to produce a trip) develops. If a different
psychedelic is then taken and this also fails to produce a trip, the two
compounds are said to produce cross tolerance, which strongly indicates
that they act in the same way and create roughly the same kind of trip.
LSD, mescaline, and psilocybin (and probably the hallucinogenic
amphetamines) all produce cross tolerance, and there are some studies which
indicate that people are unable to tell them apart. In comparing trips, it
should be kept in mind that mescaline has seldom and psilocybin very rarely
been available on the black market. Virtually all "psilocybin," as well as
most of the "mescaline" has been LSD or one of the hallucinogenic
amphetamines (when they haven't been atropine, PCP, speed, etc.)
PharmChem Dept. AA, 3925 Bohannon Drive, Menlo Park, CA 94025, will
qualitatively analyze any sample mailed in for $10 and will give results by
phone (415-328-6200) five days after the sample is received. Anonymity can
be achieved by assigning an arbitrary 6 digit number to your sample and
giving only this number when you call. They would like to know what you
think your sample is, its street price and general area of origin.
Envelopes with significant size specimens should be marked "Hand Cancel".
The feds won't let anyone give out quantitative results anymore. PharmChem
desires that letters be marked "Hand Cancel" and that you allow 5 days
after receipt for results. Their rates are now $10 for a qualitative and $15
for a quantitative analysis (for the latter, you must first get from them a
controlled drug transfer form to send with the sample and the $15).
Perhaps the only reliable way to identify a psilocybin trip is by
its short duration; most trips are completely over in six hours or less.
THC, DMT, glycolate esters and very likely muscimole probably do not
produce cross tolerance with each other or with the
LSD-mescaline-psilocybin group, as would be expected from the distinct
kinds of trips produced by each of the former compounds. Other than the
synthesis of new compounds, the most fertile source of new trips lies in
the combination of varying amounts of known psychedelics.
Although tranquilizers tend to inhibit the effects of psychedelics
if taken shortly before or during a trip, pretreatment (several hours to
several days) with a tranquilizer will often enhance the effects. This
enhancement is highly variable depending on the type and amount of
tranquilizer and psychedelic, time between ingestion, etc. Prior
administration of some tranquilizers is also useful in combatting the
nausea which, though transient, is a common unpleasant side effect of most
psychedelics. Certain phenothiazines (Stelazine, Compazine, Prolixin,
Vesprin, Trilafon) are most effective as antiemetics. Immediate relief of
nausea may be obtained from various nonprescription products, of which
Emertrol is perhaps the best.
With most psychedelics, their activity can probably be considerably
enhanced by prior (or possibly concomitant) use of a monoamine oxidase
inhibitor (e.g., isocarboxazid (Marplan), nialamide (Niamid), phenelzine
(Nardil), and tranylcypromine (Parnate)). Some compounds (e.g., DMT) which
have no oral activity, can probably become orally active. These compounds
The males are generally taller and thinner until almost mature (3 - 4
months), when the females may become taller. Males tend to yellow and die
some weeks before the females. Harvest takes place around September in
Europe and Japan and around July in North Africa. The sex of the plants can
be influenced by soil conditions, some experiments giving more males in
moist, heavily manured soils. Long light periods tend to masculinize,
whereas plants grown under short day conditions (for example, those seeded
in northern latitudes in winter) tend to produce intersexual flowers, males
changing to females; a condition also resulting from debudding males. It
has recently been found that male flowers tend to change to females after
early spraying with Ethrel (2-chloro-ethane-phosphonic acid). Under some
conditions, flowering may occur in as little as two weeks. A sizable
portion of the leaves can be harvested after about two months and the
plants will continue to grow. The effects of these various manipulations on
the THC yield of a single plant, or the crop as a whole, have yet to be
determined. "The Induction of Flowering," L. Evans (ed.), 205(1969) is a
good reference on Cannabis flowering.
Pinching off the shoot tip when the plants are just beyond the
seedling stage, and pinching off subsequently developing side shoots at
about weekly intervals thereafter in order to keep the plant only a few
feet tall, can produce plants so altered in shape, color and leaf
morphology as to be unrecognizable as cannabis. The resins are said to
accumulate on the surface of such distorted plants to such an extent that
it looks crystalline, and the resulting grass is supposed to be as strong
as hashish.
For definitive references on the cultivation and chemistry of
marijuana, see MARIJUANA GROWERS GUIDE, And/Or Press (1978) and MARIJUANA
POTENCY, And/Or Press (1977).
THC Extraction
Some samples of grass have considerable THC acid. In order to
extract this it is first necessary to decarboxylate it by heating it to
110 for fifteen minutes. Grass grown commercially for its fiber content,
as well as that grown in northern Europe or much of the U.S.A., contains
mostly the inactive cannabidiol and cannabidiolic acid. These compounds can
be extracted and used to synthesize the active THC and THC acid (by
smoking, not active orally) in one step. See TET 21,1228(1965) or the
following. To extract, add 50g grass/liter petroleum ether or benzene; soak
twelve hours with occasional shaking; filter and extract petroleum ether
three times with a solution containing 5% NaOH and 5% Na2SO3. Acidify the
aqueous extracts with cold dilute sulfuric acid and extract with ether or
chloroform which is dried, evaporated in a vacuum to yield the
cannabidiolic acid. THC and cannabidiol remain in the petroleum ether which
can be dried and evaporated in a vacuum and the residue added to grass. THC
acid is converted to THC by boiling in benzene for seven hours.
THC Extraction for Smuggling or Converting Poor Grass to Good
This is recommended to anyone who wants to smuggle or otherwise
conceal grass or hash. One hundred kilos of grass will convert to about two
or three kilos of resin, which can later be redissolved and absorbed on
alfalfa, etc. See Lloydia 33,453(1970) for a method of large scale
extraction.
Cover grass or hash with methanol, benzene, petroleum ether, or
isopropyl (rubbing) alcohol. Allow to soak for about twelve hours, filter
and repeat soaking with fresh solvent. This process can be speeded up by
gently heating the solvent plus grass (no flames) for about three hours,
adding more solvent if necessary. Evaporate the combined solvent extracts
until a resin is obtained or until syrupy and absorb the syrup on grass,
etc. Repeat the process until no more resin is obtained, or until smoking
some of the residual grass indicates that all the THC has been extracted.
Methylene chloride works very well. Unleaded gas, preferably without
additives (white gas), paint thinner or remover, or turpentine should be
satisfactory. For a detailed discussion, see MARIJUANA POTENCY, And/Or
Press (1977).
Dosage
Smoking seems to destroy most of the THC, but even so, this is
several times more efficient than eating it, since the smoking dose of
delta-1 THC is about 2mg and the eating dose about 10mg. Based on a 5% THC
content, 1g of hash efficiently used should (by smoking) stone about 25
people.
Partial tolerance to THC develops rapidly and most users observe
that they get much higher the first time a given batch of grass is smoked
than on subsequent occasions. However, for unknown reasons, tolerance to
grass of different origin seems less, leading some people to desire a
different batch for each day of the week.
Official THC Tests
One-tenth gram powdered grass, 5ml petroleum ether; grind in mortar
and let soak fifteen minutes. Filter and add 1ml of the petroleum ether
carefully to 2 ml 15% HCl in absolute ethanol. Red color at boundary of two
layers indicates THC. After shaking, the upper layer is colorless and the
lower orange-pink which turns colorless after addition of 1 ml of water.
Alternatively, evaporate the petroleum ether, add 2 ml Duquenois reagent (
12 drops acetaldehyde, 1 g vanillin, 50 ml ethanol), 2 ml HCl and stir. Let
stand 10 minutes and add 2 ml chloroform; shake and let separate. A purple
chloroform layer indicates THC.
Also useful but less specific is the fact that THC gives a purple
color with 5% KOH in ethanol. A few grains of sucrose will often intensify
color development in these tests. (See Bulletin on Narcotics 22,33(1970)).
THC Chemistry
[ Pictures of "some widely tested synthetic cannabinoids", not available in
this ASCII version :) ]
Is It Legal?
The delta-1 and delta-1(6) THC's with the n-pentyl in the 5'
position (obtained by using olivetol in the syntheses) are naturally
occurring and hence illegal, but the delta-3 THC's and the numerous
isomers, homologs and analogs of the delta-1 and delta-1(6) compounds are
probably legal.
Apparently, recent federal legislation outlaws delta-1, delta-1(6),
delta-3,4-THC's, both cis and trans and D and L and compounds. This still
leaves hundreds of legal cannabinoids.
Structure-Activity Relationships
THC refers to tetrahydrocannabinol, and delta refers to the position
of the double bond. Various numbering systems are used, so the following
equivalences should be noted: delta-1-THC = delta-1-3,4-trans-THC =
delta-9-THC and delta-6-THC = delta-1(6)-THC = delta-8-THC = delta-6-3,4trans-THC.
Little careful human testing has been done, so data given here and
elsewhere on the relative psychedelic activity of various cannabinoids is
often only a rough guess. Delta-1-THC and delta-6-THC have about the same
activity which is about five times that of delta-3-THC. Cannabidiol,
cannabidiolic acid, cannabinol, cannabigerol and cannabichromene all have
very little or no activity. Only the L (-) isomer of THC seems to be
active. When the n-pentyl at the 5' position is replaced by
1,2-dimethylheptyl, potency and duration of action increases about five
times, giving the most active THC analog yet tested.
It should be noted that recent testing has indicated that a
1,1-dimethylheptyl or 1-methyloctyl and probably similar side chains give
THC's of equal or greater activity than the 1,2-dimethylheptyl cpd.
However, the difficulty of synthesizing these compounds plus their very
long action (up to several days or more) makes it doubtful whether they
deserve all the interest they have generated among psychedelic enthusiasts.
More concern should be devoted to the shorter side chains, since they would
presumably allow one to get very stoned but to be straight again within a
few hours, thus allowing the drug to be more easily manipulated.
Substituting N, O, or S atoms at various places or saturating the
double bond to produce hexahydrocannabinol probably retains activity. (See
CA 74,125667(1971) for S analogs.) Alkoxy side chains at 5' retain
activity. Unsaturated side chains are as active as saturated ones. Ether
moieties at the 5' position, but not at the 3', retain activity. Activity
is retained if an additional alkyl is placed at 4' but lost if placed at
6'. Activity is greatly decreased or lost if the H at the 4' or 6'
positions is replaced by carboxyl, carbomethoxyl, acetyl or acetoxyl; if
the hydroxyl is replaced by H; if the OH is at 5' and the side chain at 4'.
Methyl and/or ethyl at 1 and 5 retains activity, as does removal of the
methyl at 1. An hydroxyl in the side chain is active, but not on the first
carbon of the side chain. Esterifying the OH retains activity, but
etherifying eliminates activity.
THC can be synthesized via cannabigerol and cannabichromene in low
yield (TET 24,4830(1968), TL 5349,5353(1969), Proc. Chem. Soc. 82,(1964)).
For several moderately difficult routes leading to delta-1(6)-THC via
cannabinol in about 10% yield, see LAC 685,126( 1965). For a synthesis of
delta-1(6)-THC from cinnamyl derivatives and isoprene see JACS
89,4551(1967). A rather difficult synthesis of delta-1 and delta-1(6)-THC
is given in JACS 89,5934(1967). For a variety of THC analogs of unknown
activity see BSC 1374, 1384(1968); JCS 952(1949); JACS 63,1971,
1977,2766(1941), 64,694,2031,2653(1942), 67,1534(1945), 70,662( 1948),
71,1624(1949), 82,5198( 1960); CA 75,48910 (1971); TL 3405(1967); JMC
11,377(1968); CT 2,167(1967); CA 76,126783(1972).
Since 0 or 1 and perhaps 2 double bonds anywhere in the lefthand
ring below, as well as changes in the size and position of the alkyl groups
will probably all produce compounds with THC activity, many compounds
similar to menthadieneol, menthatriene, verbenol, epoxycarene, pulegone and
4-carbethoxy-1-Me-3-cyclohexanone can be used in the methods below to get
active THC analogs (e.g., isopipertinol will work (TL 945 (1972))). Also,
5-chlororesorcinol and 5-methylresorcinol (orcinol) have been shown to give
weakly active THC's (see CA 76,33946(1972), US Patent 3,028,410 (1962), and
TET 23,3435(1967) for syntheses of orcinol and related compounds).
Unfortunately, recent data indicate that orcinol gives a THC with very low
activity. It appears that delta-5 and delta-7 THC have very little
activity. If the methyl groups at carbon 8 in THC are changed to longer
alkyl groups, the activity decreases, but the replacement of the alkyl
groups by hydrogen or other groups has not been carried out. Open chain
analogs also have activity (see CT 2,167( 1967)).
For new information on the structure-activity relationships of
cannabinoids see JMC 16, I 200( 1973), Arzneim, Forsch 22,1995 (1972), and
Chem. Revs. 76,75(1976).
For THC analogs see JMC 19,445-71,549-53(1976); Eur. JMC
10,79(1975); Phytochem.14,213(1975); CA 82,57564,170672-3(1975); Diss.
temperature and the use of cis rather than trans verbenol (the latter
gradually decomposes at room temperature). The reaction is also carried out
under nitrogen, using twice as much verbenol as olivetol, 0.85 ml BF3
etherate and 85 ml methylene chloride/g verbenol (both freshly distilled
over calcium hydride) to give ca. 50% yield. See also JACS 94,6159(1972)
for the use of citral and Arzneim. Forsch. 22,1995(1972) for use of p-TSA.
In the synthesis of THC with verbenol, the cis isomer is preferable
to the trans since the latter decomposes at room temperature. Pinene or
cawone give active THC's (JMC 17,287(74)).
Method 3
L(-)-delta-1 and delta-1(6) THC JACS 92,6061(1970), U.S. Patent
3,734,930.
1M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog,
0.05 M p-toluenesulfonic acid in 10L benzene; reflux two hours and
evaporate in vacuum (or can separate the unreacted olivetol as above) to
get about 30% yield THC. Olivetol can also be separated as described below.
For synthesis of 2-epoxycarene (delta-4 carene oxide) from delta-4 carene
(preparation given later) see p-methadieneol preparation (Method 2).
3-carene oxide gives 20% yield of delta-1(6) THC.
Methods for Racemic THC
Delta-3 THC JACS 63,2211 (1941)
1M pulegone, 1M olivetol or analog, 0.3 M POCl3, reflux four hours
in 1 L benzene and evaporate in vacuum or pour into excess saturated NaHCO3
and extract with dilute NaOH to recover unreacted olivetol. Dry, and
evaporate in vacuum the benzene layer to get the THC.
Delta-1(6) THC from Cannabidiol HCA 52,1123(1969)
Reflux 1g cannabidiol, 60 mg p-toluenesulfonic acid (or 0.003 M
trifluoroacetic acid) in 50 ml benzene for 1 1/2 hours. Evaporate in vacuum
to get about 0.7 g THC. Alternatively, add 1.8g cannabidiol to 100 ml
0.005N HCl and reflux four hours. Proceed as above to get about 0.5 g THC
(cf. JACS 94,6159 (1972)).
Nitrogen Analogs of Delta-3 THC
CA 72,66922(1970); JACS 88,3664(1966), TL 545(1972).
5.4 g olivetol or 0.03M analog, 5.8 g 4-carbethoxy-N-benzyl-3piperidone hydrochloride or 0.03M analog (JACS 71,896(1949) and
55,1239(1933) give an old and clumsy synthesis, and Heterocyclic Compounds,
Klingenberg (Ed.), part 3, chaps. IX-XII (1962) gives information on
related compounds) in 10 ml concentrated sulfuric acid. The concentrated
sulfuric acid should be added dropwise, with cooling (cf. U.S. Patent
3,429,889). Add 3 ml POCl3 and stir at room temperature for 24 hours.
Neutralize with NaHCO3 to precipitate 2.3g (I). Filter; wash precipitate
with NaHCO3 and recrystallize from acetonitrile. Dissolve 4.3 g (I) in 30
ml anisole and add 0.1 M methyl MgI in 50 ml anisole. Stir 12 hours and
evaporate in vacuum or acidify with sulfuric acid, neutralize with NaHCO3
and filter; wash to get 2.4 g N-benzyl analog of THC. For other N-analogs
of unknown activity see JOC 33,2995(1968). Recover unreacted olivetol as
usual.
The 5-aza analogs given in the JOC ref. seem to be active but they
use the pyrone intermediate from certain routes of THC synthesis for a
precursor. See U.S. Patent 3,493,579 (03 Feb 1970) for quinuclidine analogs
and JOC 38,440(1973) for a different approach to N-analogs. See JOC
39,1546(1974) and HCA 56,519(1973) for other N-analogs.
Delta-1(6) THC U.S. Patent 3,576,887
This synthetic route allows one to proceed from the alkylresorcinol
dimethyl ether without using a compound of the verbenol or cyclohexanone
type.
Synthesis of olivetol aldehyde (Aust. J. Chem. 21,2979 (1968)). To
a stirred solution of phenyllithium (1.6g bromobenzene and 0.16g Li) in 50
ml ether, add 0.01M olivetol dimethyl ether (or analog -- see elsewhere
here for preparation) in 5 ml ether and reflux 4 hours. Add 5 ml
N-methylformanilide, reflux 1 hour and wash with 2x50 ml dilute sulfuric
acid, 50 ml water, 25 ml saturated NaCl and dry, evaporate in vacuum the
ether (can dissolve in benzene and filter through 100g of alumina) to get
60% yield of the dimethylolivetol aldehyde (I) (recrystallize from
ether-pentane). Can recover unreacted starting material by refluxing the
vacuum distillate 3 hours with excess 10% HCl, removing the organic layer
and extracting the aqueous layer with ether: wash and dry, evaporate in
vacuum the combined ether layers.
An alternative method for (I) (JACS 65,361(1943)). In a 200 ml 3
neck round bottom flask with a stirrer, a reflux condenser, a dropping
funnel and a nitrogen inlet tube, introduce a rapid stream of nitrogen and
in the stream issuing from the central neck, cut 1.5g of lithium into ca.
70 pieces and drop into the flask containing about 25 ml dry ether. Place
the fittings in position, slow the nitrogen stream and add 1/2 of the
solution of 9.2g n-butyl-chloride in 25 ml dry ether. Start the stirring
and add the rest of the n-butyl-chloride at a rate giving a gentle reflux.
Continue stirring and reflux 2 hours and add 15 ml olivetol dimethyl ether
in 25 ml dry ether. Reflux 2 hours and add dropwise a solution of 15 ml
N-methylformanilide in 25 ml dry ether with stirring at a rate sufficient
to produce refluxing. Continue stirring 1 hour, treat with 3% sulfuric acid
and then pour into excess of this acid. Remove upper layer and extract
aqueous layer twice with ether. Wash combined ether layers with dilute
aqueous NaHCO3 and water and dry, evaporate in vacuum the ether (can
distill 148-52/0.3) to get 78% (I).
JACS 65,361(1943). A mixture of 6.5g (I) (or analog), 20 ml
pyridine, 1 ml piperidine and 9g malonic acid is warmed on a steam bath 1
hour. Add another 1 g malonic acid and heat another 1/2 hour. Reflux 1/2
hour and pour into excess iced 10% HCl, stirring occasionally over 2 hours.
Filter and dry to get 6 g 2,6-dimethoxy-4-n-amycinnamic acid (II)
(recrystallize from ethanol).
10g (II), 40 ml 80% isoprene and 40 ml dry xylene or toluene is
heated in an autoclave at 185C for 15 hours. Cool, dilute with 160 ml
petroleum ether and shake with 100 ml saturated aq. Na2CO3. Let stand and
separate the middle layer. Wash the middle layer with a mixture of
petroleum ether and dilute aq. Na2CO3 and again separate the middle layer
and treat with 75 ml 10% HCl and 75 ml ether. Shake, separate the aqueous
layer and wash the ether 3 times with water. Dry and evaporate in vacuum
the ether and dissolve the residue in petroleum ether. The solid which
ppts. after about 10 minutes is unchanged (II). Filter and let stand in
refrigerator overnight and dry and evaporate in vacuum to precipitate about
7 g of the 1-methyl-5 (2,6-dimethoxy-4-n-amylphenyl)-1-cyclohexene-4-COOH
(III) (recrystallize from petroleum ether).
1g (III) in 5 ml dry ether is added to 10 ml 3M MeMgI (from 0.21 g
Mg and 1.2g methyl iodide) in ether, heated to 130C to evaporate the
solvent and the oil kept at a bath temperature of 165 C for 1/2 hour. Cool
in dry ice-acetone bath and cautiously add ammonium chloride-ice water mix
to decompose the excess Grignard reagent. Acidify with dilute HCl and
extract with ether. Wash with NaCl, dilute K2CO3, NaCl and dry, evaporate
in vacuum to get the dimethyl derivative (IV). Reflux (IV) in 25 ml benzene
with 100 mg p-toluenesulfonic acid for 1 hour with a Dean-Stark trap and
dry, evaporate in vacuum (or wash with NaHCO3, NaCl first) to get the THC
or analog.
Hydrolysis of benzopyrones (for synthesis see elsewhere here) will
produce compounds of type (III) which will work in this synthesis. The
hydrolysis proceeds as follows (JCS 926(1927)): Add 10g of the benzopyrone
to 20g 30% NaOH, cool and shake 1 hour with 19 ml methylsulfate. Extract
the oil with ether and dry, evaporate in vacuum to get the ester. Acidify
the aqueous solution and filter, wash, dissolve ppt. in sodium carbonate
and acidify, filter to get the free acid. Both the acid and the ester will
work in this synthesis.
For a possible route to benzopyrones via condensation of isoprene
and 3-CN-5-OH-7-alkyl-coumarin see JACS 82,5198( 1960). See JMC 16,1200
(1973) for another ref. on the pyrone route to THC.
Delta-3 THC Analogs TET 23,77(1967)
11.6g 5-(1,2-dimethy))-heptyl resorcinol or equimolar amount of
olivetol or other analog, 9.2g 2-carbethoxy-5-methyl cyclohexanone
(4-carbethoxy-1-methyl-3-cyclohexanone), 5 g POCl3, 70 ml dry benzene
(protect from moisture with CaCl2 tube). Boil 5 minutes (HCl evolution) and
let stand at room temperature 20 hours. Pour into 10% NaHCO3, separate the
benzene layer and wash with 3x50 ml 10% NaHCO3. Dry and evaporate in vacuum
the benzene and recrystallize from 50 ml ethyl acetate to get 6.6 g of the
pyrone (I). 4.5g (I), 150 ml benzene; add dropwise to a solution prepared
from 7.8 g Mg, 18 ml methyl iodide, and 90 ml ether. Reflux 20 hours and
add 45 ml saturated NH4Cl. Separate the organic layer and extract the
aqueous phase with benzene. Combine the organic layer and benzene and dry,
evaporate in vacuum to get the THC analog.
Delta-3 THC analogs from Resorcinol TET 23,83(1967)
22g resorcinol,36 g 4-carbethoxy-1-methyl-3-cyclohexanone, 20g
polyphosphoric acid; heat to 105C and when the exothermic reaction which
occurs subsides, heat at 140C for one-half hour. Pour onto ice-water;
filter; wash with water and recrystallize-ethanol to get 34g of the pyrone
(I). 6.4g (I), 8 ml caproyl-Cl or analog (for preparation see above
reference, page 84); heat on oil bath (can use mineral oil) at 120C until
the exothermic reaction subsides (HCl evolution). Cool and pour into
ethanol. Filter to get 8g precipitate (II). 3.2g (II), 4.4g dry AlCl3; heat
on oil bath at 170C for one hour. Cool and add HCl; filter and dissolve
precipitate in 7 ml 2N NaOH. Filter and acidify with HCl to precipitate 1.4
g (III) (recrystallize-ethanol). Test this for activity. Use benzoyl-Cl or
benzoic anhydride to esterify the OH group (this may not be necessary),
methyl MgBr or methyl MgI to methylate the keto group, and sulfuric acid to
dehydrate and hydrogenate as described elsewhere here to get the THC
analog. Since the resulting THC analog has the side chain at the 6'
position, it may not be active. This paper also gives a synthesis for THC
analogs with the side chain in the 4' position, but again their activity in
man is unknown. Verbenol, etc., should work in this synthesis, thus
obviating the need for the methylation step.
Delta-1(6) THC JACS 88,367(1966)
1 M olivetol or analog, 1 M citral in 10% BF3 etherate in benzene
about eight hours at 5-10C. Extract unreacted olivetol with dilute
NaOH and evaporate in vacuum the ether to get about 20% yield of
the trans THC, and 20% of the cis THC which can be converted to
in vacuum to get 100 g of a mix containing about 40% (+) Delta-4 carene
(can separate by fractional distillation).
Delta-4 carene can also be obtained from Delta-3 carene as follows:
(JCS(C)46(1966)): Dissolve 1 g Delta-3 carene in 50 ml propionic acid and
heat at a suitable temperature (e.g., one-half hour at room temperature may
do) in presence of 1/2g Palladium-Carbon catalyst (5%) in ethanol and
filter, evaporate in vacuum (can distill 63.5/19.5). See J.Soc. Cosmet.
Chem. 22,249(1971) for a review of (+) Delta-3 carene chemistry.
Delta-2 Carene oxide (2-epoxycarene) LAC 687,22(1965), (cf. TL2335(1966),
and CA 68:22063(1968))
To 136 g 04 carene in 330 ml methylene chloride and 120 g anhydrous
sodium acetate, add dropwise with vigorous stirring in an ice bath, 167 g
of 50% peracetic acid and continue stirring for ten hours. Heat to boiling
for two hours, cool, wash with water, sodium carbonate, water, and dry,
evaporate in vacuum the methylene chloride to get about 100 g
p-menthadieneol. Apparently (CA 68,22063(1968)) substituting sodium
carbonate for sodium acetate results in the production of Delta-2 carene
oxide (2-epoxycarene) in about 50% yield (can distill 63/7).
4-Carbethoxy-1-methyl-cyclohexanone LAC 630,78(1960)
Cool 20 g of sodium metal in 325 ml ethanol to -15C in an ice-salt
bath and add in small amounts over one hour a solution of 100 g
3-methyl-cyclohexanone and 150 g diethyloxalate (keep temperature below
-10C). Keep three hours in cold and then twelve hours at room temperature.
Add solution of 1.3 L of water, 60 ml 2N sulfuric acid. Separate the
yellow-brown oil and extract the water with ether or CHCl3 until the yellow
is removed. Combine the oil and the extract and distill the solvent and the
unchanged starting material (100C bath, 13 mm). Slowly heat the residue in
a one-half liter flask with air cooling. CO2 evolution starts at 160C.
Continue heating to 220C and keep at this temperature for 1 1/2 hours or
until a test with 1% ethanol-FeCl3 solution shows the end of the reaction
by a violet color (unconverted material gives a brown color). Can distill
two times in Vigreux column to give about 83 g of oily colorless product.
(-)Verbenol JCS 2232(1961)
Racemic alpha-pinene will yield racemic verbenol which will give
one-half the yield of (-)verbenol.
27 g (-)alpha-pinene in 500 ml dry benzene; heat and keep
temperature at 60-65C throughout. Add with stirring over 20 minutes 84 g
dry (dry over P2O5) lead tetra-acetate. Stir one-half hour; cool and filter
and add filtrate to water. Filter and evaporate in vacuum the benzene layer
(can distill 96-7/9) to get 21.2 g cis-2-acetoxy-pin-3-ene(I). 5 g (I) in
25 ml glacial acetic acid; keep at 20C for one-half hour and add water and
extract with ether. Wash the extract with aqueous Na2CO3 and evaporate in
vacuum the ether (can distill 97-8/9) to get 4.3 g trans verbenyl acetate
(II). Hydrolyze (II) with NaOH to give the (-) cis and trans verbenol. For
other methods of producing verbenol see CA 37,361(1943), CA 57,16772(1962)
and BSC 2184(1964), JCS (B) 1259(1967). The last paper also gives a method
for converting (-) beta-pinene to (-) alpha-pinene. See also CA
65,2312(66). 5-Alkyl Resorcinols from Acyl Resorcinols CA 72,66922(1970)
Compounds I-III may be able to give active THC analogs if used in
place of olivetol for synthesis.
45 g 1-(3,5-dimethoxyphenyl)-1-hexanone(I) or analog (for
preparation see the following methods) in 400 ml ether and 0.3 M methyl-MgI
in 150 ml ether react to give 49 g 2-(3,5-dimethoxyphenyl)-2-heptanol(II).
Heat 49 g (II) with 1 ml 20% sulfuric acid to 105-125C/30mm for 1 1/2
hours to get 34 g of the 2-heptene compound (III). 33 g (III) in 100 ml
ethanol, 6 g Raney- Ni,1500 PSI hydrogen,150C to get 26 g of the 2-heptane
(IV). 26 g (IV), 118 ml 57% hydrogen iodide; add 156 ml acetic anhydride
and heat at 155o C for two hours to get 22 g of the resorcinol.
5-Alkyl Resorcinals BER 69,1644(1936)
25g ethyl-3,4,5-trimethoxybenzoyl acetate and 2.1 g Na in 100 ml
ethanol; warm to react. Add 2 g n-propyl iodide (or n-amyl iodide, etc.)
and heat twelve hours on steam bath; neutralize and distill off the
ethanol. Extract with ether and dry, evaporate in vacuum to get about 32 g
of the alkyl acetate (I). Heat 22 g (I) in 5% KOH in ethanol for one hour
at 50C to get 14 g 3,4,5-trimethoxyvalerophenone (II), which crystallizes
on standing. 11 g (II), 600 ml ethanol, 60 g Na; warm and after Na is
dissolved, add 2 L water. Acidify with HCl, distill off the ethanol and
extract with ether. Dry, evaporate in vacuum the ether to get 7.8 g
olivetol dimethyl ether (or analog) (III). 7.2 g (III), 70 ml hydrogen
iodide; boil two hours and distill (164/760) to get Olivetol.
Olivetol HCA 52,1132(1969)
Reduce 3,5-dimethoxybenzoic acid with lithium aluminum hydride to
3,5-dimethoxybenzyl alcohol (I). to 10.5 g (I) in 100 ml methylene chloride
at 0 C add 15 g PBr3; warm to room temperature and stir for one hour. Add
a little ice water and then more methylene chloride. Separate and then dry,
evaporate in vacuum the methylene chloride. Add petroleum ether to
precipitate about 11.5 g of the benzyl bromide (II). To 9.25 g (II), 15 g
CuI, 800 ml ether at 0 C, add butyl (or other alkyl)-Li (16% in hexane),
and stir for four hours at 0 C. Add saturated NH4Cl and extract with
ether. Dry and evaporate in vacuum the ether (can distill 100/0.001) to get
about 4.5 g olivetol dimethyl ether (III) or analog. Distill water from a
mixture of 90 ml pyridine, 100 ml concentrated HCl until temperature is 21
0C. Cool to 140C and add 4.4 g (III); reflux two hours under N2. Cool and
pour into water. Extract with ether and wash with NaHCO3. Make pH 7 and
dry, evaporate in vacuum to get 3.8 g olivetol which can be chromatographed
on 200 g silica gel (elute with CHCl3) or distill (130/0.001) to purify.
5-Alkyl Resorcinols TET 23,77(1967)
Since the method as given originally leads to 4-alkyl resorcinols
which do not produce an active THC, it is here modified to give the 5-alkyl
isomers. The method is illustrated for 1.2-dimethyl-heptyl resorcinol which
gives a much more active THC than olivetol.
Convert 3,5-dihydroxyacetophenone (5-acetyl resorcinol) to
3,5-dimethoxyacetophenone(I) in the usual way with dimethylsulfate.
To 24 g Mg, 1 crystal 12, 100 ml ether, add dropwise under N2, 180
g 2-Br-heptane in 100 ml ether over one hour and then reflux two hours. Add
over 1 1/2 hours a solution of 90 g (I) in 200 ml tetrahydrofuran and
reflux 10 hours. Cool and add 180 ml saturated NH4Cl; decant the solvents
and extract the residue with tetrahydrofuran. Combine the solvents and the
tetrahydrofuran and dry, evaporate in vacuum. Add a few drops 20% sulfuric
acid to the residual oil and evaporate in vacuum the water (oil bath
temperature 120-130C/10mm). Distill the oil at oil bath temperature
285C/0.2. Fraction boiling 128-140/0.2 yields about 60 g
2-(3,5-dimethoxyphenyl)-3-methyl-2-octene(II). If saponified and used to
synthesize a THC, this might give an active product, thus disposing of the
described above to get (I). Brominate 20.2g (I) with 12g bromine over 2
hours as described and stir 1 hour at room temperature. Add 500 ml water
and let stand overnight at 5-10C. Filter, wash precipitate with about 4x75
ml cold water and dry in vacuum at 50C to get 26g 3-bromo-2-OH-4-oxo-6(1,2-dimethylheptyl)-cyclohex-2-ene-1-methylcarboxylate(II).
In a 3 liter 3 necked flask with a stirrer, thermometer, reflux head and
Dean-Stark trap, add 350g (II) and 522g pyridine hydrochloride and heat on
oil bath at 90C 4 hours. Heat with the heating mantle (removing volatiles
with the Dean-Stark trap) until the internal temperature reaches 190-200C
and hold at this temperature 2 hours. Cool to room temperature and shake
with 3 liters ether and 660 ml 1.2N HCl and then 2x300 ml water. Extract
the ether solution with 4x350 ml 10% NaOH and then extract the combined
NaOH extracts with 2x300 ml ether. Acidify the alkaline solution with about
700 ml concentrated HCl and extract with 3x800 ml ether. Wash the combined
ether extracts with 3x300 ml 10% sodium dithionite, 2x300 ml saturated
NaHCO3 and 300 ml water and dry, evaporate in vacuum the ether to get the
5-(1,2-dimethyl-heptyl) resorcinol.
To prepare the 3-nonene-2-one condense excess acetone with
n-hexaldehyde (or 2,3-dimethyloctanal for 5,6-dimethyl-undec-3-ene-2-one)
in the presence of NaOH in an inert medium if desired (benzene, toluene,
xylene, etc.), at 10-70C to get (I). Dehydrate (I) with sodium sulfate or
cupric sulfate in an inert medium at reflux temperature or simply reflux in
benzene, xylene or toluene.
5-Alkylresorcinols JOC 37,2901(1972)
For 5-alkylresorcinols see Chem. and Ind. 685( 1973) also.
This is an improved version of a previously given synthesis (LAC
630,71 (1960)). The ethanol used is distilled from Ca ethoxide;
dimethoxyethane from potassium. Cupric bromide is produced from cupric
oxide and 5% excess of HBr, plus sufficient bromine to remove the milkiness
on addition of a drop of the mixture to water; concentrate and dry,
evaporate in vacuum over KOH flakes.
650g (5.3M) ethyl chloroacetate and 880g (5.3M) triethyl phosphite
are mixed and placed in a 3 liter flask fitted with a thermometer and
condenser under nitrogen. Heat and stir and slowly bring to 125C.
Discontinue heating as ethyl chloride evolution proceeds over 1/2 hour.
Heat to 160C over a 75 minute period and keep at 160o C 8 hours.
Cool,distill (e.g., through 12" Vigreux column) (74-7/0.03) to get 96%
yield of triethylphosphonoacetate (I). In a 3 liter flask fitted with a
stirrer, dropping funnel and condenser, place 45.3g NaH (1M in mineral oil)
and 1 liter of dry ether. Flush with nitrogen and keep at positive nitrogen
pressure. Stir in ice bath while 224 g (1M) (I) is added dropwise over 75
min. Stir and reflux 1 hour (H2 evolution stops). Cool in ice-salt bath and
add 1M of aldehyde (e.g., hexaldehyde for olivetol) over 1 hour. Continue
to cool and stir an additional 10 minutes and then slowly bring to reflux
and reflux for 10 minutes (ppt. prevents stirring). Decant the ether and
dissolve the oil layer in 500 ml warm water and separate the upper organic
layer. Extract the aqueous layer with 200 mI ether and extract the combined
organic solutions with 200 ml saturated NaHCO3. Dry and evaporate in vacuum
(can distill) to get the ethyl--alkylacrylates in about 90% yield (II).
In a flask with nitrogen and fittings as in preceding step, add 156
g ethyl acetoacetate to Na ethoxide from 25.3g Na and 500 ml dry ethanol,
and stir and reflux 1/2 hour. Add 1M of (II) dropwise over 90 minutes and
reflux 20 hours. Cool in ice, filter, wash ppt. with 500 ml ice cold
absolute ethanol and several times with portions of ether and dry,
evaporate in vacuum to get the dione Na salt (III) in about 80% yield (for
olivetol precursor). In a 250 ml flask place 0.1 M (III),100 ml
1,2-dimethoxyethane and flush with nitrogen and stir at room temperature
to get the octenes (V). Add 25g (V), 2.5g 65% Ni on kieselguhr in dry
hexane to hydrogenator and hydrogenate at 1750 psi and gradually increase
the temperature to 125o C. After 3 hours, increase the pressure to 1850 psi
and hold there 2 1/2 hours. filter and evaporate in vacuum to get
2-(3,5-dimethoxyphenyl)-3-methyl-octane (VI).
Add 20g (0.08M) (VI) to 38% HBr in glacial acetic acid and stir and
reflux for 6 hours. Pour onto ice and water, neutralize with solid sodium
carbonate and extract with ether. Extract the ether with 10% aqueous NaOH,
acidify the aqueous solution with HCl, extract with ether and dry,
evaporate in vacuum (can distill) to get 2-(3,5-dihydroxyphenyl)-3-methyloctane (VII) (5-(1,2-dimethylheptyl)-resorcinol).
As an alternative process for getting from (III) to (VI), combine
64.2g (0.18M) methyltriphenylphosphonium bromide in dry benzene with 11.6g
(0.18M) (in 14% solution) butyllithium in benzene. Heat to 60C and cool.
49.0g (0.176M) (III) in 40 ml dry benzene is added (keep temperature below
40C) and then reflux 2 hours. Cool, filter and evaporate in vacuum to get
the octene, which after catalytic hydrogenation as described for (V) yields
(VI).
5-A Alkylresorcinols Aust. J. Chem. 21,2979(1968)
Mix 50g 3,5-dihydroxybenzoic acid, 250 g K2CO3, 200 ml
dimethylsulfate and one liter acetone and reflux 4 hours. Remove the
acetone, add one liter water and one liter ether to the residue and
extract. Wash the ether extract with 2x100 ml concentrated NH4OH, 2x100 ml
dilute HCl and 100 ml water and dry, evaporate in vacuum to get 48g
methyl-3,5-dimethoxybenzoate (I). Recrystallize from aqueous methanol. To a
stirred suspension of 19g lithium aluminium hydride in 200 ml ether add
78.4g (I) in 300 ml ether at a rate which gives gentle refluxing. Reflux 2
1/2 hours, cool and add 50 ml wet ether; then 100 ml dilute sulfuric acid.
Wash and dry, evaporate in vacuum the ether extract to get 62g oily
3,5-dimethoxybenzyl alcohol (II). Recrystallize from ether-pentane. To a
cooled stirred slurry of 15g CrO3 and 250 ml pyridine add 8.4g (II) in 25
ml pyridine and let stand 1 hour at room temperature. Add 60 ml methanol,
let stand 2 hours, and dilute with 500 ml 5% NaOH and 500 ml ether. Extract
the aqueous layer with ether and wash the combined ether layers with 500 ml
water, 3x500 ml 5% sulfuric acid, 500 ml water and 200 ml saturated NaCl
and dry, evaporate in vacuum to get 7g 3,5-dimethoxybenzaldehyde (III).
Re-crystallize from ether-pentane. To a flask with a dropping funnel and
condenser add 0.58g Mg turnings and 10 ml ether. Add a few drops of a
solution of lauryl bromide (5.7g) or equimolar amount of homolog in 15 ml
ether and start reaction by adding 2 drops methyl iodide. Add the remaining
bromide solution with stirring and gentle refluxing over 15 minutes and
then reflux 3 hours. Cool in an ice bath and add 3.1g (III) in 5 ml ether
dropwise with stirring over 45 minutes. Reflux 4 hours, cool and dilute
with ice water. Wash the organic layer with 2x25 ml 3N sulfuric acid, 2x25
ml 10% K2CO3, 25 ml water, 25 ml saturated NaCl and dry, evaporate in
vacuum to get 5g 3,5-dimethoxyphenyldodecyl methanol (IV) or homolog.
Recrystallize from methanol. Hydrogenate 4.2g (IV) in 50 ml ethyl acetate
with 5 drops concentrated sulfuric acid and 0.5g 10% Palladium-Carbon
catalyst at room temperature and 5 atmospheres hydrogen for 4 hours. Filter
and evaporate in vacuum to get the aklylresorcinol dimethyl ether.
Aust. J. Chem. 26,799(1973) gives a 2 step synthesis of
5-alkylresorcinols by condensation of beta-ketosulphones with
3,5-dimethoxybenzyl bromide and then reduction. Aust. J. Chem. 26,183(1973)
gives a synthesis from 3,5-dimethoxy-N,N-dimethylbenzylamine in 7 steps
(but perhaps only 4 will reach a cpd. that can give an active THC analog).
5-alkylresorcinols CPB 20,1574(1972)
to produce. Also, it is rumoured that N,N-dibutyl and longer alkyls are not
only active but (along with the dipropyl, diisopropyl etc. cpds.) orally
active.
Ken Kesey has reputedly said that alpha-methyltryptamine, in oral
doses of ca. 30 mg, peaks in about 12 hours, produces a trip similar to
psilocybin, but nicer, and is the "Rolls Royce of psychedelics," but others
find it unpleasant. Alpha-ethyltryptamine produces minimal LSD-type effects
at 150 mg orally, but effects of these when smoked or inhaled are unknown.
N,N-disubstituted tryptamines which have substituents in the alpha or beta
positions should also be quite interesting.
Identification of Indoles
Keller Test
Add a little of the powdered substance (about 0.2 mg to 1 ml
glacial acetic acid containing 0.5% FeCl3, layer underneath with 1 ml
concentrated sulfuric acid and shake. The color varies with the indole,
being olive green for psilocin and red-violet for psilocybin.
Van Urk Test
Prepare Van Urk reagent by adding 0.5 g p-dimethylaminobenzaldehyde,
100 ml water, 100 ml concentrated sulfuric acid. Dissolve 1 mg substance in
1 ml ethanol and mix with 2 ml Van Urk reagent and illuminate for 10
minutes with an ultraviolet lamp (black light). Psilocin gives a blue-grey,
psilocybin a red-brown color.
Colors produced in these two tests by many indole derivatives are
given in HCA 42,2073(1959).
Quick, Easy, On-the-Spot Test JPS 56,1526(1967)
Saturate strips of filter paper with 2% p-dimethylaminobenzaldehyde
in 45% ethanol; air dry and store in tightly stoppered amber bottles (or
keep in stoppered container in dark) which will keep them useful for
several months. Put a little of the suspect substance in a few drops of
ethanol (gin may do, but do a control), wet a filter paper strip in this
and allow to dry. Put one drop concentrated HCl on the dried paper (don't
let it touch anything). Alternatively, the powder can be placed directly on
the strip and the HCl dropped on it. A violet red or violet blue spot
indicates indole derivatives such as LSD. With DMT or psilocybin the color
is redder. The color must be observed soon after adding the HCl since it
rapidly changes.
Dialkyltryptamine Syntheses
Dialkyltryptamines HCA 42,2073(1959) and many others
To 25 g indole (or 50 g 4-benzyloxyindole or 0.21 M other indole)
in 1 L dry ether at 0 add a solution of 50 ml (75 g) oxalyl chloride in
1 L dry ether carefully and with good stirring a little at a time over 1/2
hour and stir until bubbling ceases (about one-half hour more). Some
indoles require a longer reaction time (e.g., 4-Cl-indole requires fifteen
hours refluxing) and some will not react (e.g., 4-Br-indole). Add
portionwise, carefully with stirring at 0, a solution of 225 ml (160 g)
diethylamine (DEA) (or 0.46M dipropylamine, pyrrolidine, etc.) in 100 ml
dry ether at 0. Stir and let warm to room temperature; cool, filter, and
wash precipitate two times with ether to get (I). This can be
recrystallized by dissolving in the minimum volume of 1:1 methanol:benzene
(or 95% ethanol), gently heated, cooled to 0 and filtered (or add
petroleum ether to induce precipitation). Dissolve 25 g (or 0.102 M) (I) in
the least volume (about 200 ml) THF and add very carefully and slowly
(preferably dropwise) to 20 g lithium aluminum hydride dissolved in the
least volume (about 200 ml) tetrahydrofuran at room temperature. Stir and
heat under reflux for about fifteen hours. Cool to O and slowly and
carefully add a little cold methanol and water until no more bubbles are
formed. Filter, wash precipitate with hot tetrahydrofuran and add washings
to filtrate. Dry, evaporate in vacuum the tetrahydrofuran (or add petroleum
ether) to precipitate the dialkyltryptamine. To purify, add 500 ml
saturated sodium sulfate and filter. Wash precipitate with tetrahydrofuran;
acidify with a few ml 0.1 M HCl and shake with ether. Separate the organic
layer and neutralize with 0.1 M NaOH. Extract with CHCl3 and dry, evaporate
in vacuum the extract (or can evaporate until a few ml left and precipitate
by adding petroleum ether). The 4-benzyloxy-DET which would be produced if
4-benzyloxyindole is used as the starting material is probably a good
psychedelic. lf however, it is desired to change this to 4-OH-DET, add
37.5 g 4-benzyloxy-DET in 1.2 L methanol to 20 g 5% Palladium catalyst on
alumina (or 14 g 10% Palladium-Carbon) with 2.8 kg/cm2 H2 in a Parr
hydrogenator and shake twelve hours. Filter, evaporate in vacuum. Other
hydrogenating methods might also split off the benzene ring. Other methods
(LAC 576,69(1952)) must be used for reducing a methoxy group to a OH group
(another demethylation method is given here later).
If (I) has an alkyl group in position 1 (as in some of the
following syntheses), reduction will give the indolylhydroxylamine. This
may be active, but if the indolamine is desired (I) (substituted or not)
may be reduced with the diborane method given later in this section.
Dialtryltryptamines JCS (C) 2220(1967)
This procedure gives about 20% yield with indole, but the yield
with substituted indoles (e.g., 4-OH-indole for producing psilocin) has not
been reported.
Cool 32 g ethyl iodide to 0C; dissolve in 50 ml anisole (other
solvents won't work) and add 8 ml to 5.28 g Mg turnings in 50 ml anisole,
and add the rest gradually. Warm gently to start the reaction, and if
necessary add a crystal of iodine or a small amount of ether for a rapid
rate. Stir well and heat at 50-60 for one hour (under N2 if possible).
Cool to 10 and add dropwise over one-half hour 12 g (0.1 M) indole in 50
ml anisole (keep temperature below 25). Stir forty-five minutes at 50 and
cool to -5. Finely grind 0.2 M (34 g) 1-Cl-2-diethylaminoethane-HCl (or
the corresponding diisopropyl, pyrrolidyl, etc. compounds) and suspend in
about 20 ml benzene at O. The free base in benzene can also be used, if
obtainable. Stir and take pH to 8.5 with 40% NaOH. Add anhydrous potassium
carbonate until the water layer is semisolid. Decant the benzene and
extract the residue with 4X 15 ml benzene. Dry the combined benzene
extracts with KOH pellets for less than an hour and quickly proceed to the
next step. Add the benzene solution (about 80 ml) slowly over one hour to
the above solution of indole in anisole at -5. Stir three hours at -5 and
let sit five hours at -5. Then let warm to room temperature and dry,
evaporate in vacuum (or to purify, break up the precipitate and pour the
solution on 500 ml saturated aqueous NH4Cl. Stir one-half hour; separate
the organic layer and extract the aqueous layer with ether. Combine the
organic solutions and extract three times with 10% HCl. Wash HCl extract
with ether; cool to O, basify with 40% NaOH and extract three times with
ether. Dry, evaporate in vacuum this second ether extract to get the oily
DET or analog).
4-Substituted Dialkyltryptamines CT 279( 1970)
isopropanol). Shake the ether with water and filter to get about 5 g of the
4-OH compound (VIIb) (recrystallize-isopropanol). 7.8 g (VIIa or b or
mixture obtained by evaporating in vacuum the ether above), 17 g lithium
aluminum hydride, 150 ml tetrahydrofuran or dioxane; reflux seventeen
hours, carefully add water and stir until bubbling ceases and evaporate in
vacuum to get about 4.7 g of psilocin or analog (about 5% overall yield).
For other methods of synthesizing (1V) see JOC 36,1232(1971) and references
therein. For another method of reducing (IV) see Chem. Het. Cpds.
(Russian), 572(1972).
4-Substituted Dialkyltryptamines
HCA 42,2073(1959), 38,1452 (1955), CT 276( 1970)
Method is illustrated for 4-benzyloxyindole (I) but will probably
work for most other substituted indoles.
A: Convert (I) to 4-benzyloxygramine (II) as described elsewhere
here.
B: Add 30 g (II) over one-half hour to 420 ml methyl iodide and let
stand fifteen hours at 5. Separate the iodomethylate which precipitates,
dry briefly at 50 and heat with vigorous stirring at 80 for two hours
with 60 g NaCN in 1 L water. Extract with CHCl3, dry and evaporate in
vacuum the extract and dissolve the residue in 250 ml ether. Filter,
evaporate in vacuum to a few ml and precipitate the acetonitrile (III) by
adding petroleum ether. The acetonitrile can also be prepared directly from
the indole via the Grignard reagent as given elsewhere here.
B (Alternative): 0.05 M (II), 0.76 ml glacial acetic acid in 75 ml
tetrahydrofuran (dry) are added slowly with stirring and cooling over
one-half hour to a solution of 25.2 ml dimethylsulfate and 0.76 ml glacial
acetic acid in 30 ml dry tetrahydrofuran. After two hours, filter and wash
the precipitate with ether. Dissolve precipitate in 10% aqueous solution of
KCN and heat one hour at 70. Filter, wash precipitate with water and dry
to get (III).
C: 0.04 M (III) in 200 ml 33% ethanol solution of DMA or other
amine, 2.5 g Raney-NI, 40o, 100 kg/cm2 (about 100 atmospheres) H2. Heat
about three hours; filter and evaporate in vacuum to get the
dialkyltryptamine.
C (Alternative): 5.8 g (III), 12 g KOH, 36 ml ethanol, 28 ml water;
reflux fifteen hours, add 15 ml glacial acetic acid, filter and add 150 ml
water to precipitate 4-benzyloxyindole acetic acid (IV). Filter, wash
precipitate with water and recrystallize from methanol.
D 1.76 g (IV), 1.4 g PCl5, 50 ml ether at O. Stir until dissolved
and add dropwise to solution of 5.36 g DEA (or equimolar amount other
amine) in 10 ml ether. Let warm to room temperature, let stand one-half
hour and precipitate by adding water. Filter, dry, evaporate in vacuum the
ether and add the residue to the precipitate to get the diethylacetamide
(V) (recrystallize-benzene).
D (Alternative): 20.6 g (IV) in 50 ml methanol; add excess
diazomethane in ether, evaporate in vacuum and dissolve the oil in 90 ml
dry hydrazine. Heat at 135 1 1/2 hours, add 150 ml water and cool to
precipitate the hydrazide (recrystallize-aqueous methanol). 14.7 g of the
hydrazide in 250 ml tetrahydrofuran or dioxane and add 50 ml 1 N NaNO2.
Cool to 4 and add dropwise over 4 minutes with vigorous stirring, 60 ml 1N
HCl; let stand fifteen minutes at 4 and add 500 ml water. Extract the oily
azide with ether and dry, evaporate in vacuum. Add 77 ml (0.75 M) DEA (dry)
to the azide and let stand three hours at 5o with care to exclude moisture.
Evaporate in vacuum and take up the residue in NaHCO3. Extract with CHCl3
and dry, evaporate in vacuum the extract to get (V).
E. 0.7 g (2.28 mM) (V) in 20 ml dry tetrahydrofuran; add slowly to
and cool to precipitate.Filter, wash precipitate with CHCl3 and dry to get
25 g gamma-Br-diethylacetoacetamide (II) (use crude since decomposes on
distillation). 4.72 g (II), 4.28 g N-methyl-aniline, 20 ml dimethyl
formamide and let stand twelve hours (or 90 ml ethanol and reflux eighteen
hours) at room temperature. Slowly add 300 ml water and extract the oil
which forms with benzene. Wash with water and dry, evaporate in vacuum the
benzene extract to get 4 g precipitate (recrystallize-80% ethanol). 4 g
precipitate, 4 g ZnCl2 finely ground; heat in oil bath and keep temperature
100-110 for forty-five minutes. Cool and dissolve precipitate in 40 ml 4N
HCl and 160 ml benzene. Separate the benzene and wash with water; basify
and dry, evaporate in vacuum to get 1.3 g 1-methyl-3-indole-N, N-diethylacetamide (III) (recrystallize-ethanol). Test for activity. Recover
N-methyl-aniline by basifying the water or ethanol, extract precipitate
with ether, wash extract to neutrality and dry, evaporate in vacuum. 1.1 g
(III), 0.38 g finely ground lithium aluminum hydride, 300 ml ether and
reflux two days. Carefully add a little water and filter, evaporate in
vacuum to get 1-methyl-DET (recrystallize-ethanol). (III) can probably also
be reduced by the method described in the chemical hints section or even
more simply as follows: Dissolve 1M NaBH4 and 0.1 M (III) in 500 ml
pyridine or other solvent and reflux eight hours or more.
Alpha-alkyl-DMT TET 29,971(1973)
21.6 g (0.1M) alpha-bromopropionyl (or butyryl etc.) bromide is
added dropwise over 1 hour to a well stirred mixture of 11.7 g (0.1 M)
indole and 8.1 ml (0.1 M) pyridine in 300 ml toluene at 60. Stir 1 hour,
cool and pour into 500 ml water. Separate the oil and dissolve in methanol.
Let stand 1-24 hours until crystals separate. Filter (recrystallize from
acetonitrile) to get 18.4 g (72%) 3-(2-bromopropionyl)indole (I). 5.2 g
(0.02M) (I), 7 ml 33% aq. dimethylamine and 3 g NaI in 100 ml ethanol are
refluxed for 20 hours, concentrated to 25 ml and poured into 200 ml aqueous
0.5M HCl. Extract with ether and basify with concentrated NH4OH.
Recrystallize from ethanol to get ca. 3g (50%) 3-(2-dimethylaminopropionyl)indole (II). 2.7g (II) in 50 ml tetrahydrofuran is added to a well stirred
mixture of 2.7 g lithium aluminum hydride in 60 ml tetrahydrofuran. Reflux
23 hours, carefully add 5 ml 2N KOH, filter and wash the the ppt. with
ether and dry, evaporate in vacuum the ether to get 1.65 g (66%)
alpha-methyl-DMT (recrystallize-benzene-n-hexame).
Alpha-methyl-DET JMC 9,343(1966)
46.8 g (0.4 M) indole in 100 ml toluene; add to 54.5 g ethylbromide
and 12.5 g Mg turnings in 125 ml ether. After one-half hour convert the
indolyl-Mg-Br to 3-indolyl-2-propanol with propylene oxide (CA 56,3455(1962)).
8.8 g of the indolyl-propanol, 200 ml ether; add 4.4 g PBr3 and let stand
four hours. Add excess DEA and stir for a few minutes. Evaporate in vacuum
or extract with dilute HCl and basify the extract with NaOH to precipitate
the alpha-methyl-DET.
Dialkyltryptamines from Tryptamines BCSJ 11,221(1936)
Illustrated for 5-methoxy-tryptamine (I). 1.5 g (I), 30 ml ethanol;
add 5 g methyl iodide (or equimolar amount ethyl iodide) and 4.5 g dry
sodium carbonate and heat five hours on water bath. Filter hot, heat
precipitate with ethanol and filter hot again. Evaporate in vacuum to get
2.5 g 1-methyl-5-methoxy-DMT.
Dialkyltryptamines AP 294,486(1961)
Convert indole to indolyl-3-methyl-ketone (I) by treating indolylMg-Br (preparation already described) with acetyl-Cl, by treating indole in
POCl3 with dimethylacetamide (Vilsmeier reaction), or by reacting indole
with diketene (ACS 22,1064(1968)). 15.9 g (I) in 50 ml methanol; cool, stir
and add dropwise 16 g Brz. Reflux 1 1/2 hours on water bath; cool, filter,
wash with ether and recrystallize-methanol to get 18 g
indolyl-3-Br-methyl-ketone (II). Dissolve 11.9 g (11) in 60 ml warm
isopropanol and add 11 g 38% aqueous DMA (or equimolar amount other amine);
reflux one hour on water bath. Filter (recrystallize-ethanol) to get 8.5 g
indolyl-3-dimethylamino- methyl ketone (III). Add 4.6 g (0.02 M) (III) in
30 ml tetrahydrofuran to 2.3 g lithium aluminum hydride in 50 ml
tetrahydrofuran, stir one-half hour at room temperature and reflux two
hours. Add a little water dropwise and extract the precipitate with
acetone. Dry, evaporate in vacuum the combined organic phases to get an oil
which will precipitate with ether-petroleum ether to give DMT. (III) should
be tested for psychedelic activity.
Dialkyltryptamines BCSJ 11,221(1936), BSC 2291(1966)
30 g 5-methoxy-indolyl-3-acetonitrile is heated with KOH in aqueous
methanol until no more ammonia is evolved (about 20 hours). Evaporate the
methanol in vacuum and extract the water remaining with ether. Acidify the
aqueous layer with HCl to precipitate 28 g 5-methoxy-tryptophol (I).
Alternatively, dissolve 2.3 g indole in 15 ml glacial acetic acid and 5 ml
acetic anhydride. Add with stirring 0.025M ethylene oxide, heat to 70 for
25 hours, then hold at 20o for 50 hours in a closed flask. Pour into water
and extract with ether. Wash with water, dry, evaporate in vacuum and
saponify (e.g., heat with NaOH) the residue to get 1.5 g tryptophol (can
purify on alumina; benzene elutes indole, ether elutes tryptophol). 2g (I)
or tryptophol in 100 ml ether. Mix with 1 g PBr3 dissolved in ether and let
stand 12 hours at room temperature. Decant the liquid from the precipitate;
wash with water and NaHCO3 and dry, evaporate in vacuum the ether to get
1.3 g of the oily bromide (II). 1 g (II), 4 ml methanol, 4 ml 33% aqueous
DMA (or DEA etc.) and heat on steam bath in sealed container 15 hours.
Acidify with about 50 ml dilute HCl, extract with ether and dry, evaporate
in vacuum the ether to get about 0.5 g DMT or analog.
Dialkyltryptamines BSC 1335(1966)
To 600 ml liquid NH3 add 23.5 g Na: 40 g Na-amide are thus prepared
and the NH3 evaporated in vacuum. Mix 170 g 5-CI-2-methoxy-phenylacetonitrile (preparation given elsewhere) in 900 ml benzene with the Na-amide
and stir and reflux two hours. Cool to 40 and add dropwise 111 g
2-dimethylaminochloroethane (or diethyl etc. analogs) prepared freshly in
benzene as described in a previous method, or use the base freshly
distilled. Reflux two hours, cool and add a little ethanol and water and
extract the amine by evaporating in vacuum or pouring on cool water and
filtering to get 157 g (I) (recrystallize-petroleum ether). 105 g (I) in
150 ml methanol containing 15% NH3. Hydrogenate at 50, 70 kg pressure, in
presence of Raney-Ni. Filter, dry and evaporate in vacuum to get 97 g of
the phenethylamine (II). Cyclise (II) with Na and naphthalene as described
later for 4-methoxyindole to get the yellow, oily indoline (111)
(recrystallize-ethanol). Test this for activity. If desired, the
noncyclised material can be eliminated by tosylation. 3.1 g (III),
preferably as the HCl salt, 200 ml water; stir and heat fifteen hours with
10 g Raney-Ni and 1.5 g maleic anhydride. Filter, dry and evaporate in
vacuum to get 4-methoxy-DMT.
Dialkyltryptamines
dropwise with stirring 3.5 g 38% aqueous formaldehyde. Two minutes after
the end of the addition shake with water and CHCl3: dry and evaporate in
vacuum the CHCl3 phase to get 5 g oily 4-dimethyl-aminomethyl-5-OH-indole
(I) (can chromatograph on 100 g alumina and elute with ethyl acetate). It
has been claimed that this method does not work.
Alternatively (CA 72,66732(1970)), add 1.6 g 5-OH-indole, 1g
bis-dimethyl-aminomethane in 5 ml dioxane. Heat 2 1/2 hours on water bath
to get 1 g (I) (recrystallize-methanol-dimethylformamide). For the
transformation of the dimethylaminomethyl substituent of (I) into methyl,
aminomethyl, formyl or cyanomethyl see BSC 2046(1973).
4-Hydroxydimethyltryptamine (Psilocin) from DMT
C.R. Acad. Sci. Paris 275,613(1972)
See also C.R.A.S.P. 269,51(1969) and BSC 1523(1959).
Mix 0.01 M dimethyltryptamine, 0.02 M phosphate buffer pH 7.2
containing 5 mM ascorbic acid, 0.02 M disodium EDTA and 0.01 M ferrous
sulfate (CuCl may substitute) and add with stirring at 20-22 0.02M H2O2
(0.01 M may increase yield). Let reaction proceed to completion (2 hours or
less) and extract with ethyl acetate. Dry and evaporate in vacuum to get
about 30% yield of psilocin. The product, which contains the other OH-DMT's
as well, can be chromatographed on silica thin layer with t-butanol-acetic
acid-water (ACS 22,1210 (1968)) or on a 5% alumina-Nickel column or 10%
alumina-Nickel plate with CHCl3-methanol and the psilocin eluted with
methanol.
Tryptamine from Tryptophan Synthesis 475(Sept. 1972)
Cently reflux a suspension of 250 mg L-tryptophan in 10g warm
diphenylmethane in a stream of nitrogen (if possible) for 5-20 minutes
until there is no more CO2 evolution. Cool and evaporate in vacuum or treat
with 20 ml benzene saturated with dry HCl and filter, wash precipitate with
hexane and dry to get about 60% yield of tryptamine.
4-Acetylation of 5-OH-indoles BCSJ 44,550(1971)
To 2 g 5-OH-indole (or analog) in 50 ml nitrobenzene add 4 g AlCl3
in 50 ml nitrobenzene. Add 1.26 g Acetyl-Cl and heat three hours at 50;
evaporate in vacuum or add dilute HCl to get 1g 4-Acetyl-5-OH-indole
(recrystallize-ethyl acetate).
4-Substituted Tryptamines JMC 8,200(1965)
Heat 85.5 g 3-carbethoxy-2-piperidone and 30 g KOH in 1 L water for
twelve hours at 30o. Filter, cool to 0, add 50 ml 6N HCl. Prepare a fresh
solution by diazotizing at 0-5 a mixture of 85 g 3-amino-4-Cl-acetophenone,
250 ml concentrated HCl and 750 ml water with a solution of 36 g Na nitrite
in 125 ml water. Add the piperidone solution at 0 to the diazonium salt
solution and stir five hours at 10. Filter, wash precipitate with water to
get 80% yield of the hydrazone (I) (recrystallize-95% ethanol). Reflux 62 g
(I) in 310 ml 88% formic acid to get 40 g of the carboline (II)
(recrystallize-absolute ethanol) (test for activity). Reflux 40 g (II), 100
g KOH, 480 ml ethanol and 360 ml water for eighteen hours and evaporate in
vacuum. Add 480 ml water to the residue, cool and adjust pH to 6 with
glacial acetic acid. Scratch glass to precipitate; filter, wash precipitate
with cold water to get 41 g 4-acetyl-2-COOH-7-Cl-tryptamine
(recrystallize-50% ethanol) which can be alkylated to the active
dialkyltryptamine as described elsewhere here.
aqueous residue is filtered, acidified with HCl and filtered to get 102 g
2-nitro-6-Cl-phenylpyruvic acid (I) (recrystallize-benzene). Add 81 g (I)
in dilute NH4OH to a solution of 560 g FeSO4*7H20 and 230 ml concentrated
NH4OH and 2 L water and boil five minutes. Filter, wash precipitate with
dilute NH4OH, water and acidify filtrate with dilute HCl to get 60 g
4-Cl-2-indole-COOH (II) (recrystallize-aqueous ethanol). 9.78 g (ll) and
6.7 g CuCN in 35 g quinoline and reflux (about 237) for twenty hours. Pour
the hot solution into a mixture of 25 ml concentrated HCl and ice. Stir and
filter; wash precipitate with water and extract the filtrate and
precipitate three times with ether. Wash the ether with HCl, water and dry,
evaporate in vacuum to get 3.6 g 4-CN-indole (recrystallize-water). Or,
heat (II) alone at 290 until fusion; then heat at 250 for ten minutes
until CO2 evolution ceases to get 4-CN-indole. For conversion to
4-formyl-indole see HCA 51,1616(1968).
4-Alkyloxyindoles TET 24,6093(1968), JMC 13,983(1970)
and a longer route in CT 274(1970).
Add solution of 150 g 2-amino-6-nitrotoluene (prepared by reduction
of 2,6-dinitrotoluene with H2S in ammoniacal ethanol and recrystallizewater or ethanol) in 550 g concentrated sulfuric acid slowly to 5 Kg
crushed ice and then add dropwise a solution of 75 g Na nitrite in 100 ml
water with stirring and cool (0-5). Continue stirring two hours and add 2
L 10% sulfuric acid containing 0.1 % Cu sulfate. Heat at 75-80 twelve
hours or until N evolution ceases. Filter, cool to precipitate 135 g
2-OH-6-nitrotoluene (I) (recrystallize-aqueous ethanol) (can also prepare
by nitrating o-cresol). Add 20 g (I) in 100 methanol to a solution of 5.8 g
Na metal in 60 ml methanol or ethanol. Add dropwise with stirring, 34 g
diethyl or dimethylsulfate. After addition reflux one hour, evaporate in
vacuum most of the methanol, add 100 ml water and extract with 3x50 ml
ether. Wash ether with 50 ml 5% NaOH, 2x50 ml water: dry, filter, evaporate
in vacuum (can distill 116/2.2 for ethyl-, 94-6/0.5 for methyl-) to get 20
g 2-alkyloxy-6-nitrotoluene (11). Can also use 1-Br-propane and reflux four
hours; evaporate in vacuum the ether extract and distill residue (180/17)
to get the 2-n-propoxy-6-nitrotoluene (recrystallize-aqueous methanol). To
a suspension prepared from 7.8 g K metal (Na may do) and 25 ml absolute
ethanol in 160 ml dry ether, add dropwise a solution of 0.1 M (II) and 29.2
g diethyloxalate in 50 ml dry xylene. Stir four hours and let stand at room
temperature three days. Extract the precipitate with 100 ml ice water and
extract the resulting dark red aqueous layer with 3x50 ml ether. Filter and
remove the residual ether by blowing air through the aqueous solution. Cool
in ice bath and treat alternately with a little 20% NaOH and 30% H202 (16
ml each total) until the dark red color is gone. Filter and acidify with
concentrated HCl to get 9 g of the 2-alkyloxy-6-nitrophenylacetic acid
(III). 2 g (III) in 40 ml glacial acetic acid. Add 0.1 g 10%
palladium-carbon and hydrogenate at room temperature and atmospheric
pressure about one hour. Filter, evaporate in vacuum to get 1.2 g
4-alkyloxyindole (recrystallize-toluene). For the n-propoxy compound,
hydrogenate one-half hour in 30 ml 5% NaOH, filter, acidify with
concentrated HCl and heat on steam bath for one-half hour. Cool and filter
and recrystallize-aqueous ethanol. If desired, these indoles can be
dealkylated as described elsewhere here. Alternatively, dissolve 45 g (III)
in 600 ml water with the minimum amount of 2N NaOH (about 80 ml). Add
Na2S2O4 to the well stirred solution in small amounts until no further
increase in temperature occurs. Add 2N NaOH dropwise, at the same time add
further Na hydrosulfite, until the red color disappears (about 80 ml NaOH,
70 g Na hydrosulfite). This takes about one hour and final temperature is
about 35. Stir in 200 ml dilute (1:1) HCl to precipitate the
alkyloxyindole-COOH (IV) which can be used as is, or decarboxylated with
quinoline and Cu powder by heating to 245 and cool, filter and evaporate
hours. Evaporate in vacuum, dissolve the oily residue in 2N HCl and extract
with ether. Proceed as described to get (VII). 4 g (VII) in 200 ml dry
pyridine; add to 6 g Cu chloride in 400 ml pyridine and reflux 1 1/2 hours.
Pour on water and extract with ether. Wash extract with 4N HCl and then
water and dry and evaporate in vacuum the ether to get 2 g of the indole
(VIII). Alternatively, dissolve 4 g (VII) and 9.5 g cinnamic acid in 700 ml
mesitylene, add 1 g 5% palladium-carbon and reflux five hours. Filter, wash
with HCl and NaHCO3 and dry and evaporate in vacuum the mesitylene to get
the red, oily (VIII) (can chromatograph on alumina and elute with
benzene-petroleum ether).
5-OH-indole JCS 2525(1952)
To a solution of 4.3 g 2,5-dihydroxyphenylalanine and 2 g NaHCO3 in
150 ml water, add with stirring during ten minutes, a solution of 13 g K
ferricyanide and 3 g NaHCO3 in 200 ml water (dark solution turns pale
yellow). Extract with 3x200 ml ether and dry, evaporate in vacuum to get
2.3 g 5-OH-indole.
4-Indolecarboxylic Acid CPB 20,2123(1972)
Heat 3-nitrophthalic anhydride with ammonium carbonate to get
3-nitrophthalimide (I). Dissolve 4.3 g (I) in 50 ml 90% methanol and add
1.9 g sodium borohydride over 30 minutes while stirring vigorously at room
temperature. Stir 2 hours, acidify with 20% HCl, evaporate in vacuum and
treat the dry residue with acetone. Evaporate in vacuum to get 3.9 g (88%)
3-OH-4-nitrophthalimidine (II) (recrystallize from acetone). Dissolve 3.9 g
(II) in 40 ml 20% HCl and stir for 10 hours on water bath at 80-90.
Distill off HCl and stir residue with acetone. Filter and evaporate in
vacuum to get 3.4 g 3-OH-4-nitrophthalide (III) (recrystallize from CHCl3
and can purify on column). Prepare an ether solution of CH2N2 and add to
1.93 g (III) in a 100 ml flask until a reaction is no longer evident. Add
acetic acid to decompose excess diazomethane and evaporate in vacuum to get
about 2 g of 2-methoxycarbonyl-6-nitrostyrene oxide (IV) (can purify on
column). Dissolve 560 mg (IV) in 50 ml absolute methanol, add 50 mg PtO2
and hydrogenate as described elsewhere here (other reducing methods should
work). Filter, evaporate in vacuum and recrystallize from benzene to get
270 mg methyl-4-indolecarboxylate(V). Dissolve 250 mg (V) in 2 ml 0.05M KOH
and stir at room temperature 6 hours. Neutralize with 10% HCl carefully to
prevent excessive heat and collect the crystals by filtration. Dry to get
126 mg 4-indolecarboxylic acid.
Indole Russian Patent 306,126(29 July 1971)
To a stirred suspension of 1.9 g orthocarbamoyl cinnamamide in 50
ml methanol add 26 ml 0.77 N NaOCl and heat in a distillation apparatus at
40 for 2 hours, or until no more indole is distilled off (can use the
indole tests described earlier). Extract the distillate with CHCl3 and dry,
evaporate in vacuum (or steam distill the solvent) to get about 45% indole.
Indole German Patent 2,052,678(6 May 1971)
A molar ration of 2-(o-nitrophenyl)-ethanol to reducing gas of 1:5
is best (greater than 90% yields). The catalyst is Al2O3 or silica gel
containing 7-14% by weight of copper (or Ni, Co, Cu chromite, etc.), with
some potassium sulfate if necessary. Reducing gas is NH3 or H2, which can
be mixed with nitrogen. The temperature is 250-300. The
2-(o-nitrophenyl)-ethanol is vaporized over 30 ml catalyst in a quartz tube
56 cm long with an inner diameter of 15 mm, containing along its whole
length a thermoelement tube with an outer diameter of 8 mm. The tube is
filled to 28 cm with quartz glass fragments. The gas flow rate is 80-240
ml/minute with a contact time of 7-14 seconds. Compare CA
79,105065-66(1973).
Indole Analogs
Replacement of
nucleus by atoms of N,
some of which are very
are isoindole, indene,
and benzimidazole. The
have a high toxicity and the latter because it lasts too long (e.g., 24
hours for a minimum dose). Other 4-alkyl amphetamines also seem to be
toxic. A number of apparent fatalities due to MDA have been noted, but the
reports usually involve very large amounts, often in combination with other
drugs (e.g., 7 g MDA plus barbiturates) and screening for other, more toxic
drugs (in particular, PMA) has not been done.
These amphetamine analogs can be produced by using the
appropriately substituted benzaldehyde in place of 3,4,5-tri
methoxy-benzaldehyde, and nitroethane in place of nitro-methane in the
aldehyde method for mescaline synthesis (using nitropropane, etc., to give
a longer chain results in less activity). However, easier synthetic routes
from the naturally occurring (therefore cheap and commercially available)
ring substituted propenylbenzenes are given here.
The following table lists common names, position of ring
substitution, and approximate activity of the amphetamine derivatives for
some readily available allyl and propenyl benzenes (see J. Chromatography
30,54(1967) for further information on these compounds). Activity is
relative to mescaline which equals 1 (an activity of 12 means a dose of
about 25 mg). Parentheses indicate a methylenedioxy bridge; other
substituents are methoxy groups.
Allyl
Propenyl
Substituents
Activity
Safrole
Croweacin
Myristicin
Dillapiole
Estragole
----Apiole
Isosafrole
--Isomyristicin
Isodillapiole
Anethole
Asarone
Apiole
Isoapiole
(3,4)
2(3,4)
3(4,5)
2,3(4,5)
4
2,4,5
2(4,5)
2(3,4)5
2
2
2
6
6
12
12
12
on water bath two hours and evaporate in vacuum (or basify with KOH and
extract the oil with benzene and dry, evaporate in vacuum) to get about 11
g MDA. In this, as in the other syntheses, either the cis or trans (alpha
or beta) propenylbenzenes (or a mixture) may be used.
Amphetamines from Probenylbenzenes JMC 9,445(1966)
If the allyl isomer is at hand, it must first be converted to the
propenyl as follows (CJC 43,3437(1965)): Add equal weights of the allyl
compound and KOH flakes, and absolute ethanol and heat on steam bath or
reflux for twenty-four hours; dry and evaporate in vacuum or add two times
the volume of water and extract with ether or methylene chloride and dry,
evaporate in vacuum (recrystallize-hexane).
0.034M propenylbenzene in a mixture of 3.3 g pyridine and 41 g dry
acetone is cooled to 0 and 6.9 g tetranitro-methane added over one minute
with vigorous stirring, and stirring continued for two minutes. Add 2.2 g
KOH in 40 ml water, add more water and extract the nitropr pene with
methylene chloride and dry, evaporate in vacuum (recrystallize-methanol).
The nitropropenes (which seem to have little activity themselves) can be
reduced to the active amphetamines with lithium aluminum hydride or Zn-Hg
as described later, or reduced by another method (hydroboration,
hydrogenation, Na-ethanol, electrolytic, etc.).
Mescaline and Amphetamines from Styrenes and Propenylbenzenes
JACS 86,3565(1964)
The yield of mescaline should be about 50%; that for amphetamines
will vary. 0.1 M of ring substituted styrene or propenylbenzene in 30 ml
tetrahydrofuran in 1/2 L flask. Flush with N2 and add 33 ml 1 M borane in
tetrahydrofuran (see procedure below for preparation). Stir one hour, add 3
ml water and 50 ml 3N NaOH, and then 215 ml 0.31 M fresh chloramine
solution (prepared by treating dilute aqueous NH4OH with Na hypochlorite at
O; see BER 40,4586 (1907)). Keep at room temperature one hour, acidify
with HCl, extract with ether, basify with NaOH and extract with ether and
dry, evaporate in vacuum (or just basify and extract with ether and dry,
evaporate in vacuum) to get the amine. To prepare the diborane in
tetrahydrofuran, add 0.3 M NaBH4 (or LiBH4) and 0.4 M BF3 in total 200 ml
tetrahydrofuran and keep dry in refrigerator, or generate the diborane in
the reaction flask as follows: To a well-stirred suspension of 3.4 g NaBH4
in 150 ml tetrahydrofuran and 0.3M of the styrene or propenylbenzene, add
over one hour at room temperature, 15.1 ml BF3 in ether in 20 ml
tetrahydrofuran (keep temperature at room temperature); let stand one hour
at room temperature and decompose the excess hydride with water; then add
the NaOH and chloramine (or hydroxyl-amino-O-sulfonic acid) and proceed as
above to get the amine.
Other references on organoboranes: JACS 82,4710( 1960),
88,5853(1966), Org. Reactions 13,28(1963). Amines from Alkenylbenzenes by
Aminoboration BSC 2668 (1973)
Styrenes will give phenethylamines, 1-propenylbenzenes will give
amphetamines. The tetrahydrofuran should be dried over KOH pellets and, if
desired, distilled from sodium then from lithium aluminum hydride. The
diglyme can be vacuum distilled from calcium hydride and stored with
calcium hydride. Hydroxylamine-O-sulfonic acid can be purchased or prepared
(LAC 702,131 (1967); Inorg. Synth. 5,122(1957)). To a 3-necked flask
flushed with a nitrogen stream add 0.096M styrene or 1-propenylbenzene in
200 ml diglyme, and then a solution of 1.52 g (0.04M) NaBH4 in 70 ml
diglyme. Keep the temperature at 25 and add with stirring over 1/2 hour
7.3 g (0.052M) 48% BF3 etherate. Let temperature rise over 3 hours and then
reflux 3 hours. Cool and carefully add 11.86 g (0.105M)
hydroxylamine-O-sulfonic acid dissolved in 50 ml diglyme. Reflux 3 hours,
cool and take up in 10% HCl. Extract with ether, basify the cold acid phase
with excess NaOH, extract with chloroform, and dry, evaporate in vacuum to
get about 40% yield of the amine.
Amphetamines from Phenylacetates CA 35,5868(1941)
Add 0.44 moles ring substituted phenylacetate, 100 g acetic
anhydride and 30 g sodium acetate and heat at 145-150 for 18 hours to get
ca. 0.4 moles of the methyl-phenylacetate (I). Add (I) and formamide (or
N-methyl-formamide for the N-methyl cpd.), heat 4-5 hours at 180-195, cool
and extract with CHCl3. Evaporate in vacuum, dissolve residue in 40%
sulfuric acid and heat at 90-125 for 5-6 hours. Neutralize and add solid
NaOH to precipitate about 50% amphetamine. Treat with 10% sulfuric acid
to get the sulfate.
Amphetamines from Phenylacetones CA 61,6953(1964)
Exemplified for 2,4,5-trimethoxyamphetamine (I) preparation. Mix 25
g 2,4,5-trimethoxyphenylacetone, 9.3 g hydroxyl-amine-HCl, 15.6 g K-acetate
and 400 ml 70% ethanol and reflux 3 1/2 hours. Evaporate in vacuum and
extract the residue with 4x150 ml benzene. Wash combined extracts with 2x75
ml water; dry and evaporate in vacuum the benzene (can purify the oil by
dissolving in benzene and precipitate by adding petroleum ether) to get out
20 g precipitate (test for activity). Dissolve 18.1 g precipitate in 200 ml
methanol and hydrogenate. Acidify to get about 15 g (I).
Amphetamines from Propenylbenzenes
J. Prakt. Chem. 137,345, 138,271(1933), JACS 54,273(1932)
Illustrated for 2,4,5-trimethoxyamphetamine (I) preparation. Add a
saturated solution of 40 g Na nitrite to 10 g asarone in 90 ml ether. Add
dropwise over four hours 75 ml 20% sulfuric acid with stirring. Let stand
eight hours; filter and wash precipitate with water, ether, ethanol, and
dry. Dissolve 10 g precipitate in 60 ml 8% K carbonate in ethanol with
stirring and gentle (below 30) heating. Add 150 g ice, acidify with 100 ml
dilute HCl and let stand one-half hour at O. Filter, wash with water and
dry to get about 7 g yellow crystals (recrystallize-methanol)
(2-nitropropenylbenzene). Add 4 g crystals to 100 ml ethanol and 50 ml
glacial acetic acid; then add 10 ml concentrated HCl or 50 ml concentrated
sulfuric acid for the catholyte in a 40 cm2 Hg-cathode in a porous cell
surrounded by 3N sulfuric acid anolyte with a water cooled lead anode and
reduce at 4 amps (about 0.07 amps/cm2 cathode surface) at 30-40 for twenty
hours or until solution is colorless. Evaporate in vacuum to about 20 ml;
cool with ice, basify with NaOH and extract with ether. Wash, dry and
dilute the ether (or dry, evaporate in vacuum) to get (I).
Note that this provides an alternative to tetranitromethane for
nitration of propenylbenzenes, and an alternative to lithium aluminum
hydride or Zn-Hg for reduction of nitropropenes.
Amphetamines from Bromobenzenes JACS 63,602(1941)
0.2 M p-methoxy (or other group)-Br-benzene (see this paper for
preparation) and 4.6 g Mg. Rapidly add 18.5 g chloroacetone in 50 ml ether.
Evaporate the ether by heating in oil bath and then at about 135 for one
hour. Cool and add ice and dilute HCl; extract the oil with ether and dry,
evaporate in vacuum to get about 11 g product (can distill 106/18). 0.057 M
occasionally until all acid dissolves. Add 89g (67 ml) dimethyl sulfate,
shake twenty minutes, releasing pressure occasionally, and cool to keep
temperature below 30. Again add 89 g dimethyl sulfate and shake ten
minutes. Reflux two hours, add 20 g NaOH in 30 ml water and reflux two
hours more. Cool, acidify with HCl; filter and wash with water to get 50 g
3,4,5-trimethoxybenzoic acid (recrystallize-2 L hot water) (can recover
more by concentrating the filtrate).
A. Do a Fisher esterification by refluxing 100 g
3,4,5-trimethoxybenzoic acid in ethanol with concentrated sulfuric acid for
several hours. Cool, filter, to get the ester (I) (recrystallize-ethanol).
A. (Alternative) 100 g 3,4,5-trimethoxybenzoic acid, 20 g NaOH, 55g
NaHCO3 and 300 ml water and add with stirring 94 ml methyl or ethyl sulfate
over twenty minutes and reflux one-half hour. Cool, filter, dissolve the
precipitate in a small amount hot methanol or ethanol and cool to
precipitate (I) (acidify the filtrate to recover unreacted
trimethoxybenzoic acid).
B. 1 M (I), 10 M NaBH4; dissolve in methanol, reflux four hours and
filter, dry and evaporate in vacuum to get 3,4,5-trimethoxybenzyl alcohol
(II).
B. (Alternative) To 4.6 g lithium
add over one-half hour a solution of 23 g
50 ml ice water; decant the ether and add
acid. Extract with 3x50 ml ether and dry,
135-137/0.25) to get (II).
acetic acid, 16 ml sulfuric acid and 25 ml water and reflux 5 hours. Decant
from the small amount of tar formed with stirring into 850 ml water.
Filter, wash the precipitate with water and heat the precipitate with 225
ml 5% aqueous NaOH. Filter and acidify the filtrate with dilute HCl to give
about 80% yield of the substituted phenylacetic acid (II). Mix about 21 g
(II) and 25 g phosphorus pentachloride (caution), and after the initial
reaction subsides, warm on the steam bath 10 minutes. Distill under reduced
pressure to remove the POCl and gradually add the residue to ice cold
concentrated NH4OH. Filter, wash precipitate with water and air dry (can
recrystallize from benzene with a little ethanol added) to get about 18 g
(85%) of the substituted phenyl-acetamide (II). (III) may be reduced by
various means such as the following. To a stirred suspension of 8.6 g
lithium aluminum hydride in 500 ml dry ether add a solution of 10 g (III)
in 600 ml boiling reagent benzene, adding additional hot benzene to
redissolve any precipitate. Stir and reflux for 22 hours and then hydrolyze
by adding water cautiously and 10% sulfuric acid. Filter, heat the
precipitate with concentrated HCl to dissolve and cool to preicipitate the
substituted phenethylamine.
Phenylethylamines from Benzaldehydes
Indian J. Chem. 5,471 (1967), JMC 11,534( 1968)
A. 0.02 M substituted benzaldehyde, 27 g acetic anhydride,12 g
fused K acetate in 250 ml round bottom flask with air condenser and CaCl2
tube. Heat on oil bath at 160 one hour and then at 175 for four hours.
Pour into water (neutralize with Na carbonate and steam distill to recover
unreacted aldehyde), cool, acidify and filter to get about 60% yield
substituted cinnamic acid (I).
B. Dissolve 10 g (I) in 100 ml water containing 10% NaOH and add
with stirring, 300 g 3% Na-Hg portionwise at intervals of one hour and stir
for ten hours. Filter, concentrate to one-half volume and acidify to
precipitate the hydrocinnamic acid (II) in about 50% yield.
C. 10 g (ll) and 15 g SOCl2 are refluxed on water bath two hours
and evaporated in vacuum on water bath. Pour residue into cold liquid NH3
or NH4OH with stirring. Filter, wash precipitate with water to get about
80% yield substituted hydrocinnamamide (III) (recrystallize-benzene or
dilute ethanol).
C. (Alternative) To O.1M ethyl-chloroformate in 100 ml CHCl3 at
-30 add a cold solution of 0.1 M (Il) and 0.1 M triethylamine in 100 ml
CHCl3 over forty minutes. Stir 1 1/2 hours at -20 to 5 and bubble NH3
through the cold mixture for twenty minutes. Stir one-half hour at room
temperature, filter and extract the solid with CHCl3. Combine CHCl3
extracts and filtrate and wash two times with cold NaOH solution and two
times with water. Dry and evaporate in vacuum to get (III).
D. Pass the chlorine from 3 g KMnO4 and excess HCl into 120 ml 10%
NaOH to make a solution of hypochlorite (Clorox may do). Add 10 g finely
powdered (III) and stir to dissolve amide, while warming to 50. Heat one
hour at 85, add 30 g KOH and heat two hours. Separate the oil and extract
the aqueous layer with ether. Add ether to oil and dry, evaporate in vacuum
to get the substituted phenylethylamine (IV).
D. (Alternative) To a stirred and cooled solution of 0.1 M NaOH in
100 ml water at -5 add 0.04 M bromine over five minutes and stir one-half
hour at 0. Add 0.02 M (III) and stir 1 1/2 hours at 0-5. Stir sixteen
hours at room temperature and 70 for one hour. Cool and extract with
ether, dry and evaporate in vacuum to get (IV).
-40 and add over ten minutes with stirring 5 ml tertiary butyl nitrite in
20 ml tetrahydrofuran (temperature rises to about 10). Evaporate in vacuum
and dissolve the yellow oil in 100 ml ethyl acetate. Wash with 50 ml NaCl
containing 1% NaHCO3 and dry, evaporate in vacuum to get the azide.
Dissolve the azide in 50 ml toluene and heat at 100 until N2 evolution
stops (about thirty minutes). Add 10 ml ethanol and reflux two hours.
Evaporate (room temperature/15) to get 4 g 5-(ethoxy-carbonylamino)methyl-3-methoxy-isoxazole (VII) (can distill 129/0.2). Test for
psychedelic activity. Dissolve 4 g (VII) and 2.5 g KOH in 12 ml ethanol and
reflux eight hours. Dissolve in 20 ml water, acidify with dilute HCl and
evaporate to dryness. Dissolve residue in hot ethanol and evaporate to get
3 g 5-aminomethyl-3-methoxy-isoxazole (VIII). Test for activity. 1 g (VIII)
in 10 ml glacial acetic acid and 4.5 g HBr and reflux one hour. Evaporate
in vacuum to get muscimole.
Method 2 JACS 62,1147( 1940), TL 2077( 1963), CA 65,2267 (1966)
Pass chlorine gas into an ice cold, well-stirred solution of 5 ml
acetylketene in 30 ml CCl4 until there is a 4.5 g increase in weight
(solution is slightly yellow). Pour slowly into excess methanol or ethanol
at 0 and distill at 118/17 to get 6 ml methyl (or ethyl)-4-Cl-acetoacetate
(I). To 2.7 ml methanol saturated with dry HCl at 0, add a mixture of 10 g
(I), 20 g methyl orthoformate (trimethoxymethane) and 13 g methanol and
reflux four hours. Pour hot into 200 ml ice water and adjust pH to 8 with
30% NaOH. Extract four times with ether and evaporate and distill to get
methyl (or ethyl)-4-Cl-3,3-dimethoxy-butyrate (II). Dissolve 40 g (II) in
20 ml methanol and add hydroxylamine-HCl in methanol. After ninety-six
hours at room temperature (under N2 if possible), evaporate in vacuum. Can
purify the residue by dissolving in water and put on anionic column; wash
column to neutrality and elute with 2N acetic acid; just before the acid
elutes, the alkaline fraction giving a positive FeCl3 test appears;
evaporate in vacuum this fraction below 40 and dry at 40/0.5 for twelve
hours. Dissolve 5 g product in 130 ml glacial acetic acid and saturate at
room temperature, then at O with dry HCl. Let stand sixteen hours at room
temperature and evaporate in vacuum at 40C. Dilute with water and
evaporate three times. Extract with 2x130 ml hot ether and filter,
evaporate in vacuum to get 3-Cl-methyl-5-OH-isoxazole (III) (recrystallize
in acetone). Heat (III) sixteen hours at 90 in concentrated NH4OH in
autoclave and evaporate to get muscimole.
Method 3 GCI 91,61 (1961), JCS 172(1968)
To 1 g 3-CI-5-methyl-isoxazole in 14 ml 1.4 N NaOH add with
stirring 1.1 g KMnO4 in 20 ml water. Filter, decolorize with NaHSO3 and
acidify with dilute sulfuric acid. Extract with ether and dry, evaporate in
vacuum to get 0.8 g 3-Cl-isoxazole-5-COOH (I). To 2.5 g (I) in 7.5 ml water
add 15 g KOH in 43 ml methanol and reflux four hours (under N2 if
possible). Cool, acidify with concentrated HCl and extract with ether five
times. Dry and evaporate in vacuum to get 2 g oil which precipitates to
give 3-methoxy-isoxazole-5-COOH (11). Dissolve 5.2 g (ll) in 100 ml 3% HCl
in methanol and reflux three hours. Evaporate in vacuum and
recrystallize-petroleum ether (or dissolve residual oil in ether, wash with
NaHCO3 and dry, evaporate in vacuum) to get the methyl ester (III). Add
with stirring 0.8 g (III) to 40 ml aqueous NH3 (density about 0.88) and
stir thirty minutes at room temperature. Filter, wash with cold water and
dry to get 0.5 g 3-methoxy-isoxazole-5-carboxamide (IV). Dissolve 37.8 g
NaBH4 in 100 ml diglyme (dimethyl ester of diethylene glycol) and 23 ml BF3
etherate in diglyme; add to 4.6 g (IV) in 100 ml tetrahydrofuran and reflux
forty-eight hours. Add HCl, evaporate in vacuum and dissolve residue in
water. Basify with 50% KOH and extract with ether. Dry, filter, evaporate
-------------------------------------------------------------------------LSD
Since Hofmann's first trip in 1943, great deal of interest has been
generated in the occurrence and properties of various lysergic acid
derivatives. Fungi of the genus Claviceps, which grow on rye wheat, rice
and other grasses, were the first natural source of these alkaloids to be
discovered. In recent years related compounds have been found in the genera
Penicillium (the blue-green mold that also produces penicillin),
Aspergillus, and Rhizobus (the black bread mold). These compounds are now
produced commercially by culturing certain strains of Clavicebs which
produce as much as 4 g of ergotamine per Liter of culture medium. Growing
pure cultures of fungi is not for amateurs, but those interested will find
these references useful: JPS 58,143(1969); App. Microbiol. 18,464 (1969);
HCA 47,1052(1964); Lloydia 32,327,401(1969); Can. J. Microbiol.
16,923(1970); CA 61,15314c-f, 67,84858e, 69, 36323w; Biotech. Bioeng.
13,331(1971); CA 76,57736(1972); U.S. Patent 3,483,086; Planta Med.
23,330(1973); J. Pharm. Educ. 36,598(1972); CA 78,41492(1973); French
Patent 1,531, 205; German Patents 1,806,984 and 1,909,216; British Patent
1,158,380.
For a description of a wild American Claviceps species see
Mycologia 66,978(1974).
The occurrence of hallucinogens in the seeds (and to a lesser
degree in the leaves and stems) of various members of the family
Convolvulaceae (morning glories, etc.) was known to the Aztecs. Seeds of
the genera Rivea, Impomoea, and Argyria (Hawaiian baby woodrose) contain
lysergic acid derivatives; the woodrose being champion with about one
hundred times as much as the other genera (about 7 mg alkaloids/g seeds).
In view of the low yield (maximum 10 mg alkaloids/ 100 g seeds) even the
famed pearly gates variety of morning glory is not worthwhile extracting,
and the trip is commonly a bummer, resembling that produced by scopolamine
or ibogaline and unlike that of LSD. However, the lysergic acid amide,
etc., can be extracted, hydrolyzed to lysergic acid (as described below for
ergot alkaloid hydrolysis), and converted to LSD by any of the methods
described. For species variation of alkaloid content see Lloydia
29,35(1966). Crude ergot or woodrose seeds should yield ca. 1 g LSD/kg
after conversion of the isolated alkaloids.
Alkaloid Extraction (short method)
Finely grind seeds (preferably woodrose) and add NaHCO3. Extract
with ethyl acetate by soaking about one day. Filter and extract the ethyl
acetate with tartaric acid solution. Basify the extract with NaHCO3 and
extract it with ethyl acetate. Dry and evaporate in vacuum the ethyl
acetate to get the alkaloids. Repeat this procedure on the seeds until no
more residue is obtained.
Alternatively, add 100 ml petroleum ether to 100 g finely ground
seeds and let soak about two days. Filter, discard petroleum ether and let
seeds dry. Add 100 ml methanol to the seeds and let soak about two days.
Filter, repeat extraction with another 100 ml methanol and evaporate in
vacuum the combined methanol extracts. The residual yellow oil contains the
alkaloids.
For chromatographic purification of
extracts see Phytochem. 11,1479( 1972). For
see also Fr. Patent 2,089,081 (11 Feb 1972)
recent review of the ergot alkaloids see R.
vol. 15: 1-40(1975).
After ten days adjust the cultures to 1% ethanol using 95% ethanol under
sterile conditions. Maintain growth for another two weeks. After a total of
24 days growth period the culture should be considered mature. Make the
culture acidic with tartaric acid and homogenize in a blender for one hour.
Adjust to pH 9 with ammonium hydroxide and extract with benzene or
chloroform/iso-butanol mixture. Extract again with alcoholic tartaric acid
and evaporate in a vacuum to dryness. The dry material is the salt (i.e.,
the tartaric acid salt, the tartrate) of the ergot alkaloids, and is stored
in this form because the free basic material is too unstable and decomposes
readily in the presence of light, heat, moisture and air. To recover the
free base for extraction of the amide or synthesis to LSD, make the
tartrate basic with ammonia to pH 9, extract with chloroform and evaporate
in vacuo. If no source of pure Claviceps purpurea fungus can be found, it
may be necessary to make a field trip to obtain the ergot growths from rye
or other cereal grasses. Rye grass is by far the best choice. The ergot
will appear as a blackish growth on the tops of the rye where the seeds
are. They are approximately the same shape as the seeds and are referred to
as "heads of ergot." From these heads of ergot sprout the Claviceps
purpurea fungi. They have long stems with bulbous heads when seen under a
strong glass or microscope. It is these that must be removed from the
ergot, free from contamination, and used to inoculate the culture media.
The need for absolute sterility cannot be overstressed. Consult any
elementary text on bacteriology for the correct equipment and procedures.
Avoid prolonged contact with ergot compounds, as they are poisonous and can
be fatal.
LSD Identification
Since LSD is an indole derivative, it gives a positive reaction
(violet color) to the tests given in the indole section. LSD also
fluoresces under an ultraviolet light (black light), but so do many other
compounds. For infrared spectra of LSD and related compounds, see JACS
78,3087(1956) and J. Forensic Sci.12,538 (1967). For other information on
identification see JPS 56,1526 (1967) and JAOAC 50,1362(1967),
51,1318(1968). For a microcrystalloscopic test see J. Pharm. Pharmacol.
22,839(1970). In order to make LSD, lysergic acid is needed. This can
sometimes be obtained, but generally one of the lysergic acid containing
ergot alkaloids such as ergotamine is more readily available. Ergot is the
dried sclerotium of various species of fungi which infect rye (and other
grasses), leading to the formation of large purple growths in place of the
rye grains. These growths are collected, dried, powdered and the alkaloids
extracted. For the extraction procedure see HCA 28,1283(1945), J. Pharm.
Pharmacol. 7,1 (1955), JPS 50,201(1961), CA 75,137422(1971). Proc. Indian
Acad. Sci. 71B,28,33(1970) gives production from artificially infected rye.
Ergot is produced mainly in Europe (especially Switzerland) but some has
been grown in the USA (e.g., in Minnesota). This production occurs
primarily because of the use of ergotamine and related compounds in
medicine (contracting the post-partum uterus, terminating
migraineheadaches, etc.). Many of the ergot alkaloids are derivatives
(amides) of lysergic acid. Unfortunately, these compounds have little
hallucinogenic activity and it is necessary to hydrolyze (split with water)
off the amide, producing lysergic acid, and to synthesize a different amide
with greater psychedelic activity. This hydrolysis can be done with any of
the following compounds or a mixture of them: ergometrine, ergine,
ergotamine, ergosine, ergocristine, ergokryptine, ergonovine (ergometrine) and methysergide (Sansert). When -ine is added to the name (e.g.,
ergotaminine) this indicates the isomers which will lead to the production
of the inactive iso-LSD. The papers cited here give simple techniques for
converting these to the active forms (or see the technique for converting
iso-LSD to LSD in method 1 following): HCA 37,820,2039(1954); CA
69,36322(1968); CCCC 34,694 (1969). For a review of the ergot alkaloids see
THE ALKALOIDS, Manske and Holmes (Eds.), 8,725(1965), and F. Bove, THE
STORY OF ERGOT (1970).
Ergot Alkaloid Hydrolysis
JBC 104,549(1934); HCA 47,1929(1964). Perhaps the best method is
Hofmann's modern hydrazine hydrolysis given later, since this disposes of
the necessity for isolating the lysergic acid (I); otherwise the following
alkaline hydrolysis can be used: Dissolve 20 g of the alkaloid (e.g.,
ergotamine) in 200 ml 1M KOH in methanol (i.e., dissolve 56 g KOH pellets
in 1L 100% methanol) in a 1 L heavy walled vacuum flask and evaporate in
vacuum the methanol at room temperature. To prevent the solution from
cooling, and thus greatly prolonging the evaporation time, put the flask in
a pan of water kept at room temperature by gentle heating or by running
warm water through it. Add 400 ml 8% KOH in water to the residue and boil
for one hour (under N2 if possible, this can be done by filling the flask
with a N2 stream and loosely stoppering or by allowing a gentle stream of
N2 to flow through during heating). Cool, acidify with dilute sulfuric acid
and shake in separatory funnel with 1 L ether. Discard the upper ether
layer and filter with vacuum the aqueous suspension of lysergic acid (I).
Wash precipitate with 20 ml dilute sulfuric acid. To recover the small
amount of (I) remaining in solution, basify with Na carbonate and bubble
C02 through it. Filter and add precipitate to first batch. Some isolysergic
acid will remain in solution and can be precipitated by adding 10% HNO3. It
can be converted to (I) by adding 3 ml 10% KOH for each 0.1 g acid, boiling
on steam bath for one hour under N2 (if possible) and precipitating by
acidifying with glacial acetic acid. Maximum yield is about 9 g (I) for 20
g ergotamine. A shorter method of hydrolysis which may work as well
follows: dissolve 20 g alkaloid in 300 ml methanol and 300 ml 40% KOH and
reflux two hours under N2 (if possible). Cool, saturate with CO2 and
evaporate in vacuum. Extract the residue with hot ethanol three times and
dry, evaporate in vacuum the combined ethanol extracts to get (I). Under
ordinary conditions, about 20% of (I) will be converted by the action of
hot water, etc., to the inactive isolysergic acid. Most of this remains in
solution and can be isomerized to (I) as described above, or it can be
converted to iso-LSD by any of the methods described later and isomerized
to LSD (see method 1). It is unnecessary to purify (I), but this can be
done as follows: dissolve 9 g (I) in 20 ml NH4OH, filter and concentrate in
vacuum at room temperature to precipitate (I). After filtering, the grey
crystals can be further purified by dissolving in boiling water and cooling
in ice bath to precipitate (I). Melting point should be about 240o
(decomposes). Alternatively, the dark-colored (I) resulting from hydrolysis
can be shaken with 2x400 ml 2 M NH4OH in ethanol, and the combined extracts
evaporated in vacuum to give (I). Dissolve the remaining residue in 500 ml
hot methanol, cool to 0 and filter out the (I) (recrystallize-water). Can
remove colored impurities by shaking solution with decolorizing carbon and
filtering. Recently a method for increasing the yield of (I) about 10%
using 2.5% hydrazine hydrate was described (CA 69,36323(1968)). Dissolve 7
g alkaloid in 200 ml 6 N KOH in methanol and 200 ml ethanol, add 10 ml
hydrazine hydrate and boil four hours under N2 (if possible) and proceed as
above. Finally, the (I) must be thoroughly dried by heating at about 110/1
mm for two hours or 150 if ordinary lab vacuum of 15 mm is used. A forced
water vacuum (about 25 mm) can be used here as elsewhere. An oil bath
(e.g., mineral oil) will allow temperature regulation.
LSD Synthesis
Dangers
There are certain aspects of LSD production which are common to all
synthetic methods. The first is a certain degree of danger; each uses
dangerous reagents and solvents. Hydrazine and hydrazine hydrate are both
violent poisons, and each can cause severe skin burns and eye damage. The
vapor of each is irritating, and can cause severe eye irritation as well as
liver and blood damage, but the symptoms don't always manifest right away,
sometimes appearing three or four days after exposure, so it is easy for
exposure to be much more dangerous than is immediately realized. In
addition, anhydrous hydrazine is a sensitive and violent explosive, the
explosion of which can be set off by certain types of stainless steel and
such common things as wood and rust. Both trifluoroacetic acid and sulfur
trioxide will cause very severe skin burns, and their vapors are extremely
irritating. Sulfur trioxide is such a strong dehydrating agent that it
chars organic material, and its heat of dehydration is so high that it will
start a fire if spilled on wood, which could prove fatal were flammable
solvents in use at the time or stored nearby. Phosgene is very poisonous;
so insidious that it was used as a war gas in World War I. One deep breath
can cause immediate collapse and death, and as it is not irritating there
is no gag reflex to prevent one from taking that deep breath. Doses which
are not high enough to be immediately lethal may not be noticed at all at
the time of exposure, yet lead to death within 24 hours. Sub-lethal doses
cause pulmonary edema and serious respiratory disability; again, the
symptoms can appear well after an exposure which was hardly noticed.
Diethylamine, used in every LSD synthesis, has a very low flash point, and
its vapor is irritating. The vapor of DMF is also irritating, and prolonged
exposure can cause liver damage. In fact, most of the solvents used in LSD
production are either flammable or toxic or both. In addition to all the
above, the starting material, the ergot alkaloids, is as a class quite
toxic, and clean working conditions are necessary when working with it.
Ergot alkaloid poisoning, known in the Middle Ages as Saint Antony's fire,
can actually cause one's limbs to blacken, shrivel, and fall off! Any woman
working with these compounds should also be aware that many of them are
oxytoxics, that is, they cause uterine contractions, and are so used to
induce labor, etc.
Working Conditions
There are certain procedures common to all syntheses of LSD which are based
upon the sensitive nature of ergot compounds in general. Natural ergot
alkaloids, lysergic acid, LSD, and the intermediate products associated
with the various syntheses are all to a varying degree unstable. Even the
most stable of these compounds will readily decompose under any but
moderate conditions. Thus precautions must be taken against light,
moisture, oxygen, and heat. Light of the ultraviolet region promotes
addition of water at the delta-9-10 double bond to form the lumi-compounds.
Thus reactions are best carried out in the light of red or yellow
photographic darkroom bulbs, and storage should be in opaque or amber
bottles. Most of the reactions involved in LSD synthesis require anhydrous
conditions for good yield, and so protection must be made against moisture
during the actual production. Furthermore, the final product must be
thoroughly dried to prevent possible formation during storage of the
lumi-compounds as mentioned above. Oxidizing agents, including atmospheric
oxygen, will decompose ergot compounds. For this reason, all reactions are
carried out in an atmosphere of an inert gas such as nitrogen. The danger
of oxidation increases with temperature, so this precaution is of course
most important with those reactions proceeding at elevated temperature.
Various methods have been devised to prevent oxidation during storage. The
most obvious is to store the LSD in nitrogen filled containers, but the
excellent protection thus afforded is of course lost when the bottle or
ampule is opened. Another method is to use an antioxidant; Brown and Smith
pyrazole (II) and wash with water. Can purify by drying in vacuum at 60C
and recrystallizing from chloroform by the addition of ether. Heat 0.4 g
(ll) and 2.5 ml DEA at 100 C for 2 hours (or let stand 15 hours at room
temperature, evaporate to dryness and heat a few minutes at 100C in
vacuum). Can recrystallize from CHCl3, petroleum ether or as described
elsewhere here.
Technical Scale Details For This Method // Hydrazide Production
In dim yellow light, (preferably) three tared and fully dried 250
ml round-bottom flasks containing stirring bars are each charged with 30 g
dry ergotamine tartrate and 120 ml anhydrous hydrazine. The flasks are
fitted with gas inlet tubes adjusted to just above the liquid level and
streams of nitrogen passed through, the exhaust gas being led through wash
bottles equipped with traps and containing dilute acid to remove hydrazine
vapors. The flasks are lowered into oil baths preheated to 90C, and heated
with slow stirring for one hour. The contents of the three reaction flasks
are then emptied into a 2000 ml beaker containing 900 ml distilled water,
and this solution transferred to a 3000 ml two-neck round bottom flask. An
additional 900 ml water is used to rinse the residue in the flasks, beaker,
etc. into the 3000 ml flask. This large flask is fitted with siphon tube,
gas inlet tube, and gas outlet connected to wash bottle and trap.
The aqueous hydrazide solution is evaporated from a tared 2000 ml
flask on an efficient rotary evaporator, using a bath temperature of 40C
and an ice-cooled condenser; the 3000 ml siphon flask assembly is used as
storage for the vacuum feed. The weight of the crude hydrazide so obtained
is determined, it is dissolved in about 170 ml 1 N tartaric acid, the
aqueous solution washed with three 30 ml portions ether, made alkaline with
190 ml 1 N ammonium hydroxide, and exhaustively extracted with successive
portions of chloroform, the first two portions being 100 ml each, the
following 50 ml.
Completeness is ensured by testing with UV light, extraction
ceasing only when the chloroform extract exhibits no blue fluorescence. The
chloroform solution is washed with three 30 ml portions distilled water,
dried over chloroform moistened magnesium sulfate, and the hydrazide
recovered by vacuum evaporation in tared 500 ml flasks, one such flask
being used for each two 90 g batches. These flasks are flushed with
nitrogen, stoppered, and stored in a dark and dry refrigerator. As the
hydrazide is stable, all the ergotamine tartrate will be converted to it
prior to the next step. Theoretical yield from 1000 g ergotamine tartrate
is 429.65 g; 80% yield is 343 g.
Pyrazole Production
In dim red light, the weighed hydrazide contained in one of the 500
ml flasks (ca. 67 g; 95% of theory) is washed into a 1000 ml beaker with
263 ml 1N hydrochloric acid. 239 ml distilled water, 239 ml ethanol (95%),
and 37 ml 2,4-pentanedione are added, and the well-mixed solution left to
stand in the dark at room temperature until the reaction is complete, i.e.,
about 30 minutes. The reaction mixture is neutralized with the addition of
263 ml 1 N sodium hydroxide, and the beaker covered with parafilm and
refrigerated to ensure complete precipitation. The pyrazole is filtered at
the pump, the mother liquor being returned to the beaker and used to wash
out the last few crystals, washed with cold water, and sucked dry under a
stream of dry nitrogen. The product is dried in vacuo over barium oxide or
phosphorus pentoxide for at least twelve hours before proceeding to the
next step, wherein anhydrous conditions will increase yield. Hofmann calls
for drying the pyrazole in vacuo at 60C, which indicated the product to be
fairly stable. So all the hydrazide is converted prior to aminization.
Amide Production
In dim red light, 50 g of the well-dried pyrazole and 700 ml
freshly dried diethylamine are placed in a tared and well-dried 1500 ml
flask equipped with gas inlet tube and stirring bar. The flask is lowered
into a bath preheated to 45C, and the contents stirred under a stream of
nitrogen for four hours. On a rotary evaporator, using a 6 atm temperature
of 40C and an ice-cooled condenser, the diethylamine is removed in vacuo
and set aside for purification and re-use. Briefly and in high vacuum the
flask is heated to 100C, the split-off pyrazole being thereby driven off.
The residue so obtained is immediately placed in solution with
methanolic potassium hydroxide to effect interconversion of the
stereoisomers. Amination and Transposition will proceed simultaneously, the
first batch being transposed while the second is aminated.
Production Scale Isomerization of iso-LSD to LSD
In dim red light, the amide residue from the last step is dissolved
in the least possible amount of dry methanol and washed into a 1500 ml
round-bottom flask. A two-fold volume of 4 N methanolic potassium hydroxide
is added, and the well-mixed solution left to stand at room temperature, in
the dark and under a slow stream of nitrogen, for four hours. At the end of
this period, the solution is neutralized with methanolic hydrogen chloride
(ca. 5 N), washed into a 4000 ml Erlenmeyer flask, and dried over
methanol-moistened anhydrous magnesium sulfate (0.10 g MgSO4 per ml KOH
solution). The methanolic acid should be added slowly and with good
stirring to prevent possible hydration of the 9-10 double bond to give
lumi-LSD. Together with 100 ml dry isopropanol (to remove the last trace of
water azeotropicly) the dried solution is transfered to a 3000 ml siphon
flask assembly, and the solvent removed in vacuo in a tared 500 ml two-part
freeze-dry flask. The weighed gummy residue is scraped into the thimble of
a Soxhlet extractor, the adhering residue being washed into the thimble
with portions of warm chloroform, the total volume of which is 12.5 ml per
gram amide (total weight minus weight KCl). A 3000 ml flask is used with
the extracter, and it is previously charged with 37.5 ml dry benzene per
gram amide. Under a stream of dry nitrogen, the solvent is in vacuo at 40C
refluxed through the thimble, thus extracting the amide from the inorganic
salt and at the same time preparing the solution for use in the
chromatographic separation of the stereoisomers. The above solution is
stored over a small amount of benzene-moistened calcium sulfate in a
nitrogen flushed flask which is placed in a dark refrigerator. All the
pyrazole is converted to this benzene-chloroform solution prior to
separation of the isomers.
The following methods all proceed from lysergic acid (I). Methods
1, 2, 4, and 6 give less than 20% iso-LSD in the product but methods 2, 5,
and 9 seem to have the highest total yield (about 80%) of LSD plus iso-LSD.
Since unreacted lysergic acid can be recovered and run through the
synthesis again, and iso-LSD isomerized to LSD as described here, it is
probably best to use the simplest methods. These comparative yields come
mostly from the reference to method 9.
From Lysergic Acid - Method 1 CA 50,10803d( 1956) (Pioch)
Dissolve 5.3 g dry (I) in 125 ml acetonitrile (or dimethylformamide
or proprionitrile) and cool to -20 (freezer or dry ice-acetone or ethanol
mixture). Add 8.82 g trifluoroacetic anhydride in 75 ml acetonitrile cooled
to -20 carefully. Let stand at -20 1 1/2 hours or until all the (I)
dissolves. Then add 7.6 g DEA in 150 ml acetonitrile and let stand at room
temperature in dark two hours. Evaporate in vacuum to get LSD. If
pipette. The aliquot is run into a 250 ml Erlenmeyer flask and diluted with
10 ml water to decompose the complex. The mixture is then titrated to a
phenolpthalein endpoint with a standard base solution. A convenient
standard base solution can be made by dissolving 1 mole of lithium
hydroxide hydrate (41.96 gr) in distilled water to make one liter in a
volumetric flask. Three consecutive titrations should be done and an
average taken. One mole of sulfur trioxide reacts with two moles of lithium
hydroxide. The reagent bottle should be labeled as to sulfur trioxide
concentration (about 1.5 molar) and the temperature at which the
concentration was determined since the reagent has a rather high
coefficient of expansion.
If at any time during the distillation of the sulfur trioxide,
crystals of solid sulfur trioxide form in the condenser or receiving flask,
they may be melted by careful local heating with a propane torch flame or
by running hot water through the condenser jacket. The water in the
condenser should be above 23C during distillation of sulfur trioxide to
prevent crystallization of sulfur trioxide polymers.
5. Notes on changing the scale of reactions:
The ergotamine to lysergic acid reaction may be scaled up or down
by multiplying the quantities involved by a proportionality constant: all
quantities should be multiplied by the same constant. It has been found
that the quantities of water and potassium hydroxide used in the hydrolysis
of ergotamine are not particularly critical and their relative
concentrations may be varied somewhat to meet other considerations. As a
rule, ergotamine should be hydrolysed with about a 1.5 to 2.5 molar
potassium hydroxide solution.
The lysergic acid to lysergic acid amide reaction has been designed
to utilize minimal quantities of solvents in order to squeeze as much
material as possible into ordinary laboratory glassware.
Some workers have suggested that the quantity of dichloromethane
(or chloroform) can be further reduced and still effectively extract the
amide, but this may prove difficult, especially if emulsions are
encountered. When scaling down the reaction, if desired, the quantities of
methanol, dimethylformamide, saline solution, and dichloromethane may be in
greater quantity than calculated by direct proportion to the other
reagents. The proportional relationship between lysergic acid, lithium
hydroxide and sulfur trioxide must be strictly adhered to. The molar
proportions are: lysergic acid, 1 mole; lithium hydroxide, 1 mole; sulfur
trioxide, 2 moles. Diethylamine should be added in at least five molar
equivalents. 6.5 equivalents are used in the example given. In general, two
thirds of the dimethylformamide should be distilled off from the
lithiumlysergate solution. It is convenient to do the reaction in a small
quantity of dimethylformamide if doing large quantities of lysergic acid
since the product is contained in smaller volume and extraction may be done
with less solvent.
6. Notes on purification of amide
The chromatography detailed in the example has been used and works
fairly well, however, the removal of all colored impurities is not achieved
and there is room for improvement. It is suggested that further
experimentation be done to improve the process. An ultraviolet light is
indispensable when doing experimentation with these compounds. The lysergic
acid amide displays a blue fluorescence. Benzene has been used successfully
as an eluant on activity 4 alumina, but the results were no better than the
example given. Chloroform and chloroform-benzene mixtures also have been
used on varying grades of alumina but no useful data is available.
off-white powder.
N,N-Diethyllysergamide (LSD)
143.20 grams of lysergic acid monohydrate (0.5 mole) and 21.0 grams
of lithium hydroxide hydrate (0.5 mole) are dissolved in 2500 ml of
methanol with stirring and warming in a four liter beaker. When the
lysergic acid is completely dissolved, the contents of the beaker are
admitted to a rotary vacuum evaporator and taken to total dryness over a
boiling water bath. A little methanol is used to rinse any lysergate
residue that may remain in the beaker into the evaporator. The crumbly, tan
colored dry residue is dissolved and rinsed into a five liter boiling flask
with three liters of anhydrous dimethylformamide. Considerable care should
be exercised when transferring solutions from one vessel to another to
avoid loss of lysergate since small deviations from the calculated
quantities of reagents result in considerable reduction in overall yield.
The five liter flask is next fitted with a 600 mm helices packed
fractionating column and about 2050 ml of dimethylformamide is carefully
distilled off at 10.0 millimeters pressure to remove water from the
lysergate solution. The boiling flask containing lithium lysergate in the
remaining dimethylformamide is tightly stoppered and chilled in an ice
water bath to below 5C. 1.0 mole of sulfur trioxide is now added to the
flask by addition of the appropriate amount of sulfur
trioxide-dimethylformamide reagent (previously prepared by double
distilling sulfur trioxide from fuming sulfuric acid and slowly adding it
to anhydrous dimethylformamide to make a solution of approximately 1.5
molar strength as determined by titration against standard base solution).
Cooling and swirling are continued for 15 minutes when 335 ml of
diethylamine is added. Cooling and swirling are continued 15 minutes longer
when the reaction mixture is poured into 3800 ml of a 20% saline (sodium
chloride) solution to break the reaction complex. The reaction mixture is
now extracted with 10.0 to 12.0 liters of methylene chloride
(dichloromethane) or chloroform in divided portions in a separatory funnel.
A scheme for division of the extraction solvent is as follows:
Extract
Quantity
First
Second
third
Fourth
Fifth
Sixth
Seventh
Eighth
etc.
2000ml
1800
1500
1200
1000
1000
800
700
etc.
2000ml
3800
5300
6500
7500
8500
9300
10,000
etc.
dissolves completely. The beaker and contents are refrigerated for at least
four hours. Occasional stirring of the crystallizing solution will produce
smaller crystals, whereas if the solution is left unstirred during the
crystallization, larger crystals will grow. Either is satisfactory. After
the beaker has been allowed to stand in the cold four hours or more, the
contents are filtered off on a 110 mm buchner funnel with suction. The
crystals are washed on the funnel with first 200 ml of a two part
methanol:one part ether mixture, and then with 250 ml of a two part
ether:one part methanol mixture. Next the crystals are washed with 600 ml
of ether and sucked dry. The filter cake is broken up and allowed to air
dry in a warm, dark place.
First crop yield: Approximately 80 grams pale yellow to white needles.
The mother liquors and the two washes containing methanol are
collected and combined. A one normal solution of potassium hydroxide in
methanol is added in approximately equal volume to the combined washes and
mother liquors. The solution is then filtered and the filter washed with a
few ml of methanol. The filtrates are allowed to stand at room temperature
for two to three hours to re-equilibrate the iso-lysergic acid amides from
the mother liquors. About 500 ml of water is then added and the mixture
extracted with 2.5 liters of methylene chloride in divided portions in a
separatory funnel. The combined extracts are shaken with 25 grams of
anhydrous magnesium sulfate and filtered. The filtrate is taken to dryness
on the rotary vacuum evaporator, care taken not to heat above 55C. The
material is purified in the same manner as that from the original reaction
mixture using approximately one fourth the quantities of solvents and
alumina as for the original.
Second crop yield: Approximately 20 grams white needles.
The mother liquors may again be worked up as before, or
alternatively, they may be saved and included in subsequent batches.
Third crop yield: Approximately 5 grams white needles.
Total yield: Approximately 105 grams N,N-diethyllysergamide tartrate
MW = 430.51 (includes one mole methanol per mole of amide).
Method B
The residue from the previous step is taken up in two liters of
chloroform and filtered with suction through a column 50 millimeters in
diameter packed with 400 grams of basic alumina, Brockman activity 1. The
filtrate is then refiltered through the same column in the same manner four
or five times until the filtrate appears light amber and further repetition
of this process fails to remove significant color from the filtrate. The
column is now eluted by adding several liters of fresh chloroform to the
top and sucking it through into the previous filtrate. Sufficient
chloroform should be added to remove all blue fluorescent material from the
column but not greenish or yellow (use a blacklight in a darkened room). A
band of greenish yellow material should remain in the upper 2/3 of the
column when viewed in ultraviolet light (blacklight). The total filtrate is
taken to dryness in vacuo in a three liter round bottom flask on a rotary
evaporator over a 60 hot water bath. The residue is taken up in 500 ml of
benzene and again taken to dryness in the same manner. 500 ml of benzene is
again added and taken to dryness. The flask is left on the evaporator under
full vacuum for a considerable length of time after the residue appears dry
to remove any traces of dimethylformamide that may still remain. A bubbly,
crystalline residue should fill the interior of the flask at the end of
this step. If any tarry, gummy appearing material appears to remain on the
sides of the flask, repeat the addition of 500 ml of benzene and evaporate
to dryness again to get a glassy, crystalline appearance. When the material
in the flask is totally dry, remove the flask from the evaporator and add
sufficient petroleum ether (a commercial mixture of hexanes is excellent
for this purpose) to the flask to be able to swirl the crysalline material
around and loosen it from the sides of the flask. Filter this slurry on the
buchner funnel with a fritted glass disk and use the filtrate to further
wash the remaining material from the evaporator flask into the buchner
funnel. Suck the material dry on the funnel and then place in a vacuum
dessicator and dry to a constant weight. Record the dry weight of this
material N. Calculate the weight of one equivalent of tartaric acid as
follows:
Weight of tartaric acid =.232N
Add methanol to a small beaker in a quantity equal to four times N
in milliliters. Dissolve the dried material of weight N in this. Dissolve
one equivalent of tartaric acid in the same solution, warming the solution
gently and stirring. Slowly with stirring, add ether to the solution in the
quantity of no greater than.5 N ml. Addition of ether causes a precipitate
which dissolves quickly. Ether should be added dropwise with stirring
between drops to dissolve any precipitate before addition of the next drop.
Crystallization of LSD tartrate should begin shortly after or during
addition of the ether. This precipitate does not dissolve and should not be
confused with the precipitate caused by the addition of ether. The mixture
should be stirred until the solution becomes thickened by formation of
crystals. Once crystallization of LSD tartrate is begun it is unnecessary
to continue addition of ether. The beaker should be refrigerated several
hours and the contents then filtered on a buchner funnel with a fritted
glass disk. The crystals are sucked dry and washed with 2.0 N milliters of
methanol previously chilled below -5C and then with 4 N milliliters of a
1:1 mixture of cold ether and methanol. The crystals are sucked completely
dry, washed with 8 N ml of ether, sucked dry, and placed in a vacuum
dessicator to remove last traces of solvent.
The total filtrates from the crystals (mother liquors plus
washings) are made basic by addition of 2 molar ammoniacal ethanol in
approximately equal volume and allowed to stand several days at room
temperature when the mixture is filtered and taken to dryness and treated
in the same manner as the residue from step 2 for a second crop of
crystals.
LSD Via SO3 Method 2
Lysergic Acid
Ergotamine tartrate (10g) is added to a stirred de-aerated
(nitrogen stream) solution of 38 g potassium hydroxide in 100 ml of
methanol and 200 ml of water. The solution turns pink to red. The solution
is heated to reflux and the methanol is slowly removed using a partial
takeoff. Methanol is allowed to distill until the pot temperature reaches
90-95 C. The mixture is then maintained at total reflux until the
evolution of ammonia ceases (hold pH paper in outlet of reflux condenser to
test for ammonia). Nitrogen should be bubbled through the mixture to
entrain the ammonia.
The hot dark solution is then allowed to cool somewhat and then
cautiously acidified with a mixture of 60 ml acetic acid and 60 ml water.
The resulting hot solution is quickly treated with Norite "A" decolorizing
carbon and filtered hot.
The clear purple-hued filtrate is allowed to cool to room
(VI), and (VII)) will probably also work admirably for (VII) or lysergic
acid.
Reflux 0.5 g (IV) with 0.5 g KOH in 30 ml methanol for 4 hours.
Evaporate in vacuum and add water to the residue. Adjust the pH to between
5 and 6 and filter or centrifuge to get 0.3 g of the free acid. Suspend 1.8
g of the acid in 125 ml chloroform, cool to -5 and add 0.5 g
triethylamine, then 0.6 g ethylchloroformate and stir 45 minutes. Add 2 ml
diethylamine and stir 3 hours at room temperature to get, after the usual
workup, 1 g of the diethylamide (recrystallize from benzene).
Summary of Procedures and Materials For 1 Kilogram Ergotamine
* Starred chemicals are carefully watched.
**** diethylamine
methylethylamine
ethylisopropylamine
diethyl ether
potassium hydroxide pellets
methanol
activated charcoal powder
tartaric or maleic acid powder
small cylinder N2 or N2O or freon
HCL or sulphuric acid concentrated
chloroform
ethanol
NH4OH concentrated
500
50
50
5
2
5
100
200
g (725 ml)
g (75 ml)
g (75 ml)
lbs
Ibs
L
g
g
500
5
9
500
ml
L (optional but desirable)
L (optional but desirable)
ml (optional but desirable)
500 g
500 g
10 L
10 L
200 g
15 L
4 L
1 L
1 kg
Fourth choice
** phosphorous oxychloride
chloroform
methanol
200 ml
10 L
5 L
Fifth choice
acetonitrile or DMF
** trifluoroacetic anhydride
15 L
500 g
I think the cocaine chapter is placed in the wrong book. Psychedelic? No.
In the end of the book it's also a guide how to smuggle and sell drugs on
the street, but again, we're off topic. It isn't chemistry to sell stuff.
The chapter on misc psychedelics I also thought was unnecessary to add.
The scarce info it contained can be found in any good encyclopedia.
Because of the OCR'ing and my laziness, I cannot guarantee that
every figure is correct. Besides checking the text out for myself, I have
run the text through a spellchecker, but such a maneuver doesn't catch
incorrect figures and references. USE THIS ASCII VERSION WITH CAUTION!
I have not translated all of the molecular diagrams etc into ASCII
art. See this as a reason to buy the real book, it's worth its money. It is
also a part of my shareware text concept: if you want the whole book, then
you should go buy it :) The ISBN # is right at the top of the text.
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