This is a recipe from
PiHKAL. If you're interested in how the hardlinks
were chosen, read
noding PiHKAL for Everything2.
#162 TMA-6
2,4,6-TRIMETHOXYAMPHETAMINE
SYNTHESIS: To a
solution of 100 g
phloroglucinol dihydrate in 320 mL
MeOH there was added 55 mL of concentrated H2SO4, and the clear
solution held under reflux conditions overnight. After cooling, there
was added 500 mL H2O, and the bulk of the MeOH was removed under
vacuum. The
residual oil was extracted with
Et2O, and the removal of
this left 60 g of a red oil as residue. This was
dissolved in 300 g
methyl sulfate (caution, this is extremely toxic through skin contact,
and any exposure must be flushed thoroughly with dilute
ammonium
hydroxide). With good stirring, this was cautiously treated with 500
g of 40% aqueous KOH, and the exothermic reaction allowed to run its
course. Extraction with 3x100 mL
Et2O gave, after
evaporation of the
solvent from the pooled extracts, an oil that became largely
crystalline. This was suspended in 100 mL hexane, and filtered
through a coarse fritted funnel. With
evaporation there was obtained
57 g of
1,3,5-trimethoxybenzene as a pale amber solid that melted at
44-50 °C. A sample purified by re
crystallization from
EtOH had the
proper mp of 54-55 °C.
A mixture of 62.9 g N-
methylformanilide and 71.3 g of POCl3 was
allowed to stand for 0.5 h producing a light claret color. There was
then added 30.9 g of 1,3,5-
trimethoxybenzene and the mixture heated
on the steam bath for 2 h. The reaction mixture then was poured into
chipped ice, and allowed to stir for several h. The dark gummy mess
was extracted with 2x100 mL
Et2O (this was discarded) and then with
4x200 mL
CH2Cl2. The latter extracts were pooled, and stripped of
solvent under vacuum yielding 14 g of an amber solid. This was
re
crystallized from 80 mL boiling MeOH (with decolorizing charcoal
employed and filtration of the boiling
solution through paper) to give
10.0 g of
2,4,6-trimethoxybenzaldehyde as a white
crystalline solid
with a mp of 115-116 °C. The literature values are generally
one-degree ranges, and they are reported as high as 121 °C. The
malononitrile adduct was prepared from a
solution of 0.5 g
aldehyde
and 0.5 g
malononitrile in 10 mL warm MeOH treated with a drop of
triethylamine. There was an immediate formation of a yellow
crystalline mass which was removed by filtration, washed with
EtOH,
and air dried. The yield of
2,4,6-trimethoxybenzalmalononitrile was
0.5 g and the mp was 174-175 °C. Anal. (
C13H12N2O3) N.
A
solution of 5 g
2,4,6-trimethoxybenzaldehyde in 20 g
nitroethane was
treated with 1.0 g of
anhydrous ammonium acetate and held on the steam
bath for 24 h. The excess
solvent/reagent was stripped from the
deep-red colored
solution under vacuum yielding a residue that
spontaneously set to a
crystalline mass. This was well triturated
under 5 mL MeOH, filtered, and washed with 3 mL additional MeOH to
give 5.4 g of
2-nitro-1-(2,4,6-trimethoxyphenyl)propene as yellow
crystals. The mp of the crude material was 135-142 °C which could be
raised to 147-148 °C by re
crystallization from
EtOH. The use of an
alternate procedure for the synthesis of this
nitrostyrene, using
acetic acid as
solvent and a
stoichiometric amount of
nitroethane (and
ammonium acetate as
catalyst), gave very poor yields. The use of
butylamine as
catalyst gave considerably better results.
A suspension of 50 g LAH in 1 L
anhydrous THF was placed under an
inert
atmosphere, stirred
magnetically, and brought to a gentle
reflux. There was added a total of 56.9 g
2-nitro-1-(2,4,6-trimethoxyphenyl)propene as a saturated
solution in
THF. This was achieved by letting the condensed THF drip through a
Soxhlet thimble containing the
nitrostyrene with direct addition to
the reaction mixture. The solubility was extremely low. The stirred
mixture was maintained at reflux for 36 h, generating a smooth creamy
gray color. After being brought to room tem
perature, the excess
hydride was destroyed by the patient addition of 50 mL H2O, followed
with 50 mL 15%
NaOH (still some heat evolved) and then 150 mL
additional H2O. Stirring was continued until the in
soluble salts were
white and loose. These solids were removed by filtration, and the
filter cake washed with additional THF. The combined filtrate and
washes were stripped of
solvent under vacuum, and the 73 g of pale
amber residue
dissolved in 200 mL IPA, neutralized with approximately
50 mL concentrated HCL, and diluted with 2 L
anhydrous Et2O. A lower,
oily
phase separated slowly set up as a
crystalline mass. This was
removed by filtration,
Et2O washed, and allowed to air dry to constant
weight. The weight of
2,4,6-trimethoxyamphetamine hydrochloride was
41.3 g and the color was an off-white. There was a tendency to
discolor upon air exposure. The mp was 204-205 °C which was increased
to 207-208 °C upon re
crystallization from IPA. The literature gives a
mp of 214-215 °C for this salt after isolation and purification as the
picrate salt (with a mp 212-213 °C from
EtOH).
DOSAGE: 25 - 50 mg.
DURATION: 12 - 16 h.
QUALITATIVE COMMENTS: (with 25 mg) I was outside at the
California-Washington State football game, which was completely nutty.
As was I. With the crowd activity, it was impossible to separate the
drug's action from the environment. Later I simply sat in the car,
and tried to define what the effects really were. Things were
completely benign, there was ease with concepts, and writing was good
and smooth. At twelve hours, comfortably down. Maybe a plus two.
(with 35 mg) My body was tingling all over, and there were times when
walking was unsteady. Thinking was a little difficult, as I was quite
intoxicated most of the day (all of the day, now that I think that
over). To accomplish anything, such as toasting the toast in the
toaster, was difficult. And things were so funny most of the time.
Setting the table for supper, six hours later, proved to be hilarious.
I like to think of the day as a mixture of the mad hatter's tea party,
and a trip to the moon. We were all still intoxicated at bedtime,
whatever time that was. Had difficult time sleeping. If I were to
repeat, would go lighter in dosage, I feel.
(with 40 mg) This experiment was begun at noon of a cool rainy day.
Almost all of the day had to be spent indoors, without benefit of
sunshine, This is worth mentioning because there was, for the first
eight hours of the experiment, a decided feeling of inner chill which
might not have occurred so strongly had it been a warm day. Most, if
not all, of the other eight subjects also reported the same chill.
There was some visual sparkle which persisted throughout. At the two
hour point a minor but persistent stomach queasiness came on, preceded
by a
diarrhea-like bowel movement. There was no impairment of speech,
but there was some halting quality to all thought processes. It was
easy to talk about personal matters, but there did not seem to be a
significant insight increase. Appetite for food was lessened. Sleep
was decidedly difficult after the effects of the material seemed
otherwise gone.
(with 40 mg) As the experience grows in intensity for the first four
hours, I feel a strange mixture of plateaus, exuberance, and strong
negative feelings, all replacing each other. I found myself inside a
stout,
hemispherical shell, curled up in the solid part, thoroughly
walled off but absolute master within the shell, calling all shots,
making all decisions, in complete control. Moving beyond the
half-shell meant becoming vulnerable, which I refused to do.
Consequently my difficulty in hearing what other people say, becoming
involved in their perceptions and lives. I keep relationships
shallow, pull away inside my shell rather than become involved. I
like to be by myself. This was a great revelation; I had never seen
it before. This material had an enormous drive. I feel extremely
grateful for exposing a very deep personal problem.
(with 50 mg) My previous try at this level produced a record that
said, 'alteration of consciousness, but no visual, no anything,' and
oh my, surprise! It was very, very active, visual, colorful, etc.,
etc. Good talking, clear and steady control of body, despite intense
energy flow. Extremely funny--great humor, wonderful laughter.
EXTENSIONS AND COMMENTARY: Here is a simple and easily made compound
that might well bid fair to be one of the most rewarding and
pleasurable of the
methoxylated
amphetamines. It is fully as potent
as its counterpart, TMA-2. This latter compound, with its
2,4,5-trisubstitution pattern, has served as a template from which an
immense family of very active and fascinating drugs have arisen. The
2,5-dimethoxy aspect has been kept intact, and modifications in the
4-position have given rise to treasures such as DOM, DOB, DOET, DOI,
and the Aleph compounds. And, of course, the entire world of the
2C-X's has exploited this same orientation.
Here, there is the blatant, parallel call from TMA-6. It can serve,
as the
2,4,6-counterpart, as a similar template compound. And the
first indicators are that, in keeping the
2,6-dimethoxy aspect intact,
a completely
analogous series could be made, again with modifications
of the 4-position. These have been named the psu-series, or
psi-series, as an abbreviation for the prefix, pseudo, and can be
differentiated from the
2,4,5-things with the use of the Greek letter
"gamma". Thus there is the gamma-DOM (called Z-7 in this book, and certainly
an active compound), and gamma-DOB, gamma-DOET, gamma-DOI, and the gamma-ALEPH
compounds. And, of course, the gamma-2C-X counterparts. I would expect
all of them to be active and, certainly, some of them interesting.
They will be considerably more difficult to
synthesize. However, some
of them, specifically things such as gamma-2C-T-4, have already been
prepared, and are being evaluated.
One of the guiding premises of this Book II was to make all recipes
employ commercially available materials as starting materials. And in
the case of TMA-6, the required
benzaldehyde
(
2,4,6-trimethoxybenzaldehyde) is an easily obtained trade item from
any of several supply houses. Why not start the recipe there? Why
tell how to make it from
1,3,5-trimethoxybenzene (also presently
available from commercial sources) and how to make the
ether in turn,
from
phloroglucinol? This simply reflects a valid paranoia of our
times. Today the
aldehyde is available (at $2/g) and can be easily
purchased. But tomorrow? What about in the year 2003? Who can tell
what will, or will not, be easily available then? There might be a
world-wide acknowledgment that the "war on drugs" is more destructive
than any drug itself could ever be, and every law that had been
written in the attempt to dictate human behavior will have been
transformed into a force that truly educates and allows choice. This
might really happen. But maybe, on the other hand, no fine chemicals
may be permitted to be held in any hands, at any price, except for
those of licensed chemists and in authorized laboratories. The black
market price for the
aldehyde might be $1000/g with another $1000 for
protection.
But, it will be impossible to remove
phloroglucinol from availability.
It is available as a natural component in the free form, in sources as
diverse as the cones of the Sequoia sempervirens (the coast redwood
tree) and species of
Camillia (that provides the leaves of our morning
tea). And combined with a molecule of
glucose in the form of its
glucoside, it is called
phlorin, and it is present in the discarded
rinds of almost all citrus fruits as well as the
resins from many of
the Eucalyptus species. And one step yet further back into nature,
there is a
dihydrochalcone glucoside called
phloridzin which
practically drips out of all parts of the apple and pear trees except
for the apple or pear itself. It, on base hydrolysis, gives
phlorin,
which on acid hydrolysis gives
phloroglucinol, which when
dissolved in
methanol and
sulfuric acid gives Q. Nature is indeed most bountiful.
The
phenethylamine homologue of TMA-6 is well known, but is virtually
unexplored
pharmacologically. The above
benzaldehyde with
nitromethane in glacial acetic acid containing
ammonium acetate gave
the appropriate
beta-nitrostyrene as yellow
crystals with a mp
177-177.5 °C. This, with LAH in
ether, gave
2,4,6-trimethoxyphenethylamine (2,4,6-
TMPEA, or 2C-TMA-6) as the
picrate salt (mp 204-205 °C) or the
hydrochloride salt (mp 234-235
°C). It has been shown not to be a
substrate to the
soluble amine
oxidase from rabbit liver, a property it shares with mescaline, but
wh
ether it is or is not active in man is at present unknown.
Back to PiHKAL?