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#52 DESOXY
3,5-DIMETHOXY-4-METHYLPHENETHYLAMINE
SYNTHESIS: To a well-stirred
solution of 31 g
2,6-dimethoxytoluene in
200 mL
CH2Cl2 there was added 11 mL elemental
bromine, a portion at a
time. There was a copious evolution of HBr and the color gradually
faded from deep red to straw. The reaction mixture was poured into
500 mL H2O, and the organic layer separated, washed first with dillute
NaOH and finally with dilute HCl. The
solvent was removed under
vacuum, and the residue
distilled at 85-90 °C at 0.4 mm/
Hg to provide
44 g of
3-bromo-2,6-dimethoxytoluene as a white oil.
A well-stirred
solution of 42 mL
diisopropylamine in 100 mL petroleum
ether was placed in a He
atmosphere and cooled to 0 °C with an
external ice-water bath. There was then added 120 mL of a 2.5 M
solution of n-
butyllithium in hexane, producing a clear but viscous
solution of the
lithium amide. Maintaining this tem
perature, there
was added 100 mL of
anhydrous THF, followed by 10 mL dry
CH3CN, which
produced an immediate white
precipitate. A
solution of 23 g of
3-bromo-2,6-dimethoxytoluene in 75 mL
anhydrous THF was then added
which produced a light red color. The reaction mixture was allowed to
come to room tem
perature. The color became progressively darkened,
eventually becoming a deep red-brown. After 0.5 h, the reaction
mixture was poured into 500 mL of dilute H2SO4, the layers were
separated, and the aqueous layer extracted with 2x75 mL
CH2Cl2. The
organics were combined, the
solvent removed under vacuum, and the
residue
distilled. Discarding a first fraction, the cut boiling at
125-165 °C at 0.3 mm/
Hg was collected. This light yellow fraction
spontaneously
crystallized and weighed 11.0 g. Trituration under 20
mL petroleum
ether provided 1.72 g of
3,5-dimethoxy-4-methylphenylacetonitrile as a yellowish solid.
A
solution of LAH in
anhydrous THF under
nitrogen (20 mL of a 1.0 M
solution) was cooled to 0 °C and vigorously stirred. There was added,
dropwise, 0.54 mL 100% H2SO4, followed by 1.5 g
3,5-dimethoxy-4-methylphenylacetonitrile as a solid. The reaction
mixture was stirred at 0 °C for a few min, then brought to room
tem
perature for 1 h, and finally to a reflux on the steam bath for 30
min. After cooling back to 0 °C there was added IPA until no more
hydrogen was evolved, followed by sufficient 15%
NaOH to produce a
granular texture. The white solids were removed by filtration, and
washed with THF. The filtrate and washes were stripped of
solvent
under vacuum, the residue added to 150 mL dilute H2SO4 and washed with
2x50 mL
CH2Cl2. The aqueous
phase was made basic with 25%
NaOH, and
extracted with 3x100 mL
CH2Cl2. These extracts were pooled, the
solvent removed under vacuum, and the residue
distilled at 110-120 °C
at 0.45 mm/
Hg to give a colorless viscous oil. This was
dissolved in
10 mL of IPA, neutralized with 10 drops of concentrated HCl and
diluted with 20 mL
anhydrous Et2O. The product was removed by
filtration, washed with
Et2O, and air dried to give 0.55 g
3,5-dimethoxy-4-methylphenethylamine (DESOXY) as white
crystals.
DOSAGE: 40 - 120 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 40 mg) Initially I felt very chilled, so
I lay down under a blanket. Eyes-closed imagery became very
dream-like and my general state was felt as having lost my center.
Also, not much in touch with feelings, sense of strangeness, almost
alien view of the world. Not through recog-nizable eyes. Neither
pleasant nor unpleasant, just strange. Was able to drift into sleep
very easily, or sleep-like trance state, with disconnected, far-out
imagery. After 3 hours the nausea was gone, I was able to get up and
explore. A little food went down well. No drive, no strong focus in
any direction. Feel this was a quite fascinating experience.
Completely down by six hours. Would go a bit slowly because of slight
hints of
neurological sensitivity--the instant chilling and a
tendency to dart on going to sleep. The nervous system does not feel
over-exposed, but all of a sudden there will be a millisecond of
auditory
hallucination, or an out-of-the-blue startle. So take it
easy going up. [Some 24 hours after this experiment had been
completed, and a normal baseline re-established, a complex and
psycho-logically disruptive
syndrome occurred, that lasted for the
better part of a week. The temporal juxtaposition between the use of
desoxy and the subsequent "spiritual crisis" initially suggested some
possible connection, but in retrospect the events seem to be
unrelated].
(with 40 mg) I have offered to be a control on an experiment where
there had been a close relationship between a trial with desoxy and
what might have been a
psychotic break, or some kind of so-called
spiritual emergency. These two events lay within a day of one
another. I was aware of my 40 milligram dosage at about
three-quarters of an hour into the experiment, and felt that there was
no more in-
tensification at the two-hour point. At that time I felt
distinctly spaced but with a very good feeling, and I could see no
reason not to increase the dosage at some future time. There was a
good and mellow mood, and enjoyment in escapist reading. The only
physical oddity that I noted was that there had been no urge to
urinate, and only a small amount of quite concentrated urine was
passed rather late in the experiment. I was at baseline at the fifth
hour, and there was nothing unusual at any time during the following
week.
(with 100 mg) The stuff has a sweet taste! There was a slight
heart-push in the early awareness period, with a pulse up to 100 and a
feeling of pressure in the chest. There were no apparent visual
enhancements, but the eyes-closed imagery to music was noteworthy.
Thinking skills and conversation seemed to be fully under control, if
not enhanced. There was none of the colorful
psychedelic world of
mescaline, but this might be just around the corner; perhaps with a
larger dose. This is a comfortable in-between level. Sleep was not
possible at the sixth hour, but two hours later, it was easy and very
restful. There was no negative price to pay the next day.
EXTENSIONS AND COMMENTARY: All
substituents that are involved with the
several drugs being discussed in this writing are really things that
are stuck like warts on the
benzene ring that is central to every
phenethylamine. Some of these warts are things attached with a oxygen
atom; there are some of these in every single compound in this story.
No oxygen atom, no
psychedelic effect. Without them, one has
stimulants or, more frequently, no effects at all.
But the removal of an oxygen atom (in those cases where there is more
than one) can radically change the nature of the effects seen. This
is the exact meaning of the term "desoxy." "Des", without, and "oxy",
the oxygen. Since this drug is simply the structure of mescaline with
the oxygen at the 4-position plucked out of the picture, the first
impulse was to abbreviate this compound as DOM for des-
oxymescaline.
However, a long, long time ago, in a universe far, far away, a
compound was
synthesized that had a methoxy group replaced by a
methyl, and it was already named DOM. This was the first of the STP
analogs, and the initials stood for desoxy (DO, losing an oxygen) and
methyl (M, having it replaced with a methyl group). These are two
different worlds. One M stands for
Mescaline, and the other M stands
for M
ethyl. Let's call it 4-
desoxymescaline, or simply DESOXY, and be
exact.
This drug is a prime example of a
pharmacological challenge directed
to the
metabolic attack at the 4-position as a mechanism for the
expression of
biological activity. A methoxy group there would allow
easy removal of the
methyl group from the oxygen by some
demethylation
process, but a bare
methyl group there cannot be removed by any simple
process. It must be removed by a very difficult
oxidation.
This is not the first time that oxygen atoms have been removed from
the mescaline molecule. Both the
3,5-dideoxymescaline
(
3,5-dimethyl-4-methoxyphenethylamine) and
3,4,5-trideoxymescaline
(also called
desoxymescaline in the literature, but really
tri-
desoxymescaline or
3,4,5-trimethylphenethylamine) have been
studied in the cat, and have shown extraordinary
pharmacological
profiles of CNS action. The
trimethyl compound showed behavior that
was interpreted as being intense mental turmoil, accompanied by a
startling rise in body tem
perature. The significance is hard to
determine, in that LSD gave similar responses in the cat, but
mescaline was without effects at all. No human studies have been made
on these compounds, just animal studies. But they might prove upon
trial in man to be most revealing. They would have to be performed
with exceptional care.
The 3-
carbon chain
amphetamines that correspond to these mescaline
look-alikes with one or more methoxy groups replaced with
methyl
groups, are largely untested and would require independent and novel
syntheses. The
3,4,5-trimethylamphetamine is known, and is known to
be very hard on experimental cats.
A mescaline
analogue with a bromo atom in place of the 4-
methoxyl
group is an
analogue of mescaline in exactly the same way that DOB (a
very potent
am-phetamine) is an
analog of TMA-2 (the original
tri
substituted
amphetamine). This
analogue,
3,5-dimethoxy-4-bromoamphetamine, has been found to be a most
effective
serotonin agonist, and it is a possibility that it could be
a most potent
phenethylamine. But, as of the present time, it has
never been assayed in man.
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