SYNTHESIS: A solution of 100 g 1,2,4-trimethoxybenzene in 1 L hexane
was cooled to 15 °C and treated with 400 mL of a 15% solution of
n-butyllithium in hexane. A white precipitate formed immediately, and
stirring was continued for an additional 2 h while the reaction
returned to room temperature. There was then added a solution of 40 g
freshly distilled propionaldehyde in 100 mL hexane. The reaction was
exothermic and, as the stirring was continued, the precipitate
gradually dissolved. Stirring was continued overnight at room
temperature. There was then added 1 L H2O, and the reaction was
acidified with HCl. The hexane phase was separated, and the remaining
aqueous phase was extracted with hexane, then with Et2O. The pooled
organic extracts were stripped of solvent under vacuum, and the
residue distilled to give 60 g ethyl 2,3,6-trimethoxyphenyl carbinol,
with an index of refraction nD20 = 1.5192. Anal. (C12H18O4) C,H.
From the Et2O extracts above, additional carbinol was obtained,
containing a small amount of the starting 1,2,4-trimethoxybenzene.
The two materials were readily separated by vacuum distillation,
providing an additional 21 g of carbinol.
The above alcohol, 60 g of ethyl 2,3,6-trimethoxyphenyl carbinol, was
stirred without solvent and cooled to 0 °C with an external ice bath.
There was then added 80 g PBr3 at a rate that maintained the
temperature below 60 °C. At the end of the addition, there were added
quantities of chipped ice, followed by H2O. The reaction mixture was
extracted with 3x100 mL Et2O, and removal of the solvent provided 60 g
of 1-bromo-1-(2,3,6-trimethoxyphenyl)propane which was used in the
following dehydrobromination step without further purification.
A solution of the above 60 g of
1-bromo-1-(2,3,6-trimethoxyphenyl)propane in an equal weight of EtOH
was treated with 120 g of flaked KOH. The exothermic reaction was
allowed to run its course with stirring continued overnight. The
mixture was then quenched in H2O and extracted with 3x200 mL CH2Cl2.
Removal of the solvent from the pooled extracts gave a crude product
which contained no starting bromo material, but which was contaminated
with an appreciable quantity of the ethoxy analogue,
1-ethoxy-1-(2,3,6-trimethoxyphenyl)propane. This impure product was
heated briefly to 80 °C with 50% H2SO4. Cooling, dilution with water,
and re-extraction with 3x100 mL CH2Cl2 gave, after removal of the
volatiles under vacuum, 1-(2,3,6-trimethoxyphenyl)propene. This was
distilled to provide 7.0 g of a clear oil that was a 12:1 ratio of the
trans- and cis-isomers.
A well-stirred solution of 6.8 g of the mixed isomers of
1-(2,3,6-trimethoxyphenyl)propene in 40 g of dry acetone was treated
with 3.2 g pyridine and cooled to 0 °C with an external ice bath.
There was then added 6.5 g tetranitromethane over the course of 1 min,
the stirring was continued for an additional 2 min, and then the
reaction mixture was quenched by the addition of 2.2 g KOH in 40 mL
H2O. There was additional H2O added, and the organics were extracted
with 3x75 mL CH2Cl2. The solvent from the pooled extracts was removed
under vacuum, and the 5.3 g residue distilled at 0.2 mm/Hg. A
fraction boiling at 150-170 °C proved to be largely
2,3,6-trimethoxybenzaldehyde. A second fraction (170-200 °C at 0.2
mm/Hg) also spontaneously crystallized to a yellow solid. This was
recrystallized from MeOH to provide, after drying to constant weight,
2.8 g of 2-nitro-1-(2,3,6-trimethoxyphenyl)propene with a mp of 73-74
°C. Anal. (C12H15NO5) C,H.
To a refluxing and stirred suspension of 2.4 g LAH in 300 mL anhydrous
Et2O and under an inert atmosphere, there was added a solution of 2.4
g 2-nitro-1-(2,3,6-trimethoxyphenyl)propene in 100 mL anhydrous Et2O.
The mixture was held at reflux for 4 h, cooled, and then the excess
hydride cautiously destroyed by the addition of 1.5 N H2SO4. There
was then added 40 g potassium sodium tartrate followed by sufficient
aqueous NaOH to raise the pH to >9. The Et2O phase was separated, and
the remaining aqueous phase extracted with 3x100 mL CH2Cl2. The
organic phase and extracts were combined, and the solvent removed
under vacuum yielding 1.8 g of a colorless oil. This was dissolved in
200 mL anhydrous Et2O which was saturated with anhydrous HCl gas.
There was generated a thick oil that slowly crystallized. The
resulting white crystalline solid was removed by filtration, providing
2.2 g 2,3,6-trimethoxyamphetamine hydrochloride (TMA-5). The mp was
124-125 °C. Anal. (C12H20ClNO3) C,H.
DOSAGE: 30 mg or more.
DURATION: 8 - 10 h.
QUALITATIVE COMMENTS: (with 20 mg) There appeared to be a slight
stimulation. Modest eye dilation, but normal pulse. If this is the
marginal edge of intoxication, then it is not a psychotomimetic, but a
stimulant. Go up with care.
(with 30 mg) Intense introspection. Comparable to about 75
micrograms of LSD, or more.
EXTENSIONS AND COMMENTARY: TMA-5, as was the case with TMA-4, has only
been superficially explored. The above two quotations are from two
different people, and together no more than hint at the possibility
that it might be active in the several tens of milligrams.
Pharmacologists have developed quite an art in the design and
evaluation of animal behavior models for the study of psychedelic
drugs. They have always faced two formidable tasks, however. There
is the qualitative question: is the drug a psychedelic? And there is
the quantitative question: how potent is it?
The first question is addressed by taking a number of known
psychedelic drugs, and searching for some animal responses that are
common to all. Since there is little logic in the argument that
animals can experience, let alone reveal, altered states of
consciousness or fantasy fugues or colored imagery, the investigator
must look for objective signs such as conditioned responses to
stimuli, or unusual behavior. If one explores ten drugs that are
known psychedelics, and all ten produce, say, bizarre nest-building
behavior in mice, and an eleventh drug of unknown pharmacology does
exactly the same thing, then the eleventh drug can be suspected of
being a psychedelic drug.
And the second question, how potent, is answered by seeing how much of
the drug is required to evoke this standardized behavior. This is
called the dose-response curve, in which the more drug you give, the
more response you get. This curve gives confidence that the drug is
indeed responsible for the activity that is seen, as well as giving a
quantitative measure of that activity.
But this entire discipline depends on the acceptance of the fact that
the first ten drugs are indeed psychedelic materials. And these
inputs can only come from human trials. What is the validity of these
assumptions with TMA-5? Not very good. The statement that it is
psychedelic has actually been published in reviews solely on the basis
of the above two studies; the potency has been put at some ten times
that of mescaline. Mescaline is certainly an effective psychedelic
drug in the 300-500 milligram range, and this factor of ten implies
that TMA-5 is also a psychedelic drug and is active in the 30-50
milligram range. And indeed, both statements may be true, but
confidence in these conclusions must await more extensive trials.
The two-carbon analogue of TMA-5 is 2,3,6-trimethoxyphenethylamine (or
2C-TMA-5 or 2,3,6-TMPEA). This is a known material, although there
has been some controversy as to its physical properties. It has been
studied in monoamine oxidase systems, and appears to be either a
competitive substrate or an inhibitor of that enzyme. But as far as I
know, no one has nibbled it, so its human activity is unknown.
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