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2,5-DIMETHOXY-4-ETHOXYAMPHETAMINE
SYNTHESIS: A
solution of 83 g bourbonal (also called
ethyl vanillin,
or
vanillal, or simply 3-ethoxy-4-
hydroxybenzaldehyde) in 500 mL MeOH
was treated with a
solution of 31.5 g KOH pellets (85% material)
dissolved in 250 mL H2O. There was then added 71 g
methyl iodide, and
the mixture was held under reflux conditions for 3 h. All was added
to 3 volumes of H2O, and this was made basic with the addition of 25%
NaOH. The aqueous
phase was extracted with 5x200 mL
CH2Cl2. The
pooling of these extracts and removal of the
solvent under vacuum gave
a residue of 85.5 g of the product 3-ethoxy-4-
methoxybenzaldehyde,
with a mp of 52-53 °C. When this product was re
crystallized from
hexane, its mp was 49-50 °C. When the reaction was run with the same
reactants in a reasonably
anhydrous environment, with
methanolic KOH,
the major product was the
acetal,
3-ethoxy-a,a,4-trimethoxytoluene.
This was a white glistening product which
crystallized readily from
hexane, and had a mp of 44-45 °C. Acid hydrolysis converted it to the
correct
aldehyde above. The addition of sufficient H2O in the
methylation completely circumvents this by-product. A
solution of 1.0
g of this
aldehyde and 0.7 g
malononitrile in 20 mL warm absolute
EtOH, when treated with a few drops of
triethylamine, gave immediate
yellow color followed, in a few min by the formation of
crystals.
Filtration, and washing with
EtOH, gave bright yellow
crystals of
3-ethoxy-4-
methoxybenzalmalononitrile with a mp of 141-142 °C.
A well stirred
solution of 125.4 g 3-ethoxy-4-
methoxybenzaldehyde in
445 mL acetic acid was treated with 158 g 40%
peracetic acid (in
acetic acid) at a rate at which, with ice cooling, the internal
tem
perature did not exceed 27 °C. The addition required about 45 min.
The reaction mixture was then quenched in some 3 L H2O. There was the
generation of some
crystals which were removed by filtration. The
mother liquor was saved. The solid material weighed, while still wet,
70 g and was crude
formate ester. A small quantity was re
crystallized
from
cyclohexane twice, to provide a reference sample of
3-ethoxy-4-methoxyphenyl formate with a mp of 63-64 °C. The bulk of
this crude
formate ester was
dissolved in 200 mL concentrated HCl
which gave a deep purple
solution. This was quenched with water which
precipitated a fluffy tan solid, which was
hydrated
phenolic product
that weighed about 35 g, and melted in the 80-90 °C. range. The
mother liquors of the above filtration were neutralized with
Na2CO3,
then extracted with 3x100 ml
Et2O. Removal of the
solvent gave a
residue of about 80 g that was impure
formate (containing some
unoxidized
aldehyde). To this there was added 500 mL 10%
NaOH, and
the dark mixture heated on the steam bath for several h. After
cooling, the strongly basic
solution was washed with
CH2Cl2, and then
treated with 200 mL
Et2O, which knocked out a heavy semi-solid mass
that was substantially in
soluble in either
phase. This was, again,
the crude
hydrated
phenol. The
Et2O phase, on
evaporation, gave a
third crop of solids. These could actually be re
crystallized from
MeOH/H2O, but the mp always remained broad. When subjected to
distillation conditions, the H2O was finally driven out of the
hydrate, and the product
3-ethoxy-4-methoxyphenol distilled as a clear
oil at 180-190 °C at 0.8 mm/
Hg. This product, 45.1 g, gave a fine
NMR
spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1,
supporting the freedom of the OH group on the aromatic ring from
adjacent oxygen. Efforts to obtain an
NMR spectrum in D2O immediately
formed an in
soluble hydrate. This
phenol can serve as the starting
material for either
MEM (see below) or EEM (see separate recipe).
To a
solution of 12.3 g
3-ethoxy-4-methoxyphenol in 20 mL MeOH, there
was added a
solution of 4.8 g flaked KOH in 100 mL heated MeOH. To
this clear
solution there was then added 10.7 g
methyl iodide, and the
mixture held at reflux on the steam bath for 2 h. This was then
quenched in 3 volumes H2O, made strongly basic with 10%
NaOH, and
extracted with 3x100 mL
CH2Cl2. Removal of the
solvent from the
pooled extracts under vacuum gave 9.4 g of an amber oil which
spontaneously
crystallized. The mp of
1,4-dimethoxy-2-ethoxybenzene
was 42-43.5 °C, and was used, with no further purification, in the
following step.
A mixture of 17.3 g N-
methylformanilide and 19.6 g POCl3 was allowed
to stand for 0.5 h, producing a deep claret color. To this there was
added 9.2 g
1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on
the steam bath for 2 h. It was then poured into chipped ice and, with
mechanical stirring, the dark oily
phase slowly became increasingly
crystalline. This was finally removed by filtration, providing a
brown solid mat which showed a mp of 103.5-106.5 °C. All was
dissolved in 75 mL boiling MeOH which, on cooling,
deposited fine
crystals of
2,5-dimethoxy-4-ethoxybenzaldehyde that were colored a
light tan and which, after air drying to constant weight, weighed 8.5
g and had a mp of 108-109.5 °C. Search was made by gas
chromatography
for evidence of the other two theoretically possible positional
isomers, but none could be found. The
NMR spectrum showed the two
para-protons as clean singlets, with no noise suggesting other
isomers. There was a single peak by GC (for the re
crystallized
product) but the mother liquors showed a cont
amination that proved to
be N-
methylformanilide. A 0.3 g sample, along with 0.3 g
malononitrile, was
dissolved in 10 mL warm absolute
EtOH, and treated
with a drop of
triethylamine. There was the immediate formation of a
yellow color followed, in 1 min, by the
deposition of fine yellow
needles. Filtering and air drying gave 0.25 g of
2,5-dimethoxy-4-ethoxybenzalmalononitrile, with a mp of 171-172 °C.
A
solution of 7.3 g
2,5-dimethoxy-4-ethoxybenzaldehyde in 25 g glacial
acetic acid was treated with 3.6 g
nitroethane and 2.25 g
anhydrous
ammonium acetate, and heated on the steam bath. After two h, the
clear
solution was diluted with an equal volume of H2O, and cooled in
an ice bucket. There was the formation of a heavy crop of orange
crystals which were removed by filtration. The dry weight of
1-(2,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene was 4.8 g and the mp
was 120-124 °C. Re
crystallization of an
analytical sample from MeOH
gave a mp of 128-129 °C. Anal. (
C13H17NO5) C,H.
To a gently refluxing suspension of 3.3 g LAH in 400 mL
anhydrous Et2O
under a He
atmosphere, there was added 4.3 g
1-(2,5-dimethoxy-4-ethoxy)-2-nitropropene by allowing the condensing
Et2O to drip into a shunted Soxhlet thimble apparatus containing the
nitrostyrene, thus effectively adding a warm saturated
ether solution
of it to the
hydride mixture. The addition took 2 h.
Refluxing was
maintained for 5 h, and then the reaction mixture was cooled to 0 °C
with an external ice bath. The excess
hydride was destroyed by the
cautious addition of 300 mL of 1.5 N H2SO4. When the aqueous and
Et2O
layers were finally clear, they were separated, and 100 g of
potassium
sodium tartrate was
dissolved in the aqueous fraction. Aqueous
NaOH
was then added until the
pH was >9, and this was then extracted with
3x100 mL
CH2Cl2. Evaporation of the
solvent from the pooled extracts
produced an almost white oil that was
dissolved in 100 mL
anhydrous
Et2O and saturated with
anhydrous HCl gas. There was
deposited a
white
crystalline solid of
2,5-dimethoxy-4-ethoxyamphetamine
hydrochloride (
MEM) which weighed 3.1 g and had a mp of 171-172.5 °C.
Anal. (
C13H22ClNO3) C,H,N.
DOSAGE: 20 - 50 mg.
DURATION: 10 - 14 h.
QUALITATIVE COMMENTS: (with 20 mg) I experienced some physical
discomfort, but doesn't that tell us about the work to be done, rather
than the property of the material? The breakthrough I had was the
following day (and this seems to be the way
MEM operates, i.e., first
the energy and expansion, next day insight) was of the highest value
and importance for me. I was given a methodology for dealing with my
shadow parts. No small gift. And I did it all alone and the results
were immediate. I am so grateful.
(with 20 mg, at 1.5 h following 120 mg
MDMA) RThe transition was very
smooth, with no obvious loss of the
MDMA experience. I felt less of a
need to talk, but the intimate closeness with the others was
maintained. The experience continues to grow more profound and
euphoric and I prayed, in the latter part of the afternoon, that it
wouldn't stop. It continued until midnight with marvelous feelings,
good energy, and much hilarity. And it abated very little over the
next several days leaving me with the feeling of lasting change with
important insights still coming to mind one week later.
(with 25 mg, at 2 h following 120 mg
MDMA) RI found that sounds in
general were distracting. No, they were out-and-out annoying. I may
have been in an introspective mood, but I really wanted to be alone.
No body problems at all. Felt good. I developed some color changes
and some pattern movement. Not much, but then I didn't explore it
much. The wine party afterwards was certainly most pleasant. The
soup was a great pleasure. And that hard bread was good. The
material was clearly not
anorexic, or at least I overcame whatever
anorexia there might have been.
(with 30 mg) I was aware of this in thirty minutes and it slowly
developed from there to an almost +++ in the following hour. There
were visual
phenomena, with some color enhancement and especially a
considerable enhancement of brights and darks. The first signs of
decline were at about six hours, but there was something still working
there after another six hours had passed. A slow decline, certainly.
(with 50 mg) I came into the experience knowing that yesterday had
been a very fatiguing and tense day. I felt this material within the
first ten minutes which is the fastest that I have ever felt anything.
The ascent was rapid and for the first hour I tended to an inward
fantasying with a distinct sensual tinge. There was a persistent
queasiness that never left me, and it contrasted oddly with a good
feeling of outward articulation and lucidity which succeeded in coming
to the fore after the introverted first hour. Sleep was difficult,
but the next day was calm and clear.
(with 50 mg) Lots of energy, best directed into activity. Clear
imaging, thinking. Intense yet serene. Good feeling of pleasantness
and some
euphoria. I felt the need to keep moving. Hard to stay
still.
(with 70 mg, in two parts) RThe effects of the 40 milligrams were
muted by another drug experiment yesterday morning, and I never got
much over a plus 1. There is an erotic nature,
tactile sensitivity
perhaps not as delicate as with
2C-B, but it is there. At the 2 hour
point, an additional 30 milligrams increased the body impact (a
distinct tremor and sensitivity) but somehow not a lot more mental. I
have been compromised by yesterday.
EXTENSIONS AND COMMENTARY: MEM was both a valuable and dramatic
compound, as well as a drug that played a watershed role. The
completion of all the possible
trimethoxyamphetamines (the TMA's)
showed that only two of them combined the values of dependability of
positive
psychedelic effects with a reasonably high potency. Both
TMA-2 and TMA-6 are treasures, both active in similar dosages, and
both offer
methoxyl groups that are begging to be replaced by other
things. The first focus was on TMA-2, partly because the needed
synthetic chemistry was better known, and partly because I had
discovered its activity earlier. But there were three entirely
different and distinct
methoxyl groups to work on, in TMA-2. There is
one at the 2-position, one at the 4-position, and one at the
5-position. The most obvious thing to do, it seemed, was to make each
of them one
carbon longer. Replace a methoxy with an ethoxy. And a
logical naming pattern could follow the use of M for methoxy, and E
for ethoxy, in sequence right around the ring from the 2- to the 4- to
the 5-positions. The first group to be compared, then, would be EMM,
MEM, and MME. And of these three, it was only MEM that was right up
there in drama and in potency. But, by the time that became apparent,
I had already completed the diethoxy possibilities (EEM, EME, and MEE)
as well as the triethoxy
homologue, EEE. With the discovery that the
4-position was the magic leverage point, and that the
homologues at
positions 2- and 5- were clearly less interesting, all emphasis was
directed at this target, and this has led to the many 4-
substituted
families that are now known to be highly potent and felt by many to be
personally valuable.
Why put such emphasis on potency, I am frequently asked? Why should it
matter how much of a compound you take, as long as the effective level
is much lower than its toxic level? Well, in a sense, that is the
very reason. There are no guides as to what the toxic levels of any
of these many compounds might really be in man. There is simply no
way of determining this. Only a few have been explored in animals in
the pursuit of an LD-50 level. Most of them are similar to
one-another, in that they are, in mice, of relatively low toxicity
and, in rat, of relatively high toxicity. But this toxicity appears
not to be related to potency in man. So, if one might extrapolate
that they are of more or less the same risk to man (from the toxic
point of view) then the lower the dosage, the greater the safety.
Maybe. In the absence of anything factual, it makes a reasonable
operating hypothesis.
Many of the reports of
MEM effects have been with experiments in which
an effective dose of
MDMA had been taken shortly earlier. There has
developed a concept, embraced by a number of researchers, that the
ease and quietness usually seen with the development of the
MDMA
experience can mitigate some of the
physically disturbing symptoms
sometimes seen with other
psychedelics. This may be partly due to a
familiar entry into a altered place, and partly due to a lessening of
dosage usually required for full effects.
MEM seems to have had more
trials using this combination than many of the other
psychedelic
drugs.
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