SYNTHESIS: To a solution of 100 g of 2,3-dihydroxyanisole in 1 L dry
acetone there was added 110 g of powdered anhydrous K2CO3 followed by
210 g of methylene iodide. This was brought up to a reflux on the
steam bath. There was a sudden appearance of a solid phase, and then
a gentle reflux was maintained for three days, during which time much
of the heavy solid that initially formed had redissolved. The
reaction mixture was filtered to remove the insoluble salts, and these
were washed with hot acetone. The combined mother liquor and washes
were stripped of solvent under vacuum, leaving a solid residue. This
was leached with several portions of boiling hexane. These were
pooled, and removal of the solvent under vacuum provided 53.6 g of
2,3-methylenedioxyanisole as white crystals with a sharp spicy smell.
A mixture of 120 g N-methylformanilide and 137 g POCl3 was allowed to
incubate at ambient temperature for 0.5 h, then there was added 53 g
of crude 2,3-methylenedioxyanisole. The dark reaction mixture was
heated on the steam bath for 2 h and then poured into a beaker filled
with shaved ice. This was stirred until hydrolysis was complete, and
the black, almost crystalline gunk that separated was removed by
filtration. The 53.6 g of crude product was analyzed by GC using an
ethylene glycol succinate column at 190 °C. Three peaks were apparent
and had baseline separation. The major peak at 7.8 min constituted
82% of the product and was 2-methoxy-3,4-methylenedioxybenzaldehyde.
A minor peak at 12.0 min represented 16% of the product and was the
positional isomer 4-methoxy-2,3-methylenedioxybenzaldehyde. A trace
component (2%) lay intermediate (at 9.5 min) and was
myristicinaldehyde. The mps of the two major benzaldehydes were
sufficiently different that they could serve as means of
identification. The major product was obtained directly from the
black gunk by repeated extraction with boiling cyclohexane which, upon
removal of the solvent, gave 33.1 g of a yellow-colored product.
This, upon one additional recrystallization from boiling cyclohexane,
gave 24.4 g of 2-methoxy-3,4-methylenedioxybenzaldehyde as pale yellow
crystals with a mp of 103-105 °C. The mother liquors were pooled and,
after removal of all volatiles under vacuum, yielded an amber-colored
solid that upon recrystallization provided a yellowish crystals.
These, after yet another crystallization from cyclohexane, gave 4.1 g
of 4-methoxy-2,3-methylenedioxybenzaldehyde with a mp of 85-86 °C.
This latter isomer was used in the synthesis of MMDA-3b.
To a solution of 3.5 g 2-methoxy-3,4-methylenedioxybenzaldehyde in 14
g acetic acid there was added 1.4 g anhydrous ammonium acetate and 2.3
mL of nitroethane. The mixture was brought to reflux and held there
for 35 min. It was then quenched by the addition of 40 mL H2O,
knocking out an orange, gummy solid. This was removed by filtration,
and recrystallized from 50 mL boiling MeOH. After cooling for a few h
in an ice bath, the bright yellow crystals were removed by filtration,
washed with MeOH and air dried to constant weight, yielding 2.15 g
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene. The mp was
106-107 °C. Recrystallization from EtOH raised this mp to 109.5-110.5
°C.
A suspension of 2.2 g LAH in 300 mL anhydrous Et2O under an inert
atmosphere was brought to a gentle reflux. The reflux condensate was
passed through a modified Soxhlet thimble containing 1.95 g
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene effectively
adding it, over the course of 0.5 h, to the reaction mixture as a
saturated Et2O solution. The mixture was maintained at reflux for 16
h. After cooling to 0 °C with an ice bath, the excess hydride was
destroyed by the addition of 1.5 N H2SO4. The phases were separated,
and the aqueous phase washed with 2x100 mL Et2O. To the aqueous phase
there was added 50 g potassium sodium tartrate followed by sufficient
25% NaOH to raise the pH >9. This was then extracted with 3x100 mL
CH2Cl2, and the solvent from the pooled extracts removed under vavuum.
The residual white oil was dissolved in 250 mL anhydrous Et2O, and
saturated with anhydrous HCl gas. There was produced a crop of white
microcrystals of 2-methoxy-3,4-methylenedioxyamphetamine hydrochloride
(MMDA-3a) which was removed by filtration, washed with Et2O, and air
dried to a constant weight of 1.2 g. The mp was 154-155 °C.
DOSAGE: 20 - 80 mg.
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 20 mg) I became aware at about an hour,
and an hour later I found myself suddenly caught up in the marvelous
world of insects. Right alongside a pile of bricks I saw a measuring
worm, and with great tenderness and patience I picked him up, observed
his fore and aft 'feet' and finally replaced him and watched him
acclimate himself. There was also a spider on the bricks, and I was
compelled to watch him in action. I was grateful that I was not being
observed. Time was moving slowly, and I felt I should intentionally
move slowly, so as not to exhaust myself.
(with 40 mg) This developed between one and two hours into it, and
there were considerable body tremors. Talking directed the energy
outwards, and I became aware of a visually sparkling world about me.
I started dropping way too soon; it would have been interesting to
have gone higher. By early evening I was left only with an awareness
of some residual physical hypersensitivity, and there was light
diarrhea. I am not at all sure just what to compare this drug to. It
is gentle.
(with 60 mg) There were visuals of a soft sort--things moved with
eyes open, and with eyes closed the music was great. There seemed to
be some lasting stimulation, but it didn't get in the way of sleeping.
The next morning, however, I was still on. A good compound.
EXTENSIONS AND COMMENTARY: The term MMDA-3a has the feel of being
complicated, but there is a reason for the code. As had been
mentioned, MMDA was the initials for methoxy (the M) methylenedioxy
(the MD) amphetamine (the A). And with a molecule of amphetamine
there are six ways of sticking these two groupings on the aromatic
ring. The numbers 1-6 had already been assigned to the six ways of
sticking three methoxyl groups onto an amphetamine molecule (with the
trimethoxyamphetamines, the TMA's) and I decided to hew to the same
convention with the methylenedioxy counterparts. However, there are
two #3's (the methoxy and the methylenedioxy can go onto the three
oxygen atoms in a row in two different ways, whereas the three
methoxys can go on in just one way) and there can be no #6 (since a
methylenedioxy must, perforce, have two oxygens that are adjacent, and
there are none to be so found in the 2,4,6-orientation of TMA-6). So,
with two possible MMDA-3's it becomes reasonable, in fact essential,
to name one of them "a" and the other "b". The "a" orientation occurs
in nature as the essential oil croweacin, or
1-allyl-2-methoxy-3,4-methylenedioxybenzene. It thus can allow
MMDA-3a to be classified as an Essential Amphetamine, since it can
arise, in principle, by amination in the liver in vivo. But in the
laboratory, croweacin is certainly not a practical starting material
in this synthesis.
I have been told of a number of clinical trials that have explored
MMDA-3a at considerably higher levels, but I have no explicit
quotations to give, and the details are quite sketchy. Three trials
at 80 milligrams, and one at 100 milligrams, all made comparisons, in
both quantity and quality of the experience, to 100 micrograms of LSD.
However, two events occurred that may or may not be related to these
trials; one subject had a spontaneous peak experience five days after
the experiment, and another made a symbolic suicide attempt.
And, as with MMDA-2, both the 2-carbon "phenethylamine" analogue and
the 4-carbon RARIADNES analogue of MMDA-3a have been made. The
phenethylamine analog was prepared by the condensation of 7.6 g of the
above benzaldehyde with nitromethane (in acetic acid with ammonium
acetate catalyst, giving 5.4 g of the nitrostyrene with a mp of
115.5-116.5 °C from methanol) followed by lithium aluminum hydride
reduction (in ether). The product,
2-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (2C-3a)
melted at 143-145 °C. A series of subjective evaluations were made,
and there are reports of marginal effects in the 40 to 120 milligram
range. At 40 milligrams, perhaps the hint of a psychic energizer; at
65 milligrams, there was a pleasant mood elevation; at 80 milligrams,
there was a brief paresthetic twinge noted at about the hour and a
half point, and at 120 milligrams, about the same at one hour, and
then nothing. The fact that there can be such a modest change of
effect over a three-fold range of dosage suggests that this compound
might have some merit as an anti-depressant. It would be interesting
to know if it blocks serotonin reuptake!
The 4-carbon analog was made similarly (from the aldehyde and
nitropropane but using tert-butylammonium acetate as a reagent in 100%
excess and isopropanol as solvent, giving bright yellow crystals
melting at 105.5-106.5 °C from 25 volumes of boiling methanol)
followed by reduction (with lithium aluminum hydride in ether) to give
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-aminobutane hydrochloride
(4C-3a) with a mp of 183-185 °C with prior sintering at 173 °C. This
material has been tasted at up to 3.5 milligrams with nothing noted.
There have been no trials at any higher dose.
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