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3-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: (from
protocatechualdehyde) A
solution of 18 g commercial
protocatechualdehyde (
3,4-dihydroxybenzaldehyde) in 200 mL warm acetic
acid was filtered free of any in
solubles, to provide a very dark but
clear
solution. With good stirring there was then added 20 g
elemental
bromine. The reaction spontaneously heated to about 30 °C
and solids appeared in about 5 min. Stirring was continued for 1 h,
and then the light gray solids that had formed were removed by
filtration and lightly washed with acetic acid. These were air dried
on the steam bath until free of acetic acid smell. The product,
3-bromo-4,5-dihydroxybenzaldehde, weighed 11.7 g and had a mp of 222
°C.
To a
solution of 11.7 g
3-bromo-4,5-dihydroxybenzaldehyde in 36 mL
DMSO there was added 29 g
methylene iodide followed by 20.8 g
anhydrous K2CO3. This was heated on the steam bath for 3 h, added to
1 L H2O, made strongly basic with
NaOH, then extracted with 3x100 mL
CH2Cl2. These extracts were pooled, washed with H2O, and the
solvent
removed under vacuum. The dark brown semi-solid residue was
distilled
with the major fraction (6.0 g) coming over at 120-130 °C at 0.3
mm/
Hg. This, upon re
crystallization from 35 g boiling MeOH, gave 1.3
g of
3-bromo-4,5-methylenedioxybenzaldehyde as an off white
crystalline solid with a mp of 123-124 °C.
A mixture of 2.2 g
3-bromo-4,5-methylenedioxybenzaldehyde and 3.6 mL
cyclohexylamine in a
distillation flask was heated to 100 °C to effect
solution, and then with an open flame until the signs of H2O evolution
were evident. This was then placed under a hard vacuum to remove the
generated water and excess
cyclohexylamine, and the product
distilled
at 120-125 °C at 0.2 mm/
Hg. There was obtained 2.4 g of the Schiff
base of the
aldehyde and the
amine, melting at 86-96 °C.
Re
crystallization of an
analytical sample from 5 volumes of MeOH gave
3-bromo-4,5-
methylenedioxybenzylidine-N-
cyclohexylamine as a white
solid with a mp of 97.5-98.5 °C. Anal. (
C14H16BrNO2) H; C: calcd,
54.20; found, 53.78.
A
solution of 2.2 g
3-bromo-4,5-
methylenedioxybenzylidine-N-
cyclohexylamine (the above
Schiff base) in 50 mL
anhydrous Et2O was placed in a He
atmosphere,
stirred
magnetically, and cooled with a dry ice/
acetone bath. A white
fine
crystalline phase appeared. There was then added 5.2 mL 1.55 M
butyllithium in hexane (the fine solids
dissolved) followed by 4.0 mL
of
tributyl borate. After returning to room tem
perature, the reaction
was quenched with 20 mL of saturated aqueous
ammonium sulfate. The
Et2O/hexane layer was separated, washed with additional
ammonium
sulfate solution, and then stripped of
volatiles under vacuum. The
residue was
dissolved in 100 mL 50% MeOH, treated with 2 mL of 30%
hydrogen
peroxide and, after 15 min swirling, quenched with a
solution
of 10 g
ammonium sulfate in 50 mL H2O. This aqueous
phase (
pH about
8) was extracted with 2x50 mL
CH2Cl2, the extract pooled and stripped
of
solvent under vacuum, and the residue
dissolved in warm, dilute
HCl. After all the residue had
dissolved (a few min heating was
sufficient), the
solution was cooled to room tem
perature and extracted
with 2x50 mL
CH2Cl2. These organics were pooled and extracted in turn
with 2x50 mL 5%
NaOH.
Acidification of the pooled aqueous fractions
with HCl, followed by extraction with 2x50 mL
CH2Cl2 gave, after
evaporation of the
solvent, a residue that was
distilled at 140-150 °C
at 0.25 mm/
Hg to give
3-hydroxy-4,5-methylenedioxybenzaldehyde. This
was re
crystallized from
toluene (40 mL/g) to give 0.46 g of an
off-white product with a mp of 134-134.5 °C. Anal. (
C8H6O4) C,H.
A
solution of 0.44 g
3-hydroxy-4,5-methylenedioxybenzaldehyde in 10 mL
dry
acetone was treated with 0.5 g
methyl iodide and 0.5 g powdered
anhydrous K2CO3, and was held at reflux for 6 h. All
volatiles were
stripped under vacuum, the residue
dissolved in water, made strongly
basic with
NaOH, and extracted with 3x50 mL
CH2Cl2. Removal of the
solvent gave
myristicinaldehyde (mp 133-134 °C) which, on
re
crystallization from hexane, gave a final yield of 0.42 g with a mp
of 134-135 °C. Care must be taken with two sequential products that
have identical mps. A mixed mp with the un
methylated phenol above is
strong depressed, whereas that with an authentic sample is not.
A
solution of 9.8 g
myristicinaldehyde in 35 mL glacial acetic acid
was treated with 5.3 mL
nitroethane and 3.2 g
anhydrous ammonium
acetate, and heated on the steam bath for 1.5 h. It was removed,
treated with H2O with good stirring to just short of turbidity, seeded
with product
nitrostyrene, and allowed to come slowly to room
tem
perature. The bright yellow solids that formed were removed by
filtration, washed with a small amount of aqueous acetic acid, and
sucked as free of
solvent as possible. This material, pressed on a
porous plate, had a mp of 107-110 °C. Re
crystallization from 60 mL
boiling
EtOH gave, after filtering and air drying, 5.1 g of
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene as light yellow
solids with a mp of 109-110 °C.
A suspension of 7.5 g LAH in 500 mL
anhydrous Et2O was
magnetically
stirred, and heated in an inert
atmosphere to a gentle reflux. The
condensing
Et2O leached out a total of 9.8 g
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene from a Soxhlet
thimble in a shunted reflux
condenser. This, in effect, added the
nitrostyrene to the reaction medium as a warm saturated
Et2O solution.
When the addition was completed, the refluxing was maintained for an
additional 5 h, then the reaction mixture was cooled and the excess
hydride destroyed by the addition of 400 mL 1.5 N H2SO4 (the first 20
mL a drop at a time and with very good stirring). The
phases were
separated, and sufficient saturated aqueous
Na2CO3 was added to the
aqueous
phase to bring the
pH up to about 6.0. This was heated to 80
°C and filtered through a coarse sintered glass funnel to remove some
in
soluble fines. The clear filtrate was brought up almost to a boil,
and treated with a
solution of 10.2 g of 90% picric acid in 110 mL
boiling
EtOH. Crystals of the picrate formed immediately at the
edges, and as the reaction flask was cooled in an ice tub, the entire
reaction set to a yellow mass of
crystals. These were removed by
filtration, washed sparingly with 80%
EtOH, and air dried to give 14.0
g of the picrate salt of M
MDA, with a mp of 182-184 °C.
Re
crystallization of a small sample from
EtOH dropped this to 179-181
°C. This salt was treated with 30 mL 5%
NaOH, and the red
solution
decanted from some in
solubles. Additional H2O and
NaOH effectively
dissolved everything, and the resulting basic aqueous
phase was
extracted with 3x50 mL
CH2Cl2. The pooled extracts were stripped of
solvent under vacuum, and the residue
dissolved in 200 mL
anhydrous
Et2O and saturated with
anhydrous HCl gas. There was a heavy
precipitation of white
crystals, which were removed by filtration,
Et2O washed, and air dried to give 6.37 g
3-methoxy-4,5-methylenedioxyamphetamine hydrochloride (M
MDA) with a mp
of 190-191 °C. Anal. (
C11H16ClNO3) Cl.
(from Oil of Nutmeg) The careful
distillation of Oil of Nutmeg (or the
Oil of Mace) allowed the isolation of a number of compounds in varying
degrees of purity. The fraction that boiled in the 110-115 °C range
at about 1.0 mm/
Hg was myristicin
(
3-methoxy-4,5-methylenedioxyallylbenzene). It constituted some 7% of
the original oil of commerce and, in its original isolated form, was
obtained with a purity of 87%. The major contaminant was elemicin
(
3,4,5-trimethoxyallylbenzene). A
solution of 100 g myristicin in 100
g absolute
EtOH was treated with 200 g solid KOH and heated on a steam
bath overnight. Removal of the
volatiles under vacuum, flooding the
residue with H2O, and extraction with 3x100 mL
CH2Cl2 gave, after
removal of the
solvent from the combined extracts, a residue of crude
isomyristicin (a mixture of the cis- and trans-
isomers). This product
was
distilled, and the fraction boiling at 125-130 °C at 1 mm/
Hg gave
63 g of
isomyristicin as a pale yellow oil that spontaneously
crystallized. The mp was 41.5-42.5 °C. Part of the losses associated
with the purification of these solids was due to formation of the
cis-
isomer of
isomyristicin, which was an oil.
A
solution of 50 g
isomyristicin in 300 mL dry
acetone containing 24 g
pyridine was vigorously stirred and cooled to 0 °C with an ice bath.
To this there was added 54 g
tetranitromethane which had been
pre-cooled to 0 °C. Stirring was continued for exactly 2 min, and
then the reaction was quenched by the addition of a cold
solution of
16.8 g KOH in 300 mL H2O. Stirring was continued until the
tem
perature had again been lowered to near 0 °C. The product was
removed by filtration. Extraction of the filtrate with
CH2Cl2 and
removal of the
solvent provided additional
nitrostryrene, for a
combined yield of 50.7 g with a mp of 103 °C due to the presence of a
small amount of free
myristicinaldehyde. A re
crystallization from
MeOH produced
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene
with a mp of 109-110 °C. This material was completely adequate for
the above-described reduction to M
MDA. The conversion of this
nitropropene to
myristicinaldehyde is an alternative to the lengthy
synthesis given above), and can be used in the preparation of
LOPHOPHINE.
A mixture of 50 g
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene and 26 g racemic
a-methylbenzylamine was heated on the steam bath. The mixture
gradually formed a clear
solution with the steady evolution of
nitroethane. When the reaction became quiet, there was added a
mixture of 20 mL concentrated HCl in 100 mL H2O. The reaction mixture
dissolved completely, and as the tem
perature continued to rise there
was the abrupt
solidification as the formed
myristicinaldehyde
crystallized out. This product was removed by filtration and, when
combined with a second crop obtained by the hexane extraction of the
filtrate, gave 36.9 g of
myristicinaldehyde. The mp of 128-129 °C was
raised to 133-134 °C by re
crystallization from hexane.
DOSAGE: 100 - 250 mg.
DURATION: moderate.
QUALITATIVE COMMENTS: (with 100 mg) I felt completely relaxed at one
hour. Almost as if I was floating. There were no obvious effects on
taste, and the relaxation and composed feeling is much like a small
dose, maybe 20 mikes, of LSD. There was some dilation, and in the
evening I was a little restless and slightly tired. I slept well, and
awoke refreshed and happy.
(with 100 mg) It seemed to take 45 minutes to work and then it came
on very suddenly, as if my eyeballs were being pulled out and my whole
head expanding. Soon a cold feeling set in with shivering--this was
not unpleasant. My state in about two hours seemed to be one of
empathy and passivity, compassion of an impersonal sort. The music
sounded artificial and canned and tinny, in contrast to the voices,
which sounded rich and full and finely articulated and melodious.
(with 150 mg) We are on the beach at the river mouth drying seaweed,
on split redwood. There is a slight nausea, slight cramps, and then
my visual field starts to light up. Still
vertigo but only with my
eyes open, and heaviness and time stretches out; numbness in the chest
as when an
opiate is taken. There are geometric patterns, but the
excess light on my closed eyelids interferes with this. A dance of
the glittering
diamond studded sea waves, increasing motion and
beauty. More landscapes appear inside. This is a good introductory
drug to the drugs of this class, to become familiar with the drug
state in as gentle a fashion as possible. This substance seems to
have a much gentler action than others of this class; perhaps more
like cannabis or
psilocybin. There is very little paranoia. I note
hallucinations of two types: those which are strictly retinal and more
minute and small and influenced by light and focused on the light
ahead on the retina or lids; and the other, those deep in the visual
tract and occiput which are larger and more global and dream-like and,
when solid, are quite dramatic and unforgettable as in meditation.
(with 210 mg) M
MDA tastes awful. The bitter
alkaloid taste is
followed by a distinctively chemical laboratory flavor as if from old
rubber tubing. Nothing seems to happen for about 45 minutes when
rather suddenly an anvil seems to lower itself over your head; you
feel disoriented, and tend to withdraw from social contact a little.
The drug gives less feeling of being ill than mescaline. The effect
definitely reaches a climax with a pleasant
afterglow following.
Apparently there are no profound motor coordination problems. M
MDA
yields that 'Sunday afternoon' feeling of desiring to lie down and
enjoy life; a luxurious feeling of 'layback.' No enhancement of
colors in visual scene (except for some greenish tinges in faces) but
upon closing eyes
hallucinations appear to be quite real in 3-D, like
watching a movie. First these dreams appear in black and white, but
later colors start appearing.
Chartreuse and magenta first appear,
then blue and finally red. First I had visions of large numbers on
gaming tables, then people. M
MDA appears to bring dreams to the
conscious level; is a link between the subconscious and the
conscious.
(with 225 mg) I had a strange awareness of my hands in about 20
minutes--not a feeling in them as just that I was attracted to them
somehow. Then I began to get fearful, an acute experience of
aloneness. I lay face down (a depressed position for me). Next I was
talking to the kids at school (an image) or to other teachers. This
was very vivid. The scenes at school were more vivid that the real
scenes around me here. Those people were much more real. I am
actually very sleepy right now during the experiment. Of any
experience I have had, this was most like a series of dreams easily
remembered. When it was over, I felt as if I had had a long period of
sleeping--I had gone to bed and had a series of dream-like states
very vivid and colorful and real.
EXTENSIONS AND COMMENTARY: The phrase that had been used by several of
the subjects in the early trials with M
MDA, again and again, was
"brain movies." Apparently the richest of the effects were to be had
with the eyes closed. This is the compound that I had first completed
in 1962, and had named it M
MDA, and had begun the exploring of it when
I heard that Dr. Gordon A. Alles, a professor of
pharmacology at U. C.
L. A. who had his own private laboratory in Los Angeles, had also
synthesized it in 1962, had also named it M
MDA, and had also begun
exploring it. We made a date to meet and share ideas, and then he
died, at the age of 62, in 1963.
This is a material that might be a contributing factor to the
pharmacology of nutmeg. The major essential oil from that spice is
myristicin, and it is the easiest source of M
MDA. It has been
reported that the passage of this oil through the liver of a rabbit
will generate M
MDA in that animal. The only difference between the
two molecules, structurally, are the elements of
ammonia. Myristicin
plus
ammonia gives M
MDA. Another natural source of myristicin is Oil
of Parsley, which is also an excellent source of apiole, mentioned
under DM
MDA. A rumor that had currency in the 1960's, that parsley
could get you high, probably had its origins in the reports of
myristicin being present, coupled with myristicin being the principal
source of M
MDA. The relationship to myristicin (an essential oil) led
to the classifying of M
MDA as a Essential Am
phetamine. These
relationships are expanded upon, under TMA.
At the time that the
FDA issued its proclamation of dangerous drugs
(in the mid-1960's), M
MDA was being talked about, and in fact it had
just become available commercially in England through the Koch Light
Industries. But to my knowledge it had never appeared on the street,
so its having being swept into the listings of evil drugs was simply a
coincidence of bad timing. The close resemblance of initials between
M
MDA, and the currently notorious
MDMA, has led to no small amount of
confusion in the popular press. They remain totally separate and
completely different drugs.
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