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MDM; ADAM; ECSTASY; 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE
SYNTHESIS: (from
MDA) A
solution of 6.55 g of
3,4-methylenedioxyamphetamine (
MDA) as the free base and 2.8 mL
formic
acid in 150 mL
benzene was held at reflux under a Dean Stark trap
until no further H2O was generated (about 20 h was sufficient, and 1.4
mL H2O was collected). Removal of the
solvent gave an 8.8 g of an
amber oil which was
dissolved in 100 mL
CH2Cl2, washed first with
dilute HCl, then with dilute
NaOH, and finally once again with dilute
acid. The
solvent was removed under vacuum giving 7.7 g of an amber
oil that, on standing, formed
crystals of
N-
formyl-
3,4-methylenedioxyamphetamine. An alternate process for the
synthesis of this amide involved holding at reflux for 16 h a
solution
of 10 g of
MDA as the free base in 20 mL fresh
ethyl formate. Removal
of the
volatiles yielded an oil that set up to white
crystals,
weighing 7.8 g.
A
solution of 7.7 g N-
formyl-
3,4-methylenedioxyamphetamine in 25 mL
anhydrous THF was added dropwise to a well stirred and refluxing
solution of 7.4 g LAH in 600 mL
anhydrous THF under an inert
atmosphere. The reaction mixture was held at reflux for 4 days.
After being brought to room tem
perature, the excess
hydride was
destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4
mL of 15%
NaOH and then another 22 mL H2O. The solids were removed by
filtration, and the filter cake washed with additional THF. The
combined filtrate and washes were stripped of
solvent under vacuum,
and the residue
dissolved in 200 mL
CH2Cl2. This
solution was
extracted with 3x100 mL dilute HCl, and these extracts pooled and made
basic with 25%
NaOH. Extraction with 3x75 mL
CH2Cl2 removed the
product, and the pooled extracts were stripped of
solvent under
vacuum. There was obtained 6.5 g of a nearly white residue which was
distilled at 100-110 ° C at 0.4 mm/
Hg to give 5.0 g of a colorless oil.
This was
dissolved in 25 mL IPA, neutralized with concentrated HCl,
followed by the addition of sufficient
anhydrous Et2O to produce a
lasting turbidity. On continued stirring, there was the
deposition of
fine white
crystals of
3,4-methylenedioxy-N-
methylamphetamine
hydrochloride (
MDMA) which were removed by filtration, washed with
Et2O, and air dried, giving a final weight of 4.8 g.
(from
3,4-methylenedioxyphenylacetone) This key intermediate to all of
the MD-series can be made from either
isosafrole, or from
piperonal
via
1-(3,4-methylenedioxyphenyl)-2-nitropropene. To a well stirred
solution of 34 g of 30% hydrogen
peroxide in 150 g 80%
formic acid
there was added, dropwise, a
solution of 32.4 g
isosafrole in 120 mL
acetone at a rate that kept the reaction mixture from exceeding 40 ° C.
This required a bit over 1 h, and external cooling was used as
necessary. Stirring was continued for 16 h, and care was taken that
the slow exothermic reaction did not cause excess heating. An
external bath with running water worked well. During this time the
solution progressed from an orange color to a deep red. All
volatile
components were removed under vacuum which yielded some 60 g of a very
deep red residue. This was
dissolved in 60 mL of MeOH, treated with
360 mL of 15% H2SO4, and heated for 3 h on the steam bath. After
cooling, the reaction mixture was extracted with 3x75 mL
Et2O, the
pooled extracts washed first with H2O and then with dilute
NaOH, and
the
solvent removed under vacuum The residue was
distilled (at 2.0
mm/108-112 ° C, or at about 160 ° C at the water pump) to provide 20.6 g
of
3,4-methylenedioxyphenylacetone as a pale yellow oil. The oxime
(from
hydroxylamine) had a mp of 85-88 ° C. The
semicarbazone had a mp
of 162-163 ° C.
An alternate synthesis of
3,4-methylenedioxyphenylacetone starts
originally from
piperonal. A suspension of 32 g
electrolytic iron in
140 mL glacial acetic acid was gradually warmed on the steam bath.
When quite hot but not yet with any white salts apparent, there was
added, a bit at a time, a
solution of 10.0 g of
1-(3,4-methylenedioxyphenyl)-2-nitropropene in 75 mL acetic acid (see
the synthesis of
MDA for the preparation of this
nitrostyrene
intermediate from
piperonal and
nitroethane). This addition was
conducted at a rate that permitted a vigorous reaction free from
excessive frothing. The orange color of the reaction mixture became
very reddish with the formation of white salts and a dark crust.
After the addition was complete, the heating was continued for an
additional 1.5 h during which time the body of the reaction mixture
became quite white with the product appeared as a black oil climbing
the sides of the beaker. This mixture was added to 2 L H2O, extracted
with 3x100 mL
CH2Cl2, and the pooled extracts washed with several
portions of dilute
NaOH. After the removal of the
solvent under
vacuum, the residue was
distilled at reduced pressure (see above) to
provide 8.0 g of
3,4-methylenedioxyphenylacetone as a pale yellow oil.
To 40 g of thin
aluminum foil cut in 1 inch squares (in a 2 L wide
mouth
Erlenmeyer flask) there was added 1400 mL H2O containing 1 g
mercuric chloride. Amalgamation was allowed to proceed until there
was the evolution of fine bubbles, the formation of a light grey
precipitate, and the appearance of occasional silvery spots on the
surface of the
aluminum. This takes between 15 and 30 min depending on
the freshness of the surfaces, the tem
perature of the H2O, and the
thickness of the
aluminum foil. (Aluminum foil thickness varies from
country to country.) The H2O was removed by
decantation, and the
aluminum was washed with
2x1400 mL of fresh H2O. The
residual H2O
from the final washing was removed as thoroughly as possible by
shaking, and there was added, in succession and with swirling, 60 g
methylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145
mL 25%
NaOH, 53 g
3,4-methylenedioxyphenylacetone, and finally 350 mL
IPA. If the available form of
methylamine is the aqueous
solution of
the free base, the following sequence can be
substituted: add, in
succession, 76 mL 40% aqueous
methylamine, 180 mL IPA, a suspension of
50 g
NaCl in 140 mL H2O that contains 25 mL 25%
NaOH, 53 g
3,4-methylenedioxyphenylacetone, and finally 350 mL IPA. The
exothermic reaction was kept below 60 ° C with occasional immersion
into cold water and, when it was thermally stable, it was allowed to
stand until it had returned to room tem
perature with all the
in
solubles settled to the bottom as a grey sludge. The clear yellow
overhead was decanted and the sludge removed by filtration and washed
with MeOH. The combined
decantation, mother liquors and washes, were
stripped of
solvent under vacuum, the residue suspended in 2400 ml of
H2O, and sufficient HCl added to make the
phase distinctly acidic.
This was then washed with 3x75 mL
CH2Cl2, made basic with 25%
NaOH,
and extracted with 3x100 mL of
CH2Cl2. After removal of the
solvent
from the combined extracts, there remained 55 g of an amber oil which
was
distilled at 100-110 ° C at 0.4 mm/
Hg producing 41 g of an
off-white liquid. This was
dissolved in 200 mL IPA, neutralized with
about 17 mL of concentrated HCl, and then treated with 400 mL
anhydrous Et2O. After filtering off the white
crystals, washing with
an IPA/
Et2O mixture, (2:1), with Et2O, and final air drying, there was
obtained 42.0 g of
3,4-methylenedioxy-N-
methylamphetamine (
MDMA) as a
fine white
crystal. The actual form that the final salt takes depends
upon the tem
perature and concentration at the moment of the initial
crystallization. It can be
anhydrous, or it can be any of several
hydrated forms. Only the
anhydrous form has a sharp mp; the published
reports describe all possible one degree melting point values over the
range from 148-153 ° C. The variously
hydrated
polymorphs have
distinct infrared
spectra, but have broad mps that depend on the rate
of heating.
DOSAGE: 80 - 150 mg.
DURATION: 4 - 6 h.
QUALITATIVE COMMENTS: (with 100 mg)
MDMA intrigued me because
everyone I asked, who had used it, answered the question, 'What's it
like?' in the same way: 'I don't know.' 'What happened?' 'Nothing.'
And now I understand those answers. I too think nothing happened.
But something seemed changed. Before the 'window' opened completely,
I had some
somatic effects, a tingling sensation in the fingers and
temples--a pleasant sensation, not distracting. However, just after
that there was a slight nausea and dizziness similar to a little too
much
alcohol. All these details disappeared as I walked outside. My
mood was light, happy, but with an underlying conviction that
something significant was about to happen. There was a change in
perspective both in the near visual field and in the distance. My
usually poor vision was sharpened. I saw details in the distance that
I could not normally see. After the peak experience had passed, my
major state was one of deep relaxation. I felt that I could talk
about deep or personal subjects with special clarity, and I
experienced some of the feeling one has after the second martini, that
one is discoursing brilliantly and with particularly acute
analytical
powers.
(with 100 mg) Beforehand, I was aware of a dull, uncaring tiredness
that might have reflected too little sleep, and I took a modest level
of
MDMA to see if it might serve me as a stimulant. I napped for a
half hour or so, and woke up definitely not improved. The feeling of
insufficient energy and lack of spark that I'd felt before had become
something quite strong, and might be characterized as a firm feeling
of negativity about everything that had to be done and everything I
had been looking forward to. So I set about my several tasks with no
pleasure or enjoyment and I hummed a little tune to myself during
these activities which had words that went: 'I shouldn't have done
that, oh yes, I shouldn't have done that, oh no, I shouldn't have done
that; it was a mistake.' Then I would start over again from the
beginning. I was stuck in a gray space for quite a while, and there
was nothing to do but keep doing what I had to do. After about 6
hours, I could see the whole mental state disintegrating and my
pleasant feelings were coming back. But so was my plain, ornery
tiredness.
MDMA does not work like
Dexedrine.
(with 120 mg) I feel absolutely clean inside, and there is nothing
but pure
euphoria. I have never felt so great, or believed this to be
possible. The cleanliness, clarity, and marvelous feeling of solid
inner strength continued throughout the rest of the day, and evening,
and through the next day. I am overcome by the profundity of the
experience, and how much more powerful it was than previous
experiences, for no apparent reason, other than a continually
improving state of being. All the next day I felt like 'a citizen of
the universe' rather than a citizen of the planet, completely
disconnecting time and flowing easily from one activity to the next.
(with 120 mg) As the material came on I felt that I was being
enveloped, and my attention had to be directed to it. I became quite
fearful, and my face felt cold and ashen. I felt that I wanted to go
back, but I knew there was no turning back. Then the fear started to
leave me, and I could try taking little baby steps, like taking first
steps after being reborn. The woodpile is so beautiful, about all the
joy and beauty that I can stand. I am afraid to turn around and face
the mountains, for fear they will overpower me. But I did look, and I
am astounded. Everyone must get to experience a profound state like
this. I feel totally peaceful. I have lived all my life to get here,
and I feel I have come home. I am complete.
(with 100 mg of the "R"
isomer) There were the slightest of effects
noted at about an hour (a couple of
paresthetic twinges) and then
nothing at all.
(with 160 mg of the "R"
isomer) A disturbance of baseline at about
forty minutes and this lasts for about another hour. Everything is
clear by the third hour.
(with 200 mg of the "R"
isomer) A progression from an alert at thirty
minutes to a soft and light intoxication that did not persist. This
was a modest +, and I was at baseline in another hour.
(with 60 mg of the "S"
isomer) The effects began developing in a
smooth, friendly way at about a half-hour. My handwriting is OK but I
am writing faster than usual. At the one hour point, I am quite
certain that I could not drive, time is slowing down a bit, but I am
mentally very active. My pupils are considerably dilated. The
dropping is evident at two hours, and complete by the third hour. All
afternoon I am peaceful and relaxed, but clear and alert, with no
trace of physical residue at all. A very successful ++.
(with 100 mg of the "S"
isomer) I feel the onset is slower than with
the racemate. Physically, I am excited, and my pulse and blood
pressure are quite elevated. This does not have the 'fire' of the
racemate, nor the rush of the development in getting to the plateau.
(with 120 mg of the "S"
isomer) A rapid development, and both writing
and typing are impossible before the end of the first hour. Lying
down with eyes closed eliminates all effects; the visual process is
needed for any awareness of the drug's effects. Some teeth clenching,
but no nystagmus. Excellent sleep in the evening.
EXTENSIONS AND COMMENTARY: In clinical use, largely in
psychotherapeutic sessions of which there were many in the early years
of
MDMA study, it became a common procedure to provide a supplemental
dosage of the drug at about the one and a half hour point of the
session. This supplement, characteristically 40 milligrams following
an initial 120 milligrams, would extend the expected effects for about
an additional hour, with only a modest exacerbation of the usual
physical side-effects, namely, teeth clenching and eye twitching. A
second supplement (as, for instance, a second 40 milligrams at the two
and a half hour point) was rarely felt to be warranted. There are,
more often than not, reports of tiredness and lethargy on the day
following the use of
MDMA, and this factor should be considered in the
planning of clinical sessions.
With
MDMA, the usual assignments of activity to optical
isomers is
reversed from all of the known
psychedelic drugs. The more potent
isomer is the "S" isomer, which is the more potent form of
amphetamine
and
methamphetamine. This was one of the first clear distinctions
that was apparent between
MDMA and the structurally related
psychedelics (where the "R"
isomers are the more active). Tolerance
studies also support differences in mechanisms of action. In one
study,
MDMA was consumed at 9:00 AM each day for almost a week (120
milligrams the first day and 160 milligrams each subsequent day) and
by the fifth day there were no effects from the drug except for some
mydriasis. And even this appeared to be lost on the sixth day. At
this point of total tolerance, there was consumed (on day #7, at 9:00
AM) 120 milligrams of
MDA and the response to it was substantially
normal with proper chronology, teeth clench, and at most only a slight
decrease in mental change. A complete holiday from any drug for
another 6 days led to the reversal of this tolerance, in that 120
milligrams of
MDMA had substantially the full expected effects. The
fact that
MDMA and
MDA are not cross-tolerant strengthens the argument
that they act in different ways, and at different sites in the brain.
A wide popularization of the social use of
MDMA occurred in 1984-1985
and, with the reported observation of
serotonin nerve changes in
animal models resulting from the administration of the structurally
similar drug
MDA, an administrative move was launched to place it
under legal control. The placement of
MDMA into the most restrictive
category of the
Federal Controlled Substances Act has effectively
removed it from the area of clinical experimentation and human
research. The medical potential of this material will probably have
to be developed through studies overseas.
A word of caution is in order concerning the intermediate
3,4-methylene-dioxyphenylacetone, which has also been called
piperonylacetone. A devilish ambiguity appeared in the commercial
market for this compound, centered about its name. The controversy
focused on the meaning of the prefix,
piperonyl, which has two
separate chemical definitions. Let me try to explain this fascinating
chaos in non-chemical terms. Piperonyl is a term that has been used
for a two-ring system (the
methylenedioxyphenyl group) either without,
or with, an extra
carbon atom sticking off of the side of it. Thus,
piperonylacetone can be piperonyl (the two-ring thing without the
extra
carbon atom attached) plus
acetone (a three carbon chain thing);
the total number of
carbons sticking out, three. Or,
piperonylacetone
can be
piperonyl (the two-ring thing but with the extra
carbon atom
attached) plus
acetone (a three
carbon chain thing); the total number
of
carbons sticking out, four.
Does this make sense?
The three
carbon sticking out job gives rise to
MDA and to
MDMA and to
many
homologues that are interesting materials discussed at length in
these Book II comments. This is the usual item of commerce, available
from both domestic and foreign suppliers. But the four-
carbon
sticking out job will produce totally weird stuff without any apparent
relationship to
psychedelics,
psychoactives or
psychotropics
whatsoever. I know of one chemical supply house which supplied the
weird compound, and they never did acknowledge their unusual use of
the term
piperonyl. There is a simple difference of properties which
might be of value. The three
carbon (correct)
ketone is an oil with a
sassafras smell that is always yellow colored. The four
carbon
(incorrect)
ketone has a weak
terpene smell and is white and
crystalline. There should be no difficulties in distinguishing these
two compounds. But unprincipled charlatans can always add mineral oil
and butter yellow to otherwise white solids to make them into yellow
oils.
Caveat emptor.
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