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#97 4-MA
PMA; 4-METHOXYAMPHETAMINE
SYNTHESIS: A
solution of 27.2 g
anisaldehyde and 18.0 g
nitroethane in
300 mL
benzene was treated with 2.0 mL
cyclohexane and refluxed using
a Dean Stark trap until H2O ceased to accumulate. A total of 3.8 mL
was generated over about 5 days. After the removal of the
solvent
under vacuum, the viscous red oily residue was cooled and it
spontaneously
crystallized. This was ground under an equal volume of
MeOH, producing lemon-yellow
crystals of
1-(4-methoxyphenyl)-2-nitropropene. The final yield was 27.4 g of
product with a mp of 45-46 °C. Re
crystallization from 4 volumes MeOH
did not improve the mp. An excellent alternate synthesis with a
comparable yield involved letting a
solution of
equimolar amounts of
the
aldehyde and nitro-
ethane and a tenth mole of n-
amylamine stand in
the dark at room tem
perature for a couple of weeks. The product
spontaneously
crystal-lized, and could be re
crystallized from MeOH.
The more conventional synthesis involving acetic acid as a
solvent and
ammonium acetate as a
catalyst, produced a poor yield of the
nitrostyrene and it was difficult to separate from the white
diacetate
of the starting
anisaldehyde, mp 59-60 °C.
A suspension of 32 g LAH in 1 L
anhydrous Et2O was well stirred and
32.6 g
1-(4-methoxyphenyl)-2-nitropropene in
Et2O was added at a rate
that maintained a reflux. After the addition was complete, reflux was
continued for 48 h. The reaction mixture was cooled, and the excess
hydride was destroyed by the cautious addition of dilute H2SO4. The
Et2O was separated, and extracted with additional aqueous H2SO4. A
solution of 700 g
potassium sodium tartrate in 600 mL H2O was added,
and the
pH brought to >9 with 25%
NaOH. This aqueous
phase was
extracted with 3x200 mL
CH2Cl2 which provided, after removal of the
solvent, 32.5 g of a clear amber oil. This was
dissolved in 100 mL
IPA, neutralized with concentrated HCl, and then diluted with 300 mL
anhydrous Et2O. There was obtained white
crystals of
4-methoxyamphetamine hydrochloride (4-MA) that weighed, after
filtering,
Et2O washing and air drying, 22.2 g and had a mp of 208-209
°C. The
amphetamine metabolite,
4-hydroxyamphetamine hydrochloride
(4-HA), was prepared by heating 5.0 g 4-MA in 20 mL concentrated HCl
at 15 lbs/in. After re
crystal-lization from aqueous
EtOH, the product
weighed 3.8 g and had a mp of 171-172 °C.
DOSAGE: 50 - 80 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 60 mg) At just over an hour, there was a
sudden blood pressure rise, with the systolic going up 55 mm. This
was maintained for another hour. I found the effects
reminiscent of
DET, distinct after-images, and some
parasthesia. I was without any
residue by early evening (after 5 hours).
(with 70 mg) It hit quite suddenly. I had a feeling of druggedness,
almost an
alcohol-like intoxication, and I never was really high in
the
psychedelic sense.
EXTENSIONS AND COMMENTARY: This is another of the essential
amphetamines, because of the appearance of the 4-methoxy group in two
most important essential oils. These are the
allylbenzene (
estragole
or esdragol) and the
propenyl isomer (anethole). Their natural
sources have been discussed under TMA.
Two comments are warranted concerning 4-MA, one of scientific
interest, and the other about a social tragedy.
A major
metabolites of
amphetamine is
4-hydroxyamphetamine, from
oxidation at the 4-position. It has been long known that with chronic
amphetamine usage there is the generation of tolerance, which
encourages ever-increasing doses to be used. When the daily load gets
up around one or two hundred milligrams, the subject can become quite
psychotic. The question was asked: might the chronic
amphetamine user
be
methylating his endogenously produced
4-hydroxyamphet-amine to
produce
4-methoxyamphetamine (4-MA), and maybe this is the agent that
promotes the
psychosis? To address this question, several studies
were done with normal subjects, about 20 years ago, to see if 4-MA
might produce a
psychotic state (it didn't at the highest levels
tried, 75 milligrams) and to see if it was excreted to some extent
unchanged in the urines of these normal subjects (it was seen even at
the lowest dosage tried, 10 milligrams). It produced excitation and
other central effects, it produced
adrenergic pressor effects, and it
consistently produced measur-able quantities of 4-MA in the urine, but
it produced no
amphetamine-like crazies. And since the administration
of up to 600 milligrams of
amphetamine produced no detectable 4-MA in
the urine, this theory of
psychotomimesis is not valid.
On the tragic side, a few years later, 4-MA became widely distributed
in both the US (as the
sulfate salt) and in
Canada (as the
hydrochloride), perhaps in-spired by some studies in rats that had
reported that it was second only to LSD in potency as a
hallucinogen.
The several deaths that occurred probably followed overdose, and it
was clear that 4-MA was involved as it had been isolated from both
urine and
tissue during post mortems. It had been sold under the
names of Chicken Power and Chicken Yellow, and was promoted as being
MDA. I could find no record of a typical street dosage, but comments
collected in association with the deaths implied that the ingested
quantites were in the hundreds of milligrams. Rrecently, the ethoxy
homologue, 4-EA, appeared on the streets of
Canada. The dosage,
again, was not reported. It was promptly illegalized there.
The two positional
analogues of 4-MA are known; vis., 2-MA and 3-MA.
Their synthesis is straightforward, in imitation of that for 4-MA
above. The meta-compound, 3-MA, has been
metabolically explored in
man, but no central effects were noted at a 50 milligram dose (2x25
milligrams, separated by three hours). There appears to be no report
of any human trial of 2-MA. The N-
methyl homologue of 2-MA is a
commercial
adrenergic bronchodilator called
Methoxyphenamine, or
Orthoxine. It has been used in the prevention of acute asthma attacks
in doses of up to 200 milligrams, with only slight central
stimulation. The N-
methyl homologues of 3-MA and 4-MA are known, and
the latter compound is the stuff of a separate entry in this book.
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