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#54 2,5-DMA
DMA; 2,5-DIMETHOXYAMPHETAMINE
SYNTHESIS: A
solution of 10.0 g
2,5-dimethoxybenzaldehyde in 50 mL
glacial acetic acid was treated with 6.8 g of
nitroethane and 4.0 g of
anhydrous ammonium acetate. This mixture was heated on the steam bath
for 3 h and then the reagent/
solvent was removed under vacuum. The
residue was suspended in H2O and extracted with CHCl3. Removal of the
solvent from the pooled extracts yielded 11.2 g of an impure
1-(2,5-dimethoxyphenyl)-2-nitropropene which, on re
crystallization
from 75 mL boiling MeOH, gave 6.7 g of product with a mp of 73-75 °C.
Anal. (
C11H13NO4) C,H,N. This
nitrostyrene has been periodically
available commercially from a number of sources.
A
solution of 17.0 g of
1-(2,5-dimethoxyphenyl)-2-nitropropene was
prepared in 500 mL
anhydrous Et2O. This
solution was added slowly to
a well-stirred suspension of 12.0 g LAH in 700 mL
anhydrous Et2O. The
mixture was then brought up to a reflux and maintained there for 20 h,
cooled with an external ice bath, and the excess
hydride destroyed by
the cautious addition of H2O. Finally, a total of 500 mL H2O was
added, followed by the addition of 300 g
potassium sodium tartrate,
and sufficient aqueous
NaOH to bring the
pH above 9. The two
phases
were separated, and the
ether phase dried by the addition of
anhydrous
MgSO4. The drying agent was removed by filtration, and the clear
filtrate saturated with a stream of
anhydrous HCl gas. The formed
crystals of
2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) were
removed by filtration, washed with
anhydrous Et2O, and dried to
constant weight of 16.3 g. Re
crystallization from
EtOH gave an
analytical sample with a mp of 114-116 °C. The
hydrobromide salt is
reported to melt at 129-131 °C.
DOSAGE: 80 - 160 mg.
DURATION: 6 - 8 h.
EXTENSIONS AND COMMENTARY: The qualitative information on 2,5-DMA is
very sparse. I was up to a 1+ with 80 milligrams of the
hydrochloride, and since it appeared to be totally a physical trip
with tremors and some
cardiovascular push and nothing of a sensory
nature, I chose to explore it no further. A report from South
America
found the intoxication to be largely pleasant (this, at 75
milligrams), with an enhanced interest in one's surroundings, but no
perceptual changes, no overt stimulation, and no gross
physiological
effects other than a slight mydriasis (dilation of the pupils). I
have also been told of a single trial of 250 milligrams of the
tartrate (this is
equivalent to somewhere in the 150-200 milligram
range of the
hydrochloride salt, depending upon the acid/base ratio of
the
tartrate salt) with some "speedy" effects but still no sensory
changes. A
seizure of capsules reported by the drug law enforcement
authorities some 20 years ago found that each contained some 200
milligrams of the
hydrobromide salt. This is
equivalent to 170
milligrams of the
hydrochloride salt, and suggests that level may be
an effective dosage.
An intriguing, but little studied,
analogue of 2,5-DMA is the compound
with
methyls in place of the
methoxyls. 2,5-Di
methylamphetamine has
been looked at, in man, as a potential
anorexic, but there is little
effect even at 150 milligrams. The
3,4-isomer,
3,4-dimethylamphetamine or
xylopropamine, is an
adrenergic agent and
it has been found to be an
analgesic in man at as little as 10
milligrams. This was assayed, rather remarkably, by attaching
electrodes to the tooth fillings of the experimental subjects. But
with this base,
cardiovascular effects were not observed until doses
of about 100 milligrams were administered, and toxic effects (nausea
and vomiting) were reported at 150 milligrams. There was no
suggestion of anything
psychedelic.
All three
isomers of
monomethylamphetamine have also been looked at in
man. The ortho- and meta-
isomers,
2-methyl- (and
3-methyl- )
amphetamine are weak
anorexics. At doses of up to 150 milligrams
orally, there were signs of stimulation noted--talkativeness and loss
of appetite. The para-
isomer,
4-methyl-amphetamine or Aptrol, is more
potent. At 75 milligrams (orally, in man) there is clear
adrenergic
stimulation, and at twice this dosage there are signs of mild toxicity
such as
salivation, coughing and vomiting.
There is a mystery, at least to me, concerning the commercial
production of 2,5-DMA. At regular intervals, there is a public
announcement of the production quotas that are requested or allowed by
the Drug Enforcement Administration, for drugs that have been placed
in Schedules I or II. In the Schedule I category there are usually
listed amounts such as a gram of this, and a few grams of that. These
are probably for
analytical purposes, since there are no medical uses,
by definition, for drugs in this Schedule. But there is a staggering
quantity of 2,5-DMA requested, regularly. Quantities in the many tens
of millions of grams, quantities that vie with medical mainstays such
as
codeine and
morphine. I have heard that this material is used in
the
photographic industry, but I have no facts. Somewhere I am sure
that there is someone who has to keep a lot of very careful books!
In the area of
psychedelic drugs, the value of 2,5-DMA is mainly in
its role as a precursor to the preparation of materials that can come
from a direct
electrophilic attack on the activated 4-position. These
uses can be found under things such as DOB and DOI and DON. The
radio-
halogenation of N-
substituted
homologues of 2,5-DMA with
hypoiodite or
hypofluorite is part of an extensive study underway in
the search for radio-labeled brain blood flow agents. The rationale
for this work is to be found in the commentary under IDNNA. In
essence it has been found that the N-
substitution or
N,N-di
substitution of 2,5-DMA where the 4-position is un
substituted
and thus available for the introduction of a
radioactive nucleus can
give rise to potentially useful drugs. Most of these
2,5-dimethoxy
exploratory compounds were made by the reductive
alkylation of
2,5-dimethoxy-4-(radio)iodophenylacetone, using various mono or
dialkyl amines. This, too, is described under IDNNA.
However, the study of various direct
iodinations and fluoridations
that would have the N,N-
dimethyl substitution on the
amphetamine
nitrogen atom, would require the 4-proteo-
analogue, and this was made
from the above
nitrostyrene. A
solution of the above nitrostyrene,
22.3 g
1-(2,5-dimethoxyphenyl)-2-nitropropene in 100 mL acetic acid
was added to a suspension of elemental iron in acetic acid (45 g in
250 mL) and worked up with water and base washing to give, after
distillation at 92-106 °C at 0.35 mm/
Hg, 13.8 g
2,5-dimethoxyphenylacetone as a pale yellow oil. This underwent
reductive
amination with
dimethylamine hydrochloride in MeOH
solution,
using
sodium cyanoborohydride, to give the target compound
2,5-dimethoxy-N,N-di
methylamphetamine oxalate with a melting point of
133-134 °C (4.6 g
ketone gave 1.38 g of salt). Anal. (
C15H23NO6) C,H.
It has also been prepared by the N,N-
dimethylation of 2,5-DMA
directly, with
formaldehyde and
formic acid. This has been called
2,5-DNNA, or IDNNA without the "I." This intermediate, 2,5-DNNA,
underwent direct
radioiodination with labeled
iodine monochloride in
the presence of
perchloric acid to give IDNNA with a 40% incorporation
of
isotope. Reaction with labeled
acetyl hypofluorite, on the other
hand, gave only a 2% in-corporation of the radio-
isotope. This latter
compound is, chemically,
4-
fluoro-
2,5-dimethoxy-N,N-di
methylamphetamine and, using the
reasoning suggested above and with IDNNA, might best be encoded FDNNA.
The
2,5-dimethylamphetamine analogue mentioned above was also explored
in this IDNNA concept. The commercially available
2,5-dimethylbenzaldehyde was converted to the
nitrostyrene with
nitroethane (
1-(2,5-dimethylphenyl)-2-nitropropene, yellow
crystals
with a melting point of 24.5-25.5 °C) which reacted with elemental
iron in acetic acid to give the
ketone 2,5-dimethylphenylacetone
(boiling at 140-150 °C at 0.4 mm/
Hg). Reductive
amination with
dimethylamine and
sodium cyanoborohydride gave 2,5-DMNNA
(2,5,N,N-
tetramethylamphetamine) as a clear oil with a boiling point
of 115-125 °C at 0.35 mm/
Hg. It gave poor yields of the 4-
fluoro
analogue with
acetyl hypofluorite.
All of these latter materials remain unevaluated in man.
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