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#53 2,4-DMA
2,4-DIMETHOXYAMPHETAMINE
SYNTHESIS: To a
solution of 10 g
2,4-dimethoxybenzaldehyde in 50 mL
nitroethane there was added 0.5 g
anhydrous ammonium acetate, and the
mixture was heated on the steam bath for 2 h. The excess
solvent/reagent was removed under vacuum, and the residue oil
dissolved in 25 mL boiling MeOH. On cooling, this
deposited yellow
crystals of
1-(2,4-dimethoxyphenyl)-2-nitropropene that, after
filtering, MeOH washing, and air drying, weighed 10.2 g and had a mp
of 78-79 °C.
A
magnetically stirred suspension of 6.0 g LAH in 300 mL
anhydrous
Et2O was brought up to a gentle reflux under a He
atmosphere. A total
of 8.5 g
1-(2,4-dimethoxyphenyl)-2-nitropropene was introduced into
the reaction mixture by allowing the condensed
Et2O to leach it from a
modified Soxhlet
condenser. After the addition was complete, the
reaction was held at reflux for an additional 24 h. After cooling
with an external ice bath, the excess
hydride was destroyed by the
cautious addition of H2O. When the exothermic reaction had subsided,
there was added 500 mL H2O, 150 g
potassium sodium tartrate, and
sufficient base to bring the
pH above 9. The
phases were separated,
the organic
phase dried over
anhydrous MgSO4, the drying agent removed
by filtration, and the clear filtrate then saturated with
anhydrous
HCl gas to produce white
crystals of
2,4-dimethoxyamphetamine
hydrochloride (2,4-DMA) with a mp of 146-147 °C.
DOSAGE: greater than 60 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 60 mg) This is definitely threshold, or
even a bit more. There is a lot of
amphetamine-like component, and a
certain blush of
euphoria. There is also a
diffusion of association,
so it's more than just
amphetamine, no question about it. At the
three-hour point, it is definitely quieting down.
EXTENSIONS AND COMMENTARY: What can one say as to the active dosage of
2,4-DMA? Nothing. What can one say as to the duration? Probably
short. The 60 milligram report given above is the highest level that
I personally know of having been tried in man, and there is no hint as
to what might be found at a fully active dose, or just where that dose
might be. It might be fully speedy. It might be fully
psychedelic.
It might give a
cardiovascular push that would be scary. Studies of
2,4-DMA on
vascular strips (associated with
serotonin action) were not
impressive in comparison with structurally related
psychedelics, and
it seems as if its action might involve
norepinephrine release. It is
a reasonable guess that there would be
cardio-
vascular activity at
higher levels. But it will only be with human trials, someday, that
the answer will be known for sure.
The meta-orientation of the two
methoxyl groups does, however, greatly
increase the susceptibility of the aromatic ring to
electrophilic
attack. This is one of the three possible meta-
dimethoxy
substituted
amphetamines, and it is the best studied one in the pursuit of
potential radio-
halogen substituted brain blood-flow agents. This
strategy is discussed under IDNNA; the other two meta-compounds are
discussed under
3,4-DMA.
The
homologues of 2,4-DMA that were iodinated (or occasionally
fluor-inated) were mono- or di-alkylated on the
nitrogen, and the
precursor that was common to all was the corresponding
acetone. The
above
nitrostyrene,
1-(2,4-dimethoxyphenyl)-2-nitropropene, was
reduced in acetic acid with elemental iron, and the base-washed
extracts stripped of
solvent and
distilled (125-145 °C at 0.5 mm/
Hg)
to give
2,4-dimethoxyphenylacetone as a water-white oil. The
principal reductive
amination product of this, the one that was most
thoroughly explored with various
halogenation schemes, was obtained by
the reaction of
2,4-dimethoxyphenylacetone with
dimethylamine and
sodium cyanoborohydride. This product,
2,4-
dimethoxy-N,N-di
methylamphetamine or 2,4-DNNA,
distilled at
105-115 °C at 0.4 mm/
Hg and formed a
perchlorate salt that melted at
98-98.5 °C. This could be iodinated with the radio-iodide anion, when
oxidized with
chloramine-T in buffered
sulfuric acid, to give the
iodinated
analogue (2,4-
dimethoxy-N,N-
dimethyl-5-
iodoamphetamine) in
an excellent yield. Radio-
fluorination with
acetyl hypofluorite gave
the 5-
fluoroanalogue (2,4-
dimethoxy-N,N-
dimethyl-5-
fluoroamphetamine)
in an acceptable yield. Both compounds went into a rat's brain to a
pretty good extent, but both of them washed out too rapidly to be
clinically interesting.
A large family of other N-
substituted
homologues of 2,4-DMA were
similarly prepared from the above
ketone and
sodium cyanoborohydride.
Methylamine, ethylamine,
propylamine,
isopropylamine and
hexylamine
gave the corresponding N-alkyl
homologues. The N,N-
diethyl homologue
was made from the primary
amine, 2,4-DMA itself, with
acetaldehyde and
sodium cyanoborohydride but the product,
N,N-
diethyl-
2,4-dimethoxyamphetamine, could not be converted into a
crystalline hydrochloride salt.
Yet another variation on these structures was launched, again with the
design of making radio-
iodination targets which are not
psychedelic
and thus might be useful clinically. In this variation, the
nitrogen
atom
substitution pattern was held constant, with two
methyl groups,
as were the ring locations of the two oxygen atoms. But the
identities of the alkyl groups on these oxygen atoms were varied. The
synthetic procedure followed was to make the appropriate
2,4-dialkoxybenzaldehyde, convert it to the
nitrostyrene with
nitroethane, reduce this to the
phenylacetone with elemental iron, and
then reductively
aminate this
ketone with
dimethylamine. Following
this reaction scheme, five
amphetamine homologues of 2,4-DMA were
made, three with the 4-methoxy group maintained but the 2-position
extended, and two with both groups extended symmetrically. These are:
(1) N,N-
dimethyl-2-ethoxy-
4-methoxyamphetamine; (2)
2-(n)-butyloxy-N,N-
dimethyl-4-methoxy-
amphetamine; (3)
2-(n)-decyloxy-N,N-di
methylamphetamine; (4)
2,4-diethoxy-N,N-di
methylamphetamine; and (5)
N,N-
dimethyl-2,4-di-(i)-propoxy
amphetamine. I believe that most of
these have been iodinated and assayed in rats, and several of them
appear quite promising. But none of them have been assayed in man,
yet. The
bromination product of 2,4-DMA
(
5-bromo-2,4-dimethoxyamphetamine, 5-Br-2,4-DMA) is way down in
activity (see its recipe, separately). Since all iodo
analogues are
of about the same potency as the bromo counterparts, and since the
addition of two
methyl groups on the
nitrogen does not appear to
enhance central activity, I feel the
iodination products of these
N,N-
dialkyl-dialkoxy
amphetamines would not have any interesting
psychopharmacology.
There is something vaguely counterproductive, in my evaluation of
things, when the goal of a research project is to avoid activity
rather than to create it. Although this chemistry was completely
fascinating and could have produced the world's best
positron-emitting, brain-scanning diagnostic compound, I feel it quite
unlikely that it would have produced the world's best
insight-revealing, empathy-enhancing
psychedelic, so this research
direction never totally caught my fancy. I went on to other things.
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