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2,5-DIMETHOXY-4-(n)-AMYLAMPHETAMINE
SYNTHESIS: A
solution of 110 g
p-dimethoxybenzene and 102 g valeric
acid in 168 g
polyphosphoric acid was heated on the steam bath for 3
h, giving a deep red
homogeneous solution. This was poured into 1 L
H2O with good stirring. The strongly acidic, cloudy suspension was
extracted with 3x200 mL
CH2Cl2, the extracts pooled, washed with 4x150
mL 5%
NaOH, and finally once with dilute HCl. The
solvent was removed
under vacuum, and the
residual amber oil cooled overnight at 0 °C.
Some 30 g of
crystalline, unreacted
dimethoxybenzene were removed by
filtration, and the 85 g of
residual oil
distilled at the water pump.
Another 15 g of
di-methoxybenzene came over as an early cut, but the
fraction boil-ing at 184-192 °C (mostly 188-192 °C) weighed 53.0 g and
was reasonably pure
2,5-dimethoxyamylophenone. The reaction of the
acid
chloride of valeric acid with
p-dimethoxybenzene and
anhydrous
AlCl3 in
CH2Cl2 (parallel to the preparation of the
butyrophenone
analog, see DOBU) gave an inferior yield (23.2 g from 92 g
dimethoxybenzene), but did provide a sizeable sample (12.2 g) of
2-hydroxy-5-methoxyamylophenone from the basic washes of the crude
reaction mixture. This pale yellow solid, after re
crystallization
from MeOH, had a mp of 62-62.5 °C. Anal. (
C12H16O3) C,H.
To 360 g mossy
zinc there was added a
solution of 7.2 g
mercuric
chloride in 200 mL warm H2O, and this was swirled periodically for 2
h. The H2O was drained off, and the
amalgamated
zinc added to a 2 L
three-neck round-bottomed flask, treated with 200 mL concentrated HCl,
and heated with an electric mantle. A
solution of 53.0 g of
2,5-dimethoxyamylophenone in 107 mL
EtOH containing 30 mL concentrated
HCl was added drop-wise over the course of 4 h accompanied by 330 mL
of concentrated HCl added batchwise over this same period. The
mixture was held at reflux overnight and, after cooling, diluted with
sufficient H2O to allowed
CH2Cl2 to be the lower
phase. The
phases
were separated, and the aqueous
phase was extracted with 2x200 mL
additional
CH2Cl2. These organic
phases were combined, washed first
with 5%
NaOH and then with H2O, and the
solvent removed under vacuum.
Distillation at the water pump yielded two fractions. The first
distilled from about 100-130 °C, weighed 8.8 g, had a faint smell of
apples and
fennel, and was free of a
carbonyl group in the infra-red.
It proved to be only 50% pure by GC, however, and was discarded. The
major fraction was a pale amber oil
distilling between 152-170 °C and
was substantially free of smell. It weighed 18.9 g, and was (by GC)
90% pure
2,5-dimethoxy-(n)-amylbenzene.
A mixture of 36.3 g POCl3 and 40.9 g N-
methylformanilide was allowed
to incubate for 0.5 h. To this there was then added 18.5 g of
2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath
for 2 h. This mixture was poured into a large quantity of H2O and
stirred overnight. The black oily product was extracted with 3x100 mL
CH2Cl2, and the extracts combined and stripped of
solvent under
vacuum. The black residue was
distilled at 180-205 °C at 20 mm/
Hg to
give 12.5 g of a pale amber oil that slowly set up to a
crystalline
mass. An
analytical sample was re
crystallized from MeOH to provide
2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 °C. Anal.
(
C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74.
A
solution of 12.3 g
2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g
anhydrous ammonium acetate and 12
mL
nitroethane. This mixture was heated on the steam bath for 4 h,
then poured into a large quantity of H2O. This was extracted with
3x200 mL
CH2Cl2, the extracts washed with H2O, and the
solvent removed
to give a deep red oil that, on standing in the
refrigerator, slowly
set to a
crystalline mass weighing 13.5 g. An
analytical sample was
re
crystallized from MeOH to provide
1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow
micro
crystals with a mp of 44 °C sharp. Anal. (
C16H23NO4) C,H,N.
To a gently refluxing suspension of 10 g LAH in 500 mL
anhydrous Et2O
under a He
atmosphere, there was added by 13.2 g
1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the
condensing
ether drip into a Soxhlet thimble containing the
nitrostyrene which effectively added a warm saturated
solution of it
dropwise to the reaction mixture.
Refluxing was maintained for 18 h,
and the cooled reaction flask stirred for several additional days.
The excess
hydride was destroyed by the cautious addition of 1 L 8%
H2SO4. When the aqueous and
Et2O layers were finally clear, they were
separated, and the aqueous layer was washed with an additional 2x100
mL
Et2O. Removal of the
solvent from the organic
phase and washings
provided 4.7 g of a thick red oil that was discarded. The aqueous
phase was then extracted with 2x200 mL
CH2Cl2 which actually removed
the product as the
sulfate salt. This organic
phase was washed with
2x100 mL 5%
K2CO3 (removing the H2SO4) and with the
evaporation of the
solvent there was obtained 6.2 g of an oily amber residue. This was
dissolved in 200 mL
Et2O and saturated with
anhydrous HCl gas. Fine
white
crystals of
2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride
(
DOAM) separated, were removed by filtration,
Et2O-washed and air
dried, and weighed 5.2 g. The mp of 136-139 °C was increased to
145-146 °C by re
crystallization from
CH3CN. Anal. (
C16H28ClNO2) C,H,N.
DOSAGE: greater than 10 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that
in no way interfered with my day's activities. I was quite gay and
voluble at lunch and bubbled on into the afternoon with puns and high
spirits. There may have been a little motor incoordination as noted
in handwriting, and there was a strange tenseness during driving.
There were no
sequelae, there was no trouble sleeping, and with this
potency way down from the lower
homologues, I have no pressing desire
to take this compound to a higher dose.
EXTENSIONS AND COMMENTARY: The actual procedure that was published for
the isolation of this final
amine was a different one, one that would
certainly work, but which was based on the procedures tried and proven
with the lower
homologues. The process described above is just a bit
bizarre (a
sulfate salt extracting into
methylene chloride) but it was
the actual thing that was done. The work was started towards two
additional compounds but these never got past the first "
ketone and
phenol" stage. p-
Dimethoxybenzene was brought into reaction with
n-caproic acid with
polyphosphoric acid (aiming towards
2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when
DOAM proved to be down in potency. And the reaction between
p-dimethoxybenzene and
benzoyl chloride with anh.
aluminum chloride
went well (aiming towards
2,5-dimethoxy-4-benzylamphetamine, DOBZ). A
goodly amount of the
phenol (
2-hydroxy-5-methoxybenzophenone) was
obtained as fine yellow
crystals, but this line of inquiry was also
dropped.
The preparation of
DOAM was, as a matter of fact, the last of the
homol-ogous series of compounds actually completed, which stemmed from
the original discovery of DOM. The "Ten Classic Ladies" concept was
mentioned under ARIADNE, and the adding of a
methyl group in the place
of a hydrogen atom at the
4-position-methyl led to the synthesis of
Ms. HECATE and gave rise to DOET. The whole series of
methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that
the potency seemed to increase initially as the chain got longer, and
then it abruptly dropped off. Wouldn't it be nice, I thought, if I
could interest some
pharmacologist in looking at this tight set of
drugs with some animal model, to see if there is some
neurotransmitter
activity that would show a parallel action.
I learned of a curious young researcher in Washington who had an
elegant procedure for measuring
serotonin agonist action using the
(otherwise) discarded sheep
umbilical artery strips. These become
available each year at lambing time, do not cost the life of anything,
and require very little compound. He assayed my compounds and, lo and
behold, the
serotonin activity also went through a maximum in the
middle of this series. We published a short paper to this effect,
which served as a excellent vehicle to get the cogent human data into
the scientific literature.
I have never understood the reasons that there might be connection
between the twitching of a
umbilical artery in a sheep and the
appearance of an insight in the mind of man. And, I have never
personally met this
pharmacologist. Some day, I hope to do both.
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