SYNTHESIS: To a solution of 68 g 2,5-dimethoxybenzaldehyde in 250 mL
glacial acetic acid that had been warmed to 25 °C and well stirred,
there was added, dropwise, 86 g of a 40% peracetic acid solution (in
acetic acid). The reaction was exothermic, and the rate of addition
was dictated by the need to maintain the internal temperature within a
few degrees of 28 °C. External cooling was used as needed. The
addition took 1 h, and when the reaction had clearly been completed
(there was no further temperature rise) the entire reaction mixture
was added to 3 volumes of H2O. The excess acid was neutralized with
solid K2CO3. The dark solution was extracted with 3x100 mL Et2O, the
extracts pooled, and stripped of solvent under vacuum to give 59 g of
crude 2,4-dimethoxyphenyl formate. This was suspended in 200 mL 10%
NaOH, and the mixture heated on the steam bath for 1 h. On cooling,
the reaction mixture was washed with 2x200 mL methylene chloride,
acidified with HCl, and extracted with 3x200 mL CH2Cl2. The extracts
were pooled and the solvent removed under vacuum. There remained as
residue, 47.4 g 2,5-dimethoxyphenol which was deep amber in color, but
clear and fluid. It was homogenous by GC and completely correct by
NMR. It was used without further purification.
To a solution of 3.08 g 2,5-dimethoxyphenol in 20 g MeOH, there was
added a solution of 1.26 g flaked KOH in 20 g hot MeOH. There was
then added 2.46 g n-propyl bromide, and the mixture held at reflux for
2 h on the steam bath. This was quenched in 5 volumes H2O, made
strongly basic with 10% NaOH, and extracted with 3x100 mL CH2Cl2.
Removal of the solvent from the pooled extracts left 2.0 g of
1,4-dimethoxy-2-(n)-propoxybenzene as a clear, amber oil. The IR
spectrum was appropriate, no phenol was present, and this residue was
used in the following reaction without further purification or
characterization.
A mixture of 3.5 g N-methylformanilide and 4.0 g POCl3 was held at
room temperature for 0.5 h producing a deep red color. To this there
was added 2.0 g 1,4-dimethoxy-2-(n)-propoxybenzene, and the mixture
was held on the steam bath for 1.75 h. It was then poured over 400 mL
shaved ice, and vigorous stirring was maintained until the dark
complex had completely broken up. This aqueous mixture was allowed to
stand overnight, and the crude aldehyde solids that had formed were
removed by filtration, water washed, and sucked as dry as possible.
This 2.0 g damp material was crystallized from 20 mL boiling MeOH
giving, after filtering and drying to constant weight, 1.4 g
2,5-dimethoxy-4-(n)-propoxybenzaldehyde as reddish-tan solids, with a
mp of 97-98 °C. To the methanolic mother liquors of this
crystallization there was added a gram of malononitrile and a few
drops of triethylamine. The eventual addition of a little H2O
encouraged the separation of crystals which were removed, and had a mp
of 150-152 °C. Recrystallization from toluene gave gold-colored
crystals of the benzalmalononitrile with a mp of 153.5-155 °C, but the
melt remained slightly cloudy.
To a solution of 1.4 g 2,5-dimethoxy-4-(n)-propoxybenzaldehyde and
0.65 g nitroethane in 4.4 g glacial acetic acid there was added 0.4 g
anhydrous ammonium acetate, and the mixture was heated on the steam
bath for 5 h. The addition of a modest amount of H2O and scratching
with a glass rod produced crystal seed. The reaction was diluted with
about 5 mL H2O, seeded, and allowed to stand at room temperature
overnight. There was generated a crystalline product which was
removed by filtration and air dried. There was thus obtained 0.6 g
1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene as yellow-orange
crystals, with a mp of 83-84 °C. The addition of H2O to the mother
liquors provided an additional 0.3 g of an orange solid which proved
to be largely unreacted starting aldehyde.
To a stirred, warm suspension of 0.5 g LAH in 20 mL anhydrous Et2O
under a He atmosphere, there was added 0.6 g
1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene dissolved in a
little anhydrous Et2O. The mixture was heated and stirred for a few
h, and the excess hydride decomposed with 30 mL 1.5 N H2SO4. The two
layers were separated, and 15 g potassium sodium tartrate was
dissolved in the aqueous fraction. Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x50 mL CH2Cl2.
Removal of the solvent under vacuum gave 0.7 g of an amber oil that
was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.
No crystals formed, and so the ether was removed under vacuum, leaving
a residue that set up to crystals that were then no longer soluble in
ether. They were, however, very soluble in chloroform. These were
ground under dry Et2O, removed by filtration, and air dried giving
0.35 g 2,5-dimethoxy-4-(n)-propoxyamphetamine hydrochloride (MPM) with
a mp of 123 - 125 °C.
DOSAGE: 30 mg or more.
DURATION: probably short.
QUALITATIVE COMMENTS: (with 15 mg) This is just barely threshold. A
marginal intoxication at best. This level is producing less response
that the 11 mg. trial of MEM, so the propoxy is off in potency. At
four and a half hours I am out of whatever little there was.
(with 30 mg) By the mid-second hour, I am at a valid plus one. I
cannot identify the nature--with eyes closed it would be lost, as it
would also be if I were watching a play or movie. It would have been
interesting to see where it could have gone. Seventh hour, completely
clear.
EXTENSIONS AND COMMENTARY: The 4-propoxy homologue of TMA-2 and MEM is
clearly less active, and this has discouraged me from putting too much
more effort in this direction. Three additional materials of this
pattern were prepared and either shown to be even less active, or
simply were not assayed at all. These are the 4-isopropoxy isomer
(MIPM), the (n)-butoxy homologue (MBM), and the (n)-amyl homologue
(MAM). They scarcely warrant separate recipes as they were all made
in a manner similar to this one describing MPM.
For the preparation of MIPM, the above phenol, 2,5-dimethoxyphenol was
isopropylated with isopropyl bromide in methanolic KOH giving
2,5-dimethoxy-1-(i)-propoxybenzene as an oil. This formed the
benzaldehyde with the standard Vilsmeier conditions, which melted at
77-78 °C from hexane and which gave a yellow malononitrile derivative
melting at 171.5-173 °C. The nitrostyrene, from nitroethane in acetic
acid was orange colored and melted at 100-101 °C from either methanol
or hexane. This was reduced with lithium aluminum hydride in ether to
give 2,5-dimethoxy-4-(i)-propoxyamphetamine hydrochloride (MIPM). The
properties of the isolated salt were strange (soluble in acetone but
not in water) and the microanalysis was low in the carbon value. The
molecular structure had a pleasant appeal to it, with a complete
reflection symmetry shown by the atoms of the amphetamine side chain
and the isopropoxy side chain. But the nature of the actual product
in hand had no appeal at all, and no assay was ever started.
For the preparation of MBM, the starting phenol was alkylated to
2-(n)-butoxy-1,4-dimethoxybenzene in methanolic KOH with n-butyl
bromide. The benzaldehyde melted at 79.5-81 °C from methanol, and
formed a malononitrile derivative that had a melting point of
134.5-135 C. The nitrostyrene from the aldehyde and nitroethane in
acetic acid crystallized from methanol with a mp of 71-72 °C. Lithium
aluminum hydride reduction in ether gave the ether-insoluble
chloroform-soluble product 4-(n)-butoxy-2,5-dimethoxyamphetamine
hydrochloride (MBM) with a melting point of 128-130 °C. This product
met all tests for structural integrity, and assays were started. At
levels of up to 12.0 milligrams, there were no effects noted.
As to the preparation of MAM, the exact same sequence was used, except
for the employment of n-amyl bromide. The benzaldehyde crystallized
from methanol with a mp of 79-80 °C, and formed a malononitrile
derivative which was bright yellow and melted at 103-104 °C. The
nitrostyrene, when pure, melted at 57-58.5 °C but proved very
difficult to separate from the aldehyde. The final product,
4-(n)-amyl-2,5-dimethoxyamphetamine hydrochloride (MAM) was obtained
by lithium aluminum hydride reduction in ether and melted at 125-127
°C. It was assayed at up to 16 milligrams, at which level there was
noted a heaviness in the chest and head at the 2-hour point, but no
cardiovascular disturbance and no mydriasis. This was called an
inactive level, and no higher one has yet been tried.
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