SYNTHESIS: To a solution of 14.0 g 4-ethoxy-3-methoxyphenol (see the
recipe for MME for the preparation of this starting material) in an
equal volume of EtOH, there was added a solution of 5.3 g KOH in 100
mL hot MeOH. This was followed with 9.1 g ethyl bromide, and the
mixture was held at reflux for 2 h. The first deposition of KBr was
apparent in 5 min, and there was rather severe bumping by the end of
the reaction. The mixture was diluted with 3 volumes H2O and 1 volume
5% NaOH, and extracted with 2x200 mL Et2O. The extracts were pooled,
and the solvent removed under vacuum, yielding 14.3 g of a pale amber
oil that set to crystals of 2,5-diethoxyanisole with a mp of 44-45 °C.
The compound had been reported in the literature from the action of
diethyl sulfate on methoxyhydroquinone.
To a mixture of 24.1 g N-methylformanilide and 27.3 g POCl3 that had
been allowed to stand at room temperature until strongly red-colored
(about 0.5 h) there was added 13.8 g solid 2,5-diethoxyanisole and the
mixture was heated on the steam bath for 2 h. The black, thick
reaction product was poured over chipped ice and, with continuous
stirring, the color lightened and there was the formation of a
yellowish powder. After a few h standing, this was removed by
filtration and sucked as dry as possible. The 32 g of damp product
showed the presence of isomeric contaminatiion by GC, and the aqueous
mother liquor, upon extraction with CH2Cl2 and concentration, showed
yet more aldehyde-like impurities. The isolated solids were
recrystallized from 125 mL boiling MeOH giving 15.8 g yellowish
crystals (wet weight) that still showed detectable impurities by GC.
A second recrystallization from 100 mL boiling MeOH gave off-white
fluffy crystals of 2,5-diethoxy-4-methoxybenzaldehyde which weighed,
after air drying, 8.5 g. The mp was 109-110 °C. The combined mother
liquors from the two MeOH crystallizations were stripped of solvent,
and the resulting solid mass crystallized again from MeOH to give a
second crop of aldehyde, 5.7 g, with a mp of 110-111 °C. A solution
of 1.0 g of this aldehyde and 0.7 g malononitrile in 40 mL warm
absolute EtOH was treated with a few drops of triethylamine. In a
minute or so, there was the formation of crystals. These were removed
by filtration, washed with EtOH, and air dried, giving 0.6 g of
2,5-diethoxy-4-methoxybenzalmalononitrile as brilliant yellow crystals
with a mp of 156.5-158 °C.
A solution of 6.7 g 2,5-diethoxy-4-methoxybenzaldehyde in 21 g glacial
acetic acid was treated with 3.1 g nitroethane and 1.93 g anhydrous
ammonium acetate, and heated on the steam bath for 2.5 h. The
addition of a small amount of H2O to the hot reaction mixture
instituted crystallization of an orange product which, after the
mixture had come to room temperature and stood for several h, was
removed by filtration, H2O washed, and air dried. The product,
1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene, was dull orange in
color, weighed 3.0 g and had a mp of 84-86 °C. An analytical sample
from toluene had a mp of 85-86 °C. Anal. (C14H19NO5) C,H.
To a gently refluxing suspension of 2.0 g LAH in 250 mL anhydrous Et2O
under a He atmosphere, there was added 2.8 g
1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene. This effectively added a warm saturated solution of the
nitrostyrene dropwise. The addition took 1 h and the refluxing was
continued for an additional 6 h. The reaction mixture was brought
down to ice-bath temperature, and the excess hydride was destroyed by
the cautious addition of 150 mL 1.5 N H2SO4. When the aqueous and
Et2O layers were finally clear, they were separated and 50 g of
potassium sodium tartrate were dissolved in the aqueous fraction.
Aqueous NaOH was then added until the pH was >9, and this was then
extracted with 3x150 mL CH2Cl2. Removal of the solvent under vacuum
produced 2.3 g of a clear white oil that was dissolved in 300 mL
anhydrous Et2O and saturated with anhydrous HCl gas. At first the
solution remained completely clear, and finally there was the start of
the formation of fine white crystals. When the crystallization was
complete, these solids were removed by filtration, Et2O washed, and
air dried. There was thus obtained 2.2 g of
2,5-diethoxy-4-methoxyamphetamine hydrochloride (EME) with a mp of
162-164 °C with prior softening at 154 °C. Anal. (C14H24ClNO3) C,H,N.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This is another of the collection of all
possible ethoxy homologues of TMA-2. The latter and heavier members
of this series were synthesized and completed before the directions of
biological activity had become evident from the earlier ones. This
compound has never been assayed, and it is a reasonable guess that it
will have a very low potency, with hints of toxicity at higher dose
levels. I suspect that it will never be assayed, certainly not by me.
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