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#74 EEM
2,4-DIETHOXY-5-METHOXYAMPHETAMINE
SYNTHESIS: To a
solution of 12.3 g
3-ethoxy-4-methoxyphenol (see
recipe for
MEM for the preparation of this
phenol) in 20 mL MeOH,
there was added a warm
solution of 4.8 g KOH in 100 mL MeOH. There
was then added 8.2 g
ethyl bromide, and the mixture held at reflux on
the steam bath. Within 0.5 h, severe bumping ensued. An additional 3
g
ethyl bromide were added, refluxing continued for another 0.5 h,
then the reaction mixture was allowed to come to room tem
perature and
to stand overnight. It was poured into 3 volumes H2O which produced
crystals spontaneously. There was added additional base, and the
mixture was extracted with 3x150 mL
CH2Cl2. Removal of the
solvent
from the pooled extracts under vacuum gave 6.4 g of
2,4-diethoxyanisole as tan
crystals with a mp of 48-48.5 °C.
A mixture of 10.9 g N-
methylformanilide and 12.3 g POCl3 was allowed
to stand at room tem
perature for 0.5 h producing a deep red claret
color. There was then added 6.2 g
2,4-diethoxyanisole and the mixture
was heated on the steam bath for 2 h. All was poured into 200 g
chipped ice, and stirred mechanically. The dark viscous gummy oil
gradually became increasingly granular and finally appeared as
jade-green solids. These were removed by filtration and washed with
H2O, giving a wet cake weighing 18 g and having a mp (from a porous
plate) of 95.5-96.5 °C. The entire crop was re
crystallized from 75 mL
boiling MeOH which gave, after filtering, washing lightly with cold
MeOH, and air drying, 5.4 g of
2,4-diethoxy-5-methoxybenzaldehyde with
a mp of 98-99 °C. A
solution of 0.2 g of this
aldehyde, and 0.3 g
malononitrile in 2.0 mL warm
EtOH was treated with a drop of
triethyl-amine. There was an immediate generation of
crystals which
were removed by filtration,
EtOH-washed, and dried to constant weight.
The bright yellow needles of
2,4-diethoxy-5-methoxybenzalmalononitrile
weighed 0.15 g and had a mp of 172-172.5 °C.
A
solution of 5.0 g
2,4-diethoxy-5-methoxybenzaldehyde in 16 g glacial
acetic acid was treated with 2.7 g
nitroethane followed by 1.7 g
anhydrous ammonium acetate. The mixture was heated for 2.5 h on the
steam bath, then removed and diluted with a equal volume of H2O. With
cooling there was the generation of a heavy crop of orange
crystals
which was removed, washed with 50% acetic acid, and sucked as dry as
possible. The product had a mp of 97-104 °C, and there was
spectrographic evidence of some unreacted starting
aldehyde. A small
sample was re
crystallized from boiling MeOH, with considerable loss,
to give an
analytical sample of
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene as orange-yellow
crystals with a mp of 112-113 °C. Anal. (
C14H19NO5) C,H. The
unpurified first crop was employed in the following synthesis of the
corresponding
amphetamine.
To a gently refluxing suspension of 2.9 g LAH in 400 mL
anhydrous Et2O
under a He
atmosphere, there was added 4.0 g of impure
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene by allowing the
condensing
ether to drip into a shunted Soxhlet thimble apparatus
containing the
nitrostyrene. This effectively added a warm saturated
solution of the
nitrostyrene dropwise over the course of 1 h.
Refluxing was maintained for 5 h and the reaction mixture was cooled
with an external ice bath with the stirring continued. The excess
hydride was destroyed by the cautious addition of 400 mL of 1.5 N
H2SO4. When the aqueous and
Et2O layers were finally clear, they were
separated, and 100 g of
potassium sodium tartrate was
dissolved in the
aqueous fraction. Aqueous
NaOH was then added until the
pH was above
9, and this was then extracted with 3x150 mL
CH2Cl2. Removal of the
solvent under vacuum produced 2.7 g of a pale amber oil that was
dissolved in 300 mL
anhydrous Et2O and saturated with anhydrous HCl
gas. After a few minutes delay, there commenced the separation of
fine white
crystals of
2,4-diethoxy-5-methoxyamphetamine hydrochloride
(EEM). After the
crystallization was complete, these were removed by
filtration, washed with
Et2O and air dried, providing 2.55 g of a fine
white
crystalline solid with mp 158-159 °C. Anal. (
C14H24ClNO3)
C,H,N.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This particular identity and arrangement of
the alkoxy groups on the
amphetamine molecule, EEM, is a totally
unexplored molecule. It is reasonable to assume that it would be way
down in potency, but there is no way of guessing what the nature of
its activity might be at the dosage that would be active.
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