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#144 SB
SYMBESCALINE; 3,5-DIETHOXY-4-METHOXYPHENETHYLAMINE
SYNTHESIS: A
solution of 15 g
1,3-diethoxybenzene and 15 mL of
N,N,N',N'-
tetramethylethylenediamine in 200 mL
anhydrous Et2O was
placed in a He
atmosphere,
magnetically stirred, and cooled to 0 °C
with an ice bath. Over the course of 10 min there was added 63 mL of
a 1.6 M
solution of
butyllithium in hexane, which produced a fine
white
precipitate. After an additional 15 min stirring, 20 mL of
tributyl borate was added which
dissolved the
precipitate. The
stirring was continued for an additional 15 min. The reaction was
quenched by the addition of 50 mL of a concentrated aqueous
solution
of
ammonium sulfate. The resulting "cottage cheese" mass was
transferred to a beaker, treated with an additional 300 mL of the
ammonium sulfate solution, and allowed to stir until the solids had
dispersed to a fine texture. The organic
phase was separated and the
aqueous
phase extracted with 2x100 mL
Et2O. The organic
phases were
combined,
evaporated under vacuum, and the off-white residue
dissolved
in 100 mL MeOH. This cloudy
solution was cooled (ice bath) and, with
stirring, 20 mL of 35% hydrogen
peroxide was added portionwise, . The
reaction was allowed to continue stirring for 15 min, and then with
the addition of 600 mL H2O,
crystalline solids were formed. These
were removed, washed with H2O, and upon drying yielded 15.4 g of
2,6-diethoxyphenol with a mp of 79.5-81.5 °C. Efforts to
diethylate
pyrogallol produced mixtures of
2,6-diethoxyphenol and the
isomer,
2,3-diethoxyphenol, and these proved difficult to separate. The pure
2,3-isomer was
synthesized from
ortho-diethoxybenzene by the process
used above, and the product was an oil. Both
phenols yielded
crystalline 3,5-dinitrobenzoates. This derivative of
2,6-diethoxyphenol, upon re
crystallization from
CH3CN had a mp of
161-162 °C. The derivative from
2,3-diethoxyphenol, also upon
re
crystallization from
CH3CN, melted at 167-168 °C. The mixed mp was
appropriately depressed (mp 137-140 °C.).
A
solution of 7.6 g
2,6-diethoxyphenol in 40 mL MeOH was treated with
4.9 g of a 40% aqueous
solution of
dimethylamine followed by 3.6 g of
a 40% aqueous
solution of
formaldehyde. The mixture was heated 1 h on
the steam bath, and all
volatiles were removed under vacuum. The
residual dark oil was
dissolved in 36 mL IPA and 10.3 g of
methyl
iodide was added. There was spontaneous heating, and the
deposition
of fine white solids. After standing for 10 min, these were removed
by filtration, and the filter cake washed with more IPA. The crude
product was freed from
solvent (air dried weight, 1.7 g) and
dissolved
in 7 mL hot H2O. To this hot
solution there was added 1.7 g
sodium
cyanide which slowly discharged the color and again
deposited
flocculant white solids. After cooling, these were removed by
filtration, washed with H2O, and after thorough drying the isolated
3,5-diethoxy-4-hydroxyphenylacetonitrile weighed 0.5 g and had a mp of
107.5-108.5 °C. Anal. (
C12H15NO3) C,H.
To a
solution of 2.1 g
3,5-diethoxy-4-hydroxyphenylacetonitrile in 20
mL
anhydrous acetone, there was added 30 mg
triethyldecylammonium
iodide, 4.6 g
methyl iodide, and finally 2.3 g powdered
anhydrous
K2CO3. This mixture was held at reflux for 5 h. The reaction mixture
was quenched with 200 mL acidified H2O and extracted with 3x75 mL
CH2Cl2. The extracts were pooled, washed with 2x75 mL 5%
NaOH, and
finally once with dilute HCl. The
solvent was removed under vacuum,
and the residue
distilled at 110-115 °C at 0.3 mm/
Hg to provide
3,5-diethoxy-4-methoxyphenylacetonitrile as a solid. This weighed 1.3
g and had a mp of 58-59 °C. Anal. (
C13H17NO3) C,H.
To 30 mL of a 1 M
solution LAH in THF that had been cooled to 0 °C
with vigorous stirring, under a He
atmosphere, there was added
dropwise 0.78 mL of 100% H2SO4. When the addition was complete, there
was added dropwise a
solution of 1.3 g of
3,5-diethoxy-4-methoxyphenylacetonitrile in 10 mL
anhydrous THF. The
reaction mixture was brought to room tem
perature and stirred an
additional 10 min, then refluxed on a steam bath for 1.5 h. After
cooling to room tem
perature the excess
hydride was destroyed by the
addition of about 2 mL IPA, followed by sufficient 15%
NaOH to make
the reaction basic to external
pH paper and to render the
aluminum
oxides white and filterable. These were removed by filtration, the
filter cake was washed with IPA, then the filtrate and washes were
combined. The
solvents were removed under vacuum and the residue
dissolved in dilute H2SO4. This was washed with 2x75 mL
CH2Cl2, the
aqueous
phase made basic with 5%
NaOH, and extracted with 3x75 mL
CH2Cl2. The extracts were pooled, the
solvent removed under vacuum,
and the residue
distilled at 120-140 °C at 0.3 mm/
Hg to yield 0.9 g of
a white oil. This was
dissolved in 4 mL of IPA and neutralized with
concentrated HCl to an end-point determined by damp external
pH paper.
There was the immediate formation of solids which were removed by
filtration and washed first with IPA and then with
Et2O. This
provided 1.0 g of
3,5-diethoxy-4-methoxyphenethylamine hydrochloride
(SB) as white
crystals, with a mp of 186-187 °C. Anal. (
C13H22ClNO3)
C,H.
DOSAGE: above 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 120 mg) There were no effects. Sleep
that evening was strange, however, and I was fully awake at 4:00 AM,
alert, and mentally restless. And there was a strange outburst of
anger in the mid-morning. Might these be related to the material the
previous day?
(with 240 mg) There was a slight chill that reminded me that I had
taken
symbescaline a half hour earlier. There was what might be
called a vague threshold for about three hours, then nothing more.
This material had a God-awful taste that lingers in the mouth far too
long. If ever again, it will be in a gelatin capsule.
EXTENSIONS AND COMMENTARY: It must be concluded that SB is "probably"
not active. There was no convincing evidence for much effect at
levels that would clearly be active for mescaline. This is the kind
of result that puts some potentially ambiguous numbers in the
literature. One cannot say that it is inactive, for there might well
be something at 400 or 800 or 1200 milligrams. But since it has been
tried only up to 240 milligrams, I have used the phrase that the
activity is greater than 240 milligrams. This will be interpreted by
some people as saying that it is active, but only at dosages higher
than 240 milligrams. What is meant, is that there was no activity
observed at the highest level tried, and so if it is active, the
active dose will be greater than 240 milligrams, and so the potency
will be less than that of mescaline. However you phrase it, someone
will misinterpret it.
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