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 recrystallization from CH3CN had a mp of
161-162 °C. The derivative from 2,3-diethoxyphenol, also upon
recrystallization 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 temperature and stirred an
additional 10 min, then refluxed on a steam bath for 1.5 h. After
cooling to room temperature 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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