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TRESCALINE; TRISESCALINE; 3,4,5-TRIETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 16.9 g of ethyl 3,4,5-triethoxybenzoate in 25
mL THF was added to a well stirred suspension of 8 g LAH in 150 mL
THF. The mixture was heated at reflux for 24 h and and, after
cooling, treated with IPA to destroy the excess hydride. There was
then added sufficient 25% NaOH to produce a granular, white form of
the aluminum oxide. This was removed by filtration, the filter cake
washed with IPA, and the filtrate and washes were combined and
stripped of solvent under vacuum. The residue weighed 12.2 g and was
distilled at 120-140 °C at 0.4 mm/Hg to yield 8.6 g of
3,4,5-triethoxybenzyl alcohol that spontaneously crystallized. It had
a mp of 29-30 °C and was free of the parent ester carbonyl absorp-tion
at 1709 cm-1 in the infra-red.
This product 3,4,5-triethoxybenzyl alcohol was suspended in 30 mL
con-centrated HCl, heated briefly on the steam bath, cooled to room
temperature, and suspended in a mixture of 75 mL CH2Cl2 and 75 mL H2O.
The phases were separated, and the aqueous phase extracted with
another 75 mL CH2Cl2. The organic fractions were combined, washed
first with H2O and then with saturated brine. Removal of the solvent
under vacuum yielded an off-white oil that was distilled at 112-125 °C
at 0.4 mm/Hg to provide 7.5 g of 3,4,5-triethoxybenzyl chloride that
spontaneously crystallized. The crude product had a mp of 34-37 °C
which was increased to 37.5-38.5 °C upon recrystallization from
hexane. Anal. (C13H19ClO3) C,H.
A solution of 4.5 g 3,4,5-triethoxybenzyl chloride in 10 mL DMF was
treated with 5.0 g sodium cyanide and heated for 1 h on the steam
bath. The mixture was then poured into 100 mL H2O and the oily phase
that resulted immediately crystallized. This was filtered off, washed
well with H2O, air dried, and distilled at 128-140 °C at 0.25 mm/Hg to
yield 3.7 g of 3,4,5-triethoxyphenylacetonitrile which melted at
54-56.5 °C. There was a sharp nitrile band at 2249 cm-1. Anal.
To 18.8 mL of a 1 M solution of LAH in THF under N2 , vigorously
stirred and cooled to 0 °C, there was added, dropwise, 0.50 mL 100%
H2SO4. This was followed by 3.6 g 3,4,5-triethoxyphenylacetonitrile
in 10 mL anhydrous THF over the course of 5 min. The reaction mixture
was brought to room temperature and stirred for a few min, and finally
held at reflux on the steam bath for 1 h. After cooling back to room
temperature, there was added about 2 mL IPA (to destroy the excess
hydride) followed by sufficient 15% NaOH to make the aluminum oxide
granular and white, and the organic solution basic. The solids were
removed by filtration, and washed with IPA. The filtrate and washes
were stripped of solvent under vacuum, the residue added to 400 mL
dilute H2SO4. This was washed with 2x75 mL CH2Cl2, the aqueous phase
made basic with aqueous. NaOH, and the product extracted with 2x75 mL
CH2Cl2. These extracts were pooled, the solvent removed under vacuum,
and the residue distilled at 115-135 °C at 0.4 mm/Hg to give a white
oil. This was dissolved in a few mL of IPA, neutralized with
concentrated HCl, and diluted with anhydrous Et2O to the point of
turbidity. When the crystal formation was complete, the product was
removed by filtration, washed with Et2O, and air dried to give 2.8 g
3,4,5-triethoxyphenethylamine hydrochloride (TRIS) as white crystals
with a mp of 177-178 °C.
DOSAGE: greater than 240 mg.
QUALITATIVE COMMENTS: (with 240 mg) No effects were noted at any time
following 240 milligrams of trisescaline. This would have been a
thoroughly active level of the trimethoxy counterpart, mescaline.
EXTENSIONS AND COMMENTARY: With the progressive diminution of human
potency with increased ethylation of the mescaline molecule, there is
no suprise in finding that this base is devoid of activity. Studies
done years ago in the cat at a dosage of 25 mg/Kg (i.m.) gave none of
the expected, and looked for, signs of behavioral changes (pilomotor
activity, pupillary dilation, growling, hissing, aggressive behavior,
withdrawal, or salivation) that are often seen with the less bulky
substituents. It was without action.
More lengthy substituents in the 3,4,5-positions (with combinations of
ethyls and propyls, for example) are presently unknown compounds, and
there is small incentive to make them.
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