SYNTHESIS: A solution of 8.0 g 2,3,4-trimethoxybenzaldehyde in 125 mL
nitromethane containing 1.4 g anhydrous ammonium acetate was held at
reflux for 1.5 h. The conversion of the aldehyde to the nitrostyrene
was optimum at this time, with a minimum development of a slow-moving
spot as seen by thin layer chromatography on silica gel plates using
CHCl3 as a developing solvent; the Rf of the aldehyde was 0.31 and the
Rf of the nitrostyrene was 0.61. The excess nitromethane was removed
under vacuum, and the residue was dissolved in 20 mL hot MeOH. On
cooling, the yellow crystals that formed were removed by filtration,
washed with cold MeOH and air dried yielding 4.7 g yellow crystals of
2,3,4-trimethoxy-beta-nitrostyrene, with a mp of 73-74 °C. From the
mother liquors, a second crop of 1.2 g was obtained.
A solution of 4.0 g LAH in 80 mL THF under He was cooled to 0 °C and
vigorously stirred. There was added, dropwise, 2.7 mL of 100% H2SO4,
followed by a solution of 4.7 g 2,3,4-trimethoxy-beta-nitrostyrene in 40
mL anhydrous THF. The mixture was stirred at 0 °C for 1 h, at room
temperature for 1 h, and then brought briefly to a reflux on the steam
bath. After cooling again, the excess hydride was destroyed with 4.7
mL H2O in THF, followed by the addition of 18.8 mL 15% NaOH which was
sufficient to convert the solids to a white and granular form. These
were removed by filtration, the filter cake washed with THF, the
mother liquor and filtrates combined, and the solvent removed under
vacuum. The residue was added to dilute H2SO4, and washed with 2x75
mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and
extracted with 2x50 mL CH2Cl2. The solvent was removed from these
pooled extracts and the amber-colored residue distilled at 95-100 °C
at 0.3 mm/Hg to provide 2.8 g of 2,3,4-trimethoxyphenethylamine as a
white oil. This was dissolved in 20 mL IPA, neutralized with about 1
mL concentrated HCl, and diluted with 60 mL anhydrous Et2O. After
filtering, Et2O-washing, and air drying, there was obtained 3.2 g of
2,3,4-trimethoxyphenethylamine hydrochloride (IM) as a white
crystalline product.
DOSAGE: greater than 400 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 300 mg) No effects whatsoever.
(with 400 mg) Maybe a slight tingle at the hour-and-a-half point.
Maybe not. Certainly nothing an hour later. Put this down as being
without action.
EXTENSIONS AND COMMENTARY: Some fifty years ago this material was
given the name "reciprocal mescaline" in that it was believed to
exacerbate the clinical symptoms in schizophrenic patients. In the
original report, one finds: RThus we have discovered an extremely
remarkable dependency of the intoxicating action upon the position of
the three methoxy groups. Mescaline, the
3,4,5-trimethoxy-beta-phenethylamine, produces in the normal subject a
much stronger over-all intoxication than in the schizophrenic patient,
whereas 2,3,4-trimethoxy-beta-phenethylamine has quite the opposite
effect. It has little action in healthy individuals, being almost
without intoxicating properties, but it is very potent in the
schizophrenic. The metabolic conversion products of the "reciprocal"
mescaline will be further studied as soon as the study of the
metabolism of the proper mescaline is complete.
This is a pretty rich offering, and one that the present medical
community has no qualms about discarding. At the bookkeeping level,
the promised further studies have never appeared, so all may be
forgotten as far as potential new discoveries might be concerned.
One recent related study has been reported, tying together
isomescaline and schizophrenia. Through the use of radioactive
labelling, the extent of demethylation (the metabolic removal of the
methyl groups from the methoxyls) was determined in both schizophrenic
patients and normal subjects. When there was a loading of the person
with methionine (an amino acid that is the principal source of the
body's methyl groups), the schizophrenics appeared to show a lesser
amount of demethylation.
But might either of these two observations lead to a diagnostic test
for schizophrenia? At the present time, the conventional thinking is
that this probably cannot be. The illness has such social and genetic
contributions, that no simple measure of a response to an
almost-psychedelic, or minor shift of some urinary metabolite pattern
could possibly be believed. No independent confirmation of these
properties has been reported. But maybe these findings are valid. A
major problem in following these leads does not involve any complex
research protocols. What must be addressed are the present regulatory
restrictions and the Federal law structure. And these are formidable
obstacles.
Back]
]