SYNTHESIS: A mixture of 3.1 g POCl3 2.8 g N-methylformanilide was
heated on a steam bath until it was a deep claret color (about 5 min).
To this there was then added 3.0 g of 2,6-dimethoxythioanisole (see
under 4-TM for its preparation), and heating was continued for 30 min.
The reaction mixture was then added to 75 mL H2O and stirred
overnight. The dark oily mixture was extracted with 3x75 mL CH2Cl2,
the extracts pooled, and the solvent removed under vacuum. The
residue was extracted with 3x20 mL boiling hexane, each extract being
poured off from the insoluble residue. Pooling and cooling these
extracts yielded 1.5 g of 2,4-dimethoxy-3-(methylthio)benzaldehyde as
an off-white crystalline solid with a mp of 67-69 °C.
Recrystallization from either MeOH or cyclohexane tightened the mp,
but lowered it to 67-68 °C and 66-67 °C, resp. Anal. (C10H12O3S) C,H.
To a solution of 1.3 g 2,4-dimethoxy-3-(methylthio)benzaldehyde in 60
mL nitromethane there was added 0.3 g anhydrous ammonium acetate and
the mixture was heated at reflux for 3 h. The hot solution was
decanted from a little insoluble material, and the excess nitromethane
was removed under vacuum. The residue dissolved in 10 mL hot MeOH.
On cooling, yellow crystals of
2,4-dimethoxy-3-methylthio-beta-nitrostyrene were obtained which were
removed by filtration and air-dried, and weighed 0.9 g. The mp was
130-133 °C and could be improved to 136-137 °C following
recrystallization from MeOH (10 g/g). Anal. (C11H13NO4S) C,H.
A well-stirred solution of 0.6 g LAH in 10 mL anhydrous THF was cooled
to 0 °C under He. There was added, dropwise, 0.4 mL of 100% H2SO4,
followed by 0.6 g of 2,4-dimethoxy-3-methylthio-beta-nitrostyrene
dissolved in a little THF. Stirring was continued for a few min as
the reaction returned to room temperature, and then it was heated to a
reflux for 5 min on the steam bath. The reaction was cooled again,
and 25% NaOH was added dropwise until a white granular precipitate was
obtained. This was removed by filtration, and the filter cake was
washed with 2x25 mL Et2O. The filtrate was extracted into 25 mL
dilute H2SO4 which was, in turn, made basic again and extracted with
2x25 mL CH2Cl2. The extracts were pooled, and the solvent removed
under vacuum to give a residue of crude product. This was distilled
from 120-140 °C at 0.3 mm/Hg yielding 0.25 g of a clear white oil.
This was dissolved in 5 mL IPA, neutralized with about 3 drops of
concentrated HCl, and diluted with 15 mL anhydrous Et2O. Scratching
with a glass rod instigated crystallization of bright white solids
which were filtered, washed with Et2O, and air dried. The weight of
2,4-dimethoxy-3-methylthiophenethylamine hydrochloride (3-TIM) was 0.2
g and the mp was 204-206 °C with decomposition. This hydrochloride
appeared to be a hemihydrate. Anal. (C11H18ClNO2Sa1/2 H2O) C,H,N.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 240 mg) Briefly I thought that there
might have been an alert at the 2 to 3 hour point, but I now think it
was nothing. During the following day I had a mild stomach upset off
and on, but I can't believe that it was connected with 3-TIM.
EXTENSIONS AND COMMENTARY: Isomescaline itself is not active, but
there is no way of knowing just how "non-active" it really is. If it
were to be active just beyond the levels assayed, then the
introduction of a sulfur into the molecule in place of an oxygen could
have increased the potency to where it might have some effect. The
absence of any activity from this TIM, and the other two TIMs, might
well suggest that isomescaline is really very "non-active," if that
makes sense!
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