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#173 TOMSO
2-METHOXY-4-METHYL-5-METHYLSULFINYLAMPHETAMINE
SYNTHESIS: A suspension of 12.7 g
1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene (see under
5-TOM for its preparation) in 50 mL warm acetic acid was added to a
suspension of 22.5 g
electrolytic grade elemental iron in 100 mL warm
acetic acid. The tem
perature was raised cautiously until an
exothermic reaction set in, and the mixture was maintained under
reflux conditions as the color progressed from yellow to deep brown to
eventually colorless. After coming back to room tem
perature, the
somewhat gummy mixture was poured into 1 L H2O, and all in
solubles
were removed by filtration. These were washed with
CH2Cl2, and the
aqueous filtrate was extracted with 3x100 mL
CH2Cl2. The washes and
extracts were combined, washed with 5%
NaOH until the bulk of the
color was removed and the washes remained basic, and the
solvent was
then removed under vacuum. The residue, 11.6 g of a pale amber oil
that
crystallized, was
distilled at 110-120 °C at 0.4 mm/
Hg to give
9.9 g
2-methoxy-4-methyl-5-methylthiophenylacetone with a mp of 41-42
°C. This was not im-proved by re
crystallization from hexane. Anal.
(C12H16O2S) C,H.
To a
solution of 7.3 g
2-methoxy-4-methyl-5-methylthiophenylacetone in
35 mL
methanol there was added 7.3 mL 35% hydrogen
peroxide, and the
mixture held under reflux conditions for 40 min. All
volatiles were
removed under vacuum, and the residue suspended in 250 mL H2O. This
was extracted with 3x50 mL
CH2Cl2, the extracts pooled, and the
solvent removed under vacuum. The residue, 8.6 g of an oily solid,
was re
crystallized from 10 mL boiling
toluene to provide, after
filtering and air drying, 5.4 g of
2-methoxy-4-methyl-5-methylsulfinylphenylacetone as a white solid with
a mp of 89-89.5 °C. Anal. (
C12H16O3S) C,H.
To a vigorously stirred
solution of 5.2 g of
2-methoxy-4-methyl-5-methylsulfinylphenylacetone in 70 mL MeOH there
was added 17 g
anhydrous ammonium acetate followed by 1.0 g
sodium
cyanoborohydride. HCl was added as needed to maintain the
pH at about
6 as determined with damp universal
pH paper. No further base was
generated after 3 days, and the reaction mixture was poured into 500
mL H2O. After acidification with HCl (caution, highly poisonous HCN
is evolved), this was washed with 2x100 mL
CH2Cl2, made strongly basic
with
NaOH, and then extracted with 3x100 mL
CH2Cl2. The pooled
extracts were stripped of
solvent under vacuum, and the residue
weighed 7.1 g and was a pale amber oil. This was
distilled at 150-160
°C at 0.3 mm/
Hg to give a colorless oil weighing 4.4 g. A
solution of
this in 13 mL IPA was neutralized with 30 drops of concentrated HCl
and the resulting
solution warmed and diluted with 20 mL of warm
anhydrous Et2O. White
crystals separated immediately and, after
filtering,
ether washing and air drying, provided 4.4 g of
2-methoxy-4-methyl-5-methylsulfinylamphetamine hydrochloride (TOMSO)
that melted at 227-229 °C after vacuum drying for 24 hrs. Anal.
(
C12H20ClNO2S) C,H. The presence of two chiral centers (the
alpha-carbon of the
amphetamine side chain and the
sulfoxide group at
the 5-position of the ring) dictates that this product was a mixture
of
diastereoisomeric racemic compounds. No effort was made to
separate them.
DOSAGE: greater than 150 mg (alone) or 100 - 150 mg (with
alcohol).
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 100 mg) There were no effects at all, and
it was at the so-called surprise pot-luck birthday lunch for the
department chairman that I ate a little and had two glasses of
Zinfandel. I shot up to an immediate ++ and this lasted all
afternoon. I went to San Francisco by BART, and walked up Market
Street and saw all the completely bizarre faces. I was absolutely
unable to estimate the age of anybody who was female, at least by
looking at her face. All aspects, both child-like and old, seemed to
be
amalgamated into each face, all at the same time. There was
remarkable time-slowing; overall the experience was favorable. That
certainly was not the effect of the
alcohol in the wine. Food
poisoning? No. It must have been the TOMSO that had been kindled and
promoted to something.
(with 150 mg) At best there is a threshold and it is going nowhere.
At the third hour I drank, over the course of an hour, a tall drink
containing 3 oz. of
vodka. Soon I was clearly somewhere, and three
hours later I was a rolling plus three. This lasted until well after
midnight, and was not an
alcohol response.
EXTENSIONS AND COMMENTARY: This entire venture into the study of TOMSO
was an outgrowth of the extraordinary response that had been shown by
one person to
5-TOM. There were two obvious approaches that might
throw some light on the reason for this dramatic sensitivity. One
would be to see if he was unusually capable of metabolizing
sulfur-containing molecules, and the second would be to assume he was,
and to try to guess just what product he had manu-factured with his
liver.
The individual sensitivity question was addressed in a tidy and direct
manner. Why not study a simple
sulfur-containing model compound that
would probably be metabolized only at the
sulfur and that would itself
probably be
pharmacologically inactive in its own rights? Sounded OK
to me, so I made up a goodly supply of 4-tert-butyl
thioanisole, which
proved to be a gorgeous white
crystalline solid. It seemed quite
logical that this would be metabolized at the
sulfur atom to produce
either or both the
sulfoxide and the
sulfone. So I treated a
methanol
solution of this with a little hydrogen
peroxide and
distilled the
neutral extracts at 100-115 °C at 0.2 mm/
Hg to give the
sulfoxide as a
solid that melted at 76-77 °C from hexane: Anal. (C11H16OS) C,H. On
the other hand, if a
solution of the
thioanisole in acetic acid
containing hydrogen
peroxide was heated on the steam bath for a few
hours and then worked up, a new solid was isolated that proved to be
the
sulfone (a negative Fries-Vogt test). This was obtained as white
crystals with a mp of 94-95 °C from aqueous
methanol. Anal.
(
C11H16SO2) C,H. And I found that these three compounds separated
well from one another by GC, and that they could be extracted from
urine. Everything was falling into place. My thought was to
determine a safe (inactive) level of the parent
thioanisole, and
determine the distri-
bution of
metabolites in my urine, and then in
the urine of several other people, and then finally in the urine of
the person who was the intense reactor to
5-TOM. I found that there
were no effects, either physical or
psychological, at an oral dose of
60 milligrams of 4-tert-butyl-
thioanisole. But then everything fell
apart. There was not a detectable trace of anything, neither parent
compound nor either of the potential
metabolites, to be found in my
urine. The material was obviously being completely converted to one
or more
metabolites, but the
sulfoxide and
sulfone were not among
them. It would be fun, someday, to
methodically trace the fate of
this compound.
So, on to the second approach. What might the active
metabolite of
5-TOM actually be? The
sulfoxide seemed completely reasonable, and
that encouraged the synthesis of TOMSO. This name was given, as it is
the
sulfoxide analogue (SO) of
5-TOM. And since only one of these
analogues has been made, the R5S distinction is not needed. But it is
apparent that this approach to the finding of an explanation for the
idiosyncratic sensitivity to
5-TOM also failed, in that TOMSO itself
appeared to be without activity.
But the fallout of this study was the uncovering of an unusual
property that
alcohol can occasionally have when it follows the
ingestion of certain inactive drugs. Or if it is used at the tail end
of an experience with an active drug. Usually some
alcohol has been
employed as a softener of the
residual effects of the day's
experiment, or as a social habit to accompany the post-mortem
discussions of a day's experiences, and perhaps as a help to sleeping.
But if there is a rekindling of the effect, rather than the
sedation
expected, then the verb "to tomso" can be used in the notes. It
represents the promotion of an inactive situation into an active one,
with the catalysis of
alcohol. But the effect is not that of alcohol.
Might the extreme sensitivity of some
alcoholics to even a small
amount of
alcohol be due to some endogenous "inactive" factor that is
promoted in this way into some centrally
florid toxicity? I remember
seeing proposals of some
tetrahydroisoquinolines as potential
mis-
metabolites in efforts to explain the toxicity of
alcohol. Maybe
they are nothing more than
psychedelics that are thought to be
inactive, but which might be ignited with a glass of wine. And the
person is tomsoing with his small amount of
alcohol.
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