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#167 4T-MMDA-2
6-(2-AMINOPROPYL)-5-METHOXY-1,3-BENZOXATHIOL; 2-METHOXY-4,5-METHYLENETHIOOXYAMPHETAMINE
SYNTHESIS: To a well-stirred
solution of 120 g
thiourea in 800 mL 2N
HCL, there was added a
solution of 100 g
benzoquinone in 500 mL acetic
acid over the course of 15 min. Stirring was continued for an
additional 0.5 h at room tem
perature, and then the reaction mixture
was heated on the steam bath for 1 h. With cooling in ice water, a
heavy crop of
crystals separated. These were removed by filtration
and air dried to provide 90.1 g of
5-hydroxy-1,3-benzoxathiol-2-one
(2-
mercaptohydroquinone cyclic carbonate ester) with a melting point
of 170.5-172.5 °C.
To a suspension of 100 g finely powdered
anhydrous K2CO3 in 400 mL
acetone containing 50 g
methyl iodide there was added 41 g
5-hydroxy-1,3-benzoxathiol-2-one, and the mixture stirred overnight at
room tem
perature. The solids were removed by filtration, and the
solvent removed under vacuum. The residue was
distilled to give a
fraction subliming over as a solid at an oven tem
perature of 110 °C at
0.1 mm/
Hg. This was a yellowish solid, weighing 27.4 g and having a
mp of 66-72 °C. Re
crystallization from MeOH gave
5-methoxy-1,3-benzoxathiol-2-one as a white solid with a mp of
75.5-76.5 °C.
To a
solution of 30 g 85% KOH in 75 mL warm H2O, there was added an
equal volume of warm MeOH followed by 16 g
5-methoxy-1,3-benzoxathiol-2-one, and the mixture was held under
reflux conditions for 2 h. After cooling to room tem
perature, the mix
was acidified with HCl and extracted with 2x100 mL
CH2Cl2. Removal of
the
solvent from the pooled extracts gave a yellow oil that
crystallized on standing. The product,
2-mercapto-4-methoxyphenol,
weighed 14 g and had a mp of 56-57 °C.
A
solution of 10 g
2-mercapto-4-methoxyphenol in 100 mL MEK was added
over the course of 1 h to a vigorously stirred suspension of 25 g
finely powdered
anhydrous K2CO3 in 200 mL MEK that contained 14 g
methylene bromide. The reflux was maintained for 48 h. After
cooling, the mixture was freed of solids by filtration and the filter
cake washed with 50 mL additional MEK. The combined washes and
filtrate were stripped of
solvent under vacuum, and the product
distilled to give 3.3 g of
5-methoxy-1,3-benzoxathiol as a yellowing
oil that had a bp of 110-120 °C at 1.7 mm/
Hg. There was considerable
residue in the pot, which was discarded. The
NMR spectrum was
excellent, with the
methylene protons a two-hydrogen singlet at 5.6
ppm.
To a mixture of 3.2 g POCl3 and 2.8 g N-
methylformanilide that had
been heated briefly on the steam bath (to the formation of a deep
claret color) there was added 2.3 g
5-methoxy-1,3-benzoxathiol, and
steam bath heating was continued for an additional 5 min. The
reaction mixture was poured into 100 mL H2O, and after a few minutes
stirring, the in
solubles changed to a loose solid. This was collected
by filtration, H2O washed and, after sucking as dry as possible,
re
crystallized from 30 mL boiling MeOH. This provided 1.9 g of
6-formyl-5-methoxy-1,3-benzoxathiol as brownish needles that melted at
119-120 °C.
A
solution of 1.5 g
6-formyl-5-methoxy-1,3-benzoxathiol in 50 mL
nitroethane was treated with 0.3 g
anhydrous ammonium acetate and
heated on the steam bath for 5 h. Removal of the
solvent under vacuum
gave a residue that
crystallized. This was recrystallized from 110 mL
boiling
EtOH providing, after fil-tering and air drying, 1.3 g
5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol as San Francisco
Giants-orange-colored
crystals.
A
solution of AH was prepared by the treatment of a solution of 1.3 g
LAH in 10 mL THF, at 0 °C and under He, with 0.8 mL 100% H2SO4. A
solution of 1.1 g of
5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol
in 25 mL THF was added dropwise, and the stirring was continued for 1
h. After a brief period at reflux, the reaction mixture was returned
to room tem
perature, and the excess
hydride destroyed by the addition
of IPA. The salts were converted to a filterable mass by the addition
of 5%
NaOH and, after filtering and washing with IPA, the combined
filtrate and washings were stripped of
solvent under vacuum. The
residue was
dissolved in dilute H2SO4 which was washed with 3x75 mL
CH2Cl2 and then, after being made basic with 25%
NaOH, the product was
extracted with 2x75 mL
CH2Cl2. The extracts were pooled, and the
solvent removed under vacuum. Distillation of the residue gave a
fraction that boiled at 140-155 °C at 0.3 mm/
Hg which weighed 0.7 g.
This was
dissolved in 4 mL IPA, neutralized with 14 drops of
concentrated HCl, heated to effect complete
solution, then diluted
with 10 mL of
anhydrous Et2O. The white
crystals that formed were
removed,
Et2O washed, and air dried to give 0.6 g
6-(2-aminopropyl)-5-methoxy-1,3-benzoxathiol hydrochloride
(4T-M
MDA-2).
DOSAGE: greater than 25 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 25 mg) At three hours after having taken
the material, I felt that there might have been a little exhilaration.
And maybe a hint of tremor and of teeth clench. Perhaps this is a
threshold dose.
EXTENSIONS AND COMMENTARY: There is no logical way to try to guess
where the active level of this might be. In a comparison of 4-oxy
with 4-thio- and with 4-alkyl (as, for example, TMA-2, PARA-DOT and
DOM) the
analogue with the
sulfur atom lies intermediate in potency
between the oxygen atom and the
carbon atom. Then, perhaps, 4T-M
MDA-2
should be somewhat more potent than M
MDA-2. Which is where the trials
have gone to, and the absence of effects therefore declares that line
of reasoning invalid. What else could be used for clues? The whole
benzofuran project, which had the same
cyclic nature, was without
activity. They had a
carbon where the
sulfur was of 4T-M
MDA- 2, so,
by that reckoning, this compound should be even less active. Maybe
that is the formula to follow. The bottom line is inescapable. None
of these extrapolations can hold a candle to the only experiment that
can give believable findings, the actual trial of a new compound in
man.
The positional
isomer of the
heterocyclic carbonate used here is also
known. Instead of using
benzoquinone as a starting material with
thiourea as the
sulfur source (giving the 1,4- oxygen orientation),
one can start with
resorcinol in reaction with
ammonium thiocyanate as
the
sulfur source (in the presence of
copper sulfate) and get the
positional
isomer with a 1,3- oxygen orientation. This material (also
known as
thioxolone, or
tioxolone, or
6-hydroxy-1,3-benzoxathiol-2-one, and which is commercially available)
should follow the same chemistry shown here for the 5-hydroxy
analogue, and give 5T-M
MDA-2
(
5-(2-aminopropyl)-6-methoxy-1,3-benzoxathiole or
2-methoxy-5,4-methylenethiooxyamphetamine) as a final product. I
would guess, based on the findings that compare
5-TOM with DOM, that
this would be a relatively low-potency compound. At least it should
be an easy one to make!
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