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#174 TP
THIOPROSCALINE; 3,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE
SYNTHESIS: A
solution was made of 12.1 g
N,N,N',N'-
tetramethylethylenediamine and 13.8 g of
1,3-dimethoxybenzene in 200 mL 30-60 °C petroleum
ether. This was
stirred vigorously under a He
atmosphere and cooled to 0 °C with an
external ice bath. There was added 66 mL of 1.6 M
butyllithium in
hexane which produced a white granular
precipitate. The reaction
mixture was brought up to room tem
perature for a few minutes, and then
cooled again to 0 °C. There was then added 15.8 g of
di-(n)-propyl
disulfide which changed the granular
precipitate to a creamy
appearance. Stirring was continued while the reaction mixture was
brought up to room tem
perature and finally up to reflux. The reaction
mixture was then added to 600 mL of dilute H2SO4. The two
phases were
separated, and the aqueous
phase extracted with 2x75 mL
Et2O. The
organic
phases were combined, and the
solvent removed under vacuum.
The residue was 24.2 g of a pale amber liquid which was
distilled at
0.35 mm/
Hg to give two fractions. The first boiled at 85-90 °C,
weighed 0.5 g and appeared to be recovered
dipropyl disulfide. The
product
2-(n)-propylthio-1,3-dimethoxybenzene boiled at at 105-125 °C,
and weighed 20.8 g. A small sample re
crystallized from hexane had a
mp of 27-28 °C. Anal. (C11H16O2S) C,H.
To a stirred
solution of 19.8 g of
2-(n)-propylthio-1,3-dimethoxybenzene in 200 mL
CH2Cl2 there was added
15.4 g elemental
bromine dissolved in 100 mL
CH2Cl2. The reaction was
not exothermic, and it was allowed to stir for 1 h. The reaction
mixture was washed with H2O containing
sodium hydrosulfite (which
rendered it nearly colorless) and finally washed with saturated brine.
The
solvent was removed under vacuum leaving 33.5 g of a pale yellow
liquid. This was
distilled at 112-120 °C at 0.3 mm/
Hg to yield
4-bromo-2-(n)-propylthio-1,3-dimethoxybenzene as a pale yellow oil.
Anal. (C11H15BrO2S) C,H.
To a
solution of 16.8 g
diisopropylamine in 100 mL
anhydrous THF that
was stirred under a N2
atmosphere and cooled to -10 °C with an
external ice/MeOH bath, there was added in sequence 75 mL of 1.6 M
butyllithium in hexane, 3.0 mL of dry
CH3CN, and 8.7 g of
4-bromo-2-(n)-propylthio-1,3-dimethoxybenzene which had been
dissolved
in 20 mL THF. The bromo compound was added dropwise over the course
of 5 min. The color became deep red-brown. Stirring was maintained
for a total of 30 min while the reaction came to room tem
perature. It
was then poured into 750 mL dilute H2SO4, the organic layer separated,
and the aqueous
phase extracted with 2x100 mL
CH2Cl2. These extracts
were pooled, washed with dilute H2SO4, and the
solvent was removed
under vacuum yielding a residue that was
distilled. Two
distillation
cuts were taken at 0.3 mm/
Hg. The first fraction boiled at 110-138 °C
and weighed 0.7 g and was discarded. The second fraction came over at
148-178 °C and weighed 3.0 g. By thin layer
chromatography this
fraction was about 80% pure, and was used as such in the following
reduction. A small sample was ground under
methyl cyclopentane
yielding white
crystals of
3,5-dimethoxy-4-(n)-propylthiophenylacetonitrile with a mp of
35.5-37.5 °C.
A
solution of LAH in THF (15 mL of a 1 M solution) under N2 was cooled
to 0 °C and vigorously stirred. There was added, dropwise, 0.4 mL
100% H2SO4, followed by 2.7 g
3,5-dimethoxy-4-(n)-propylthiophenylacetonitrile dissolved in 10 mL
anhydrous THF. The reaction mixture was stirred at 0 °C for a few
min, then brought to a reflux for 30 min on the steam bath. After
cooling back to room tem
perature, there was added IPA to destroy the
excess
hydride and 10%
NaOH to bring the reaction to a basic
pH and
converted the
aluminum oxide to a loose, white, filterable
consistency. This was removed by filtration and washed with both THF
and IPA. The filtrate and washes were stripped of
solvent under
vacuum, the residue added to 1 L dilute H2SO4. This was washed with
2x75 mL
CH2Cl2, made basic with aqueous
NaOH, extracted with 3x75 mL
CH2Cl2, the extracts pooled, and the
solvent removed under vacuum.
The residue was
distilled at 137-157 °C at 0.3 mm/
Hg to give 1.3 g of
a colorless oil. This was
dissolved in 10 mL of IPA, neutralized with
20 drops of concentrated HCl and, with continuous stirring, diluted
with 50 mL
anhydrous Et2O. The product was removed by filtration,
washed with
Et2O, and air dried to give 1.4 g of
3,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (TP) as
bright white
crystals with a mp of 164-165 °C. Anal. (
C13H22ClNO2S)
C,H.
DOSAGE: 20 - 25 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 18 mg) There was very little effect until
more than two hours, when I came inside out of the cold and jumped to
an immediate +1. It is hard to define, and I am quite willing to have
it develop more, and if not, quite willing to go higher next time. I
got into several quite technical conversations, but through it all I
was aware of a continuous alteration. There was a drop at the seventh
hour, and nothing at all was left at twelve hours.
(with 27 mg) My body feels heavy. This is not a negative thing, but
it is there. I feel a heavy pressure at the back of the neck, which
is probably unresolved energy. The nervous system seems to be somehow
vunerable. Towards the end of the experience I considered a Miltown,
but settled on an aspirin, and I still couldn't sleep for about 24
hours. The imagery is extremely rich and there is quite a bit of
eyes-open visual, but mostly eyes closed. I think the rewards are not
worth the body price. Sometime again, maybe lower?
EXTENSIONS AND COMMENTARY: There is a high potency here, but clearly
there are signs of increased toxicity as well even over the
ethyl
homologue, TE. The butyl compound (see TB) was the last of this
series of
phenethylamines and as is noted there, the physical problems
lessen, but so do the
psychedelic properties. The three-
carbon
amphetamine homologues are completely unexplored. The most reasonable
starting material for these would be 4-
thiosyringaldehyde, with
S-
alkylation and then the conventional
nitroethane coupling followed
with LAH reduction. The most appealing target as a potential
psychedelic would be the
methylthio homologue
(
3,5-dimethoxy-4-methylthioamphetamine, 3C-TM) or, as a potential
euphoriant, the butylthio
homologue
(
3,5-dimethoxy-4-(n)-butylthioamphetamine, 3C-TB). I am not sure that
these
alkylthio analogues would justify the labor needed to make them.
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