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From: sender@mit.edu
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 5 of 6

(I'm posting this for a friend.)

This is part 5 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.





#120 MEDA; 3-METHOXY-4,5-ETHYLENEDIOXYAMPHETAMINE

SYNTHESIS: To a solution of 50 g 3,4-dihydroxy-5-methoxybenzaldehyde
in 100 mL distilled acetone there was added 70 g ethylene bromide and
58 g finely powdered anhydrous K2CO3.  The mixture was held at reflux
for 5 days.  This was then poured into 1.5 L H2O and extracted with
4x100 mL CH2Cl2.  Removal of the solvent from the pooled extracts gave
a residue which was distilled at 19 mm/Hg.  Several of the fractions
taken in the 203-210 !C range spontaneously crystallized, and they
were pooled to give 18.3 g of 3-methoxy-4,5-ethylenedioxybenzaldehyde
as white solids with a mp of 80-81 !C.  A small sample with an equal
weight of malononitrile in EtOH treated with a few drops of
triethylamine gave 3-methoxy-4,5-ethylenedioxybenzalmalononitrile as
pale yellow crystals from EtOH with a mp of 153-154 !C.

A solution of 1.50 g 3-methoxy-4,5-ethylenedioxybenzaldehyde in 6 mL
acetic acid was treated with 1 mL nitroethane and 0.50 g anhydrous
ammonium acetate, and held on the steam bath for 1.5 h.  To the cooled
mixture H2O was cautiously added until the first permanent turbidity
was observed, and once crystal-lization had set in, more H2O was added
at a rate that would allow the generation of additional crystals.
When there was a residual turbidity from additional H2O, the addition
was stopped, and the beaker held at ice temperature for several h.
The product was removed by filtration and washed with a little 50%
acetic acid, providing 0.93 g
1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene as dull yellow
crystals with a mp of 116-119 !C.  Recrystallization of an analytical
sample from MeOH gave a mp of 119-121 !C.

A stirred suspension of 6.8 g LAH in 500 mL anhydrous Et2O under an
inert atmosphere was brought up to a gentle reflux.  A total of 9.4 g
1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene in warm Et2O was
added over the course of 0.5 h.  Refluxing was maintained for 6 h, and
then the reaction mixture was cooled and the excess hydride destroyed
by the cautious addition of 400 mL 1.5 N H2SO4.  The two clear phases
were separated, and the aqueous phase was brought to pH of 6 by the
addition of a saturated Na2CO3 solution.  This was filtered free of a
small amount of insolubles, and the clear filtrate was heated to 80
!C.  To this there was added a solution of 9.2 g picric acid (90%
material) in 100 mL boiling EtOH, and the clear mixture allowed to
cool in an ice bath.  Scratching generated yellow crystals of the
picrate salt.  This salt was filtered free of the aqueous environment,
treated with 50 mL of 5% NaOH, and stirred until the picric acid was
totally in the form of the soluble sodium salt.  This was then
extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum.  The residue weighed 6.0 g, and was dissolved in
100 mL anhydrous Et2O, and saturated with dry HCl gas.  The white
solids that formed were filtered free of the Et2O, and ground up under
50 mL of slightly moist acetone, providing 4.92 g of
3-methoxy-4,5-ethylenedioxyamphetamine hydrochloride monohydrate
(MEDA) as white crystals.

DOSAGE: greater than 200 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: There are times when the Gods smile in
unexpectedly nice ways.  Having found the activity of MMDA, the
RscientificS thing to do would be to compare it against the other
RpsychotomimeticS amphetamine that was known at that time (this was
1962), namely TMA.  Comparing their structures, the only difference of
any kind was that two of the adjacent methoxyl groups of TMA were
replaced with a 5-membered ring, called the methylenedioxy ring.

Where does one go next?  Some perverse inspiration suggested
increasing the size of this ring to a 6-membered ring, the
ethylenedioxy (or dioxene) homologue.  Well, if you thought that
getting myristicinaldehyde was a difficulty, it was nothing compared
to getting this 6-membered counterpart.  But I huffed and I puffed,
and I did make enough to taste and to evaluate.  And it was here that
I got the divine message!  No activity!!  So, rather than being
condemned forever a la Sisyphus to push ever larger rings up my
psyche, I gave myself permission to pursue another path.  The message
was: RDonUt change the groups.  Leave them as they are, but relocate
them instead.S And that led directly to TMA-2 and its story.

A couple of diversions may be mentioned here.  Before the blessed
inactivity of MEDA was established, the 7-membered ring counterpart,
3-methoxy-4,5-trimethylenedioxyamphetamine (MTMA) was prepared by
essentially the same procedure.  The above
3-methoxy-4,5-dihydroxybenzaldehyde with trimethylene bromide gave
3-methoxy-4,5-trimethylenedioxybenzaldehyde, white solids, with a
malononitrile derivative with a mp of 134-135 !C; the aldehyde with
nitroethane gave the nitropropene with a mp of 86-87 !C; and this with
LAH gave MTDA as the hydrochloride (mp 160-161 !C) again isolated
first as the picrate.  It had been tasted at up to an 8 milligram
dosage (no activity, but none expected) before being abandoned.  And,
an initial effort was made to synthesize a five-member ring
(methylenedioxy) with a methyl sticking out from it.  This ethylidine
homologue got as far as the aldehyde stage.  The reaction between
3,4-dihydroxy-5-methoxybenzaldehyde and 1,1-dibromoethane in acetone
containing anhydrous potassium carbonate gave a minuscule amount of a
product that was a two-component mixture.  This was resolved by dozens
of separate injections into a preparatory gas chromatography system,
allowing the isolation of the second of the two components in a
quantity sufficient to demonstrate (by NMR spectroscopy) that it was
the desired 3-methoxy-4,5-ethylidinedioxybenzaldehyde.  Starting with
the pre-prepared dipotassium salt or the lead salt of the
catecholaldehyde gave nothing.  With no activity being found with
MEDA, all was abandoned.

There are some comments made under MDA for successful chemistry (using
a different approach) alo#ng these lines when there is no methoxyl
group present.  These are the compounds EDA and IDA.  But the
pharmacology was still not that exciting.

 

 

 



#121 MEE; 4,5-DIETHOXY-2-METHOXYAMPHETAMINE

SYNTHESIS: To a solution of 166 g bourbonal in 1 L MeOH there was
added a solution of 66 g KOH pellets in 300 mL H2O.  There was then
added 120 g ethyl bromide, and the mixture was held at reflux on the
steam bath for 3 h.  The reaction was quenched with three volumes of
H2O, and made strongly basic by the addition of 25% NaOH.  This was
extracted with 3x300 mL CH2Cl2, and the pooled extracts stripped of
solvent under vacuum.  There remained 155 g of
3,4-diethoxybenzaldehyde as a fluid oil that had an infra-red spectrum
identical (except for being slightly wet) to that of a commercial
sample from the Eastman Kodak Company.

A solution of 194 g 3,4-diethoxybenzaldehyde in 600 g glacial acetic
acid was arranged in a flask that could be magnetically stirred, yet
cooled as needed with an external ice bath.  A total of 210 g of 40%
peracetic acid in acetic acid was added at a rate such that, with ice
cooling, the exothermic reaction never raised the internal temperature
above 26 !C.  The reaction developed a deep red color during the 2 h
needed for the addition.  At the end of the reaction the mixture was
quenched by the addition of three volumes of H2O, and the remaining
acidity was neutralized by the addition of solid Na2CO3 (700 g was
required).  This aqueous phase was extracted several times with
CH2Cl2, and the solvent was removed from the pooled extracts under
vacuum.  The residue was a mixture of the intermediate formate ester
and the end product phenol.  This was suspended in 800 mL 10% NaOH,
and held on the steam bath for 1.5 h.  After cooling, this was washed
once with CH2Cl2 (discarded) and then acidified with HCl.  There was
the formation of an intensely hydrated complex of the product phenol,
reminiscent of the problem encountered with 3-ethoxy-4-methoxyphenol.
This was worked up in three parts.  The entire acidified aqueous phase
was extracted with Et2O (3x200 mL) which on evaporation gave 80 g of
an oil.  The hydrated glob was separately ground up under boiling
CH2Cl2 which, on evaporation, gave an additional 30 g of oil, and the
aqueous mother liquor from the glob was extracted with 2x200 mL CH2Cl2
which provided, after removal of the solvent, an additional 10 g.
These crude phenol fractions were combined and distilled at 1.5 mm/Hg.
Following a sizeable forerun, a fraction boiling at 158-160 !C was the
anhydrous product, 3,4-diethoxyphenol.  It was a clear, amber oil, and
weighed 70.0 g.  The slightest exposure to H2O, even moist air, give a
solid hydrate, with mp of 63-64 !C.  This phenol can be used for the
synthesis of MEE (this recipe) or for the preparation of EEE (see the
separate recipe).  A solution of 2.0 g of this phenol in 5 mL CH2Cl2
was diluted with 15 mL hexane.  This was treated with 2 g methyl
isocyanate followed by a few drops of triethylamine.  After about 5
min, white crystals formed of 3,4-diethoxyphenyl-N-methyl carbamate,
with a mp of 90-91 !C.

A solution of 26.6 g 3,4-diethoxyphenol in 50 mL MeOH was mixed with
another containing 9.6 g KOH pellets dissolved in 200 mL hot MeOH.
There was then added 21.4 g methyl iodide, and the mixture was held at
reflux for 2 h on the steam bath.  This was then quenched in 3 volumes
of water, made strongly basic with 25% NaOH, and extracted with 3x150
mL CH2Cl2.  Evaporation of the solvent from the pooled extracts gave
19.3 g of 1,2-diethoxy-4-methoxybenzene (3,4-diethoxyanisole) as a
clear, pale amber oil that solidified when cooled.  The mp was 20-21
!C.

A mixture of 32.0 g N-methyl formanilide and 36.2 g POCl3 was allowed
to stand until it was a deep red color (about 0.5 h).  To this there
was added 18.3 g 1,2-diethoxy-4-methoxybenzene and the exothermic
reaction was heated on the steam bath for 2.5 h.  This was then poured
over 600 mL chipped ice, and the dark oily material slowly began
lightening in color and texture.  A light oil was formed which, on
continued stirring, became crystalline.  After the conversion was
complete, the solids were removed by filtration producing, after
removal of as much H2O as possible by suction, 26.9 g of crude
aldehyde.  A small sample pressed on a porous plate had a mp of
87.5-88.5 !C.  Recrystallization of the entire damp crop from 50 mL
boiling MeOH gave, after cooling, filtering, and air drying, 17.7 g of
4,5-diethoxy-2-methoxybenzaldehyde as fluffy, off-white crystals with
a mp of 88-88.5 !C.  A solution of 1.0 g of this aldehyde and 0.5 g of
malononitrile dissolved in warm absolute EtOH was treated with 3 drops
triethylamine.  There was the immediate formation of crystals which
were filtered and air dried to constant weight.  The product,
4,5-diethoxy-2-methoxybenzalmalononitrile, was a bright yellow
crystalline material, which weighed 1.0 g and had a mp of 156-157 !C.

To a solution of 14.7 g 4,5-diethoxy-2-methoxybenzaldehyde in 46 g
glacial acetic acid, there was added 8.0 g nitroethane and 5.0 g
anhydrous ammonium acetate.  The mixture was heated on the steam bath
for 2 h, becoming progressively deeper red in color.  The addition of
a small amount of H2O to the hot, clear solution produced a slight
turbidity, and all was allowed to stand overnight at room temperature.
There was deposited a crop of orange crystals that was removed by
filtration and air dried.  There was obtained 7.0 g
1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene as brilliant orange
crystals that had a mp of 89-90.5 !C.  This was tightened up, but not
improved, by trial recrystallization from acetic acid, mp 89-90 !C,
and from hexane, mp 90-90.5 !C.  Anal. (C14H19NO5) C,H.

To a gently refluxing suspension of 5.0 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 6.5 g
1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added a warm saturated solution of the
nitrostyrene dropwise.  Refluxing was maintained for 5 h, and the
reaction mixture was cooled with an external ice bath.  The excess
hydride was destroyed by the cautious addition of 400 mL of 1.5 N
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and 100 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was >9,
and this was extracted with 3x200 mL CH2Cl2.  Removal of the solvent
under vacuum produced an off-white oil that was dissolved in anhydrous
Et2O and saturated with anhydrous HCl gas.  The crystals of
4,5-diethoxy-2-methoxyamphetamine hydrochloride (MEE) that formed were
very fine and slow to filter, but finally were isolated as a white
powder weighing 5.4 g and melting at 178.5-180 !C.  Anal.
(C14H24ClNO3) C,H,N.

DOSAGE: greater than 4.6 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: There were early trials made with MEE,
before it became known what direction the ethoxy substitution results
would take.  A number of progressive trials, up to a dosage of 4.6
milligrams, were without any central effects at all.

There is an instinct in structure-activity studies to think of a
change as a success or a failure, depending on whether there is an
increase or a decrease in the desired activity.  But if one were to
look at the effects of putting an ethoxy group onto TMA-2 in place of
a methoxy group as a way of decreasing the effectiveness, then the
4-position becomes the worst position (MEM is equipotent to TMA-2),
and the 5-position is perhaps a little less bad (MME is almost as
potent) and the 2-position is the best by far (EMM is out of it,
potency-wise).  In other words, in the comparison of the 2- and the
5-positions, the lengthening of the 5-position gives modest loss of
activity, and the lengthening of the whatever in the 2-position is the
most disruptive.  With this as a basis for prediction, then MEE (which
differs from MEM only by a lengthening of the 5-position substituent)
might be only a little less active than MEM and, as MEM is about the
same as TMA-2, it is distinctly possible that MEE may show activity in
the area at dosages that are not much above the 25 to 50 milligram
area.  Of all the diethoxy homologues, it would be the most promising
one to explore.

Which brings to mind a quotation of a hero of mine, Mark Twain.  RI
like science because it gives one such a wholesome return of
conjecture from such a trifling investment of fact.

 

 

 



#122 MEM; 2,5-DIMETHOXY-4-ETHOXYAMPHETAMINE

SYNTHESIS: A solution of 83 g bourbonal (also called ethyl vanillin,
or vanillal, or simply 3-ethoxy-4-hydroxybenzaldehyde) in 500 mL MeOH
was treated with a solution of 31.5 g KOH pellets (85% material)
dissolved in 250 mL H2O.  There was then added 71 g methyl iodide, and
the mixture was held under reflux conditions for 3 h.  All was added
to 3 volumes of H2O, and this was made basic with the addition of 25%
NaOH.  The aqueous phase was extracted with 5x200 mL CH2Cl2.  The
pooling of these extracts and removal of the solvent under vacuum gave
a residue of 85.5 g of the product 3-ethoxy-4-methoxybenzaldehyde,
with a mp of 52-53 !C.  When this product was recrystallized from
hexane, its mp was 49-50 !C.  When the reaction was run with the same
reactants in a reasonably anhydrous environment, with methanolic KOH,
the major product was the acetal, 3-ethoxy-a,a,4-trimethoxytoluene.
This was a white glistening product which crystallized readily from
hexane, and had a mp of 44-45 !C.  Acid hydrolysis converted it to the
correct aldehyde above.  The addition of sufficient H2O in the
methylation completely circumvents this by-product.  A solution of 1.0
g of this aldehyde and 0.7 g malononitrile in 20 mL warm absolute
EtOH, when treated with a few drops of triethylamine, gave immediate
yellow color followed, in a few min by the formation of crystals.
Filtration, and washing with EtOH, gave bright yellow crystals of
3-ethoxy-4-methoxybenzalmalononitrile with a mp of 141-142 !C.

A well stirred solution of 125.4 g 3-ethoxy-4-methoxybenzaldehyde in
445 mL acetic acid was treated with 158 g 40% peracetic acid (in
acetic acid) at a rate at which, with ice cooling, the internal
temperature did not exceed 27 !C.  The addition required about 45 min.
The reaction mixture was then quenched in some 3 L H2O.  There was the
generation of some crystals which were removed by filtration.  The
mother liquor was saved.  The solid material weighed, while still wet,
70 g and was crude formate ester.  A small quantity was recrystallized
from cyclohexane twice, to provide a reference sample of
3-ethoxy-4-methoxyphenyl formate with a mp of 63-64 !C.  The bulk of
this crude formate ester was dissolved in 200 mL concentrated HCl
which gave a deep purple solution.  This was quenched with water which
precipitated a fluffy tan solid, which was hydrated phenolic product
that weighed about 35 g, and melted in the 80-90 !C. range.  The
mother liquors of the above filtration were neutralized with Na2CO3,
then extracted with 3x100 ml Et2O.  Removal of the solvent gave a
residue of about 80 g that was impure formate (containing some
unoxidized aldehyde).  To this there was added 500 mL 10% NaOH, and
the dark mixture heated on the steam bath for several h.  After
cooling, the strongly basic solution was washed with CH2Cl2, and then
treated with 200 mL Et2O, which knocked out a heavy semi-solid mass
that was substantially insoluble in either phase.  This was, again,
the crude hydrated phenol.  The Et2O phase, on evaporation, gave a
third crop of solids.  These could actually be recrystallized from
MeOH/H2O, but the mp always remained broad.  When subjected to
distillation conditions, the H2O was finally driven out of the
hydrate, and the product 3-ethoxy-4-methoxyphenol distilled as a clear
oil at 180-190 !C at 0.8 mm/Hg.  This product, 45.1 g, gave a fine NMR
spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1,
supporting the freedom of the OH group on the aromatic ring from
adjacent oxygen.  Efforts to obtain an NMR spectrum in D2O immediately
formed an insoluble hydrate.  This phenol can serve as the starting
material for either MEM (see below) or EEM (see separate recipe).

To a solution of 12.3 g 3-ethoxy-4-methoxyphenol in 20 mL MeOH, there
was added a solution of 4.8 g flaked KOH in 100 mL heated MeOH.  To
this clear solution there was then added 10.7 g methyl iodide, and the
mixture held at reflux on the steam bath for 2 h.  This was then
quenched in 3 volumes H2O, made strongly basic with 10% NaOH, and
extracted with 3x100 mL CH2Cl2.  Removal of the solvent from the
pooled extracts under vacuum gave 9.4 g of an amber oil which
spontaneously crystallized.  The mp of 1,4-dimethoxy-2-ethoxybenzene
was 42-43.5 !C, and was used, with no further purification, in the
following step.

A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed
to stand for 0.5 h, producing a deep claret color.  To this there was
added 9.2 g 1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on
the steam bath for 2 h.  It was then poured into chipped ice and, with
mechanical stirring, the dark oily phase slowly became increasingly
crystalline.  This was finally removed by filtration, providing a
brown solid mat which showed a mp of 103.5-106.5 !C.  All was
dissolved in 75 mL boiling MeOH which, on cooling, deposited fine
crystals of 2,5-dimethoxy-4-ethoxybenzaldehyde that were colored a
light tan and which, after air drying to constant weight, weighed 8.5
g and had a mp of 108-109.5 !C.  Search was made by gas chromatography
for evidence of the other two theoretically possible positional
isomers, but none could be found.  The NMR spectrum showed the two
para-protons as clean singlets, with no noise suggesting other
isomers.  There was a single peak by GC (for the recrystallized
product) but the mother liquors showed a contamination that proved to
be N-methylformanilide.  A 0.3 g sample, along with 0.3 g
malononitrile, was dissolved in 10 mL warm absolute EtOH, and treated
with a drop of triethylamine.  There was the immediate formation of a
yellow color followed, in 1 min, by the deposition of fine yellow
needles.  Filtering and air drying gave 0.25 g of
2,5-dimethoxy-4-ethoxybenzalmalononitrile, with a mp of 171-172 !C.

A solution of 7.3 g 2,5-dimethoxy-4-ethoxybenzaldehyde in 25 g glacial
acetic acid was treated with 3.6 g nitroethane and 2.25 g anhydrous
ammonium acetate, and heated on the steam bath.  After two h, the
clear solution was diluted with an equal volume of H2O, and cooled in
an ice bucket.  There was the formation of a heavy crop of orange
crystals which were removed by filtration.  The dry weight of
1-(2,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene was 4.8 g and the mp
was 120-124 !C.  Recrystallization of an analytical sample from MeOH
gave a mp of 128-129 !C.  Anal. (C13H17NO5) C,H.

To a gently refluxing suspension of 3.3 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 4.3 g
1-(2,5-dimethoxy-4-ethoxy)-2-nitropropene by allowing the condensing
Et2O to drip into a shunted Soxhlet thimble apparatus containing the
nitrostyrene, thus effectively adding a warm saturated ether solution
of it to the hydride mixture.  The addition took 2 h.  Refluxing was
maintained for 5 h, and then the reaction mixture was cooled to 0 !C
with an external ice bath.  The excess hydride was destroyed by the
cautious addition of 300 mL of 1.5 N H2SO4.  When the aqueous and Et2O
layers were finally clear, they were separated, and 100 g of potassium
sodium tartrate was dissolved in the aqueous fraction.  Aqueous NaOH
was then added until the pH was >9, and this was then extracted with
3x100 mL CH2Cl2.  Evaporation of the solvent from the pooled extracts
produced an almost white oil that was dissolved in 100 mL anhydrous
Et2O and saturated with anhydrous HCl gas.  There was deposited a
white crystalline solid of 2,5-dimethoxy-4-ethoxyamphetamine
hydrochloride (MEM) which weighed 3.1 g and had a mp of 171-172.5 !C.
Anal. (C13H22ClNO3) C,H,N.

DOSAGE: 20 - 50 mg.

DURATION: 10 - 14 h.

QUALITATIVE COMMENTS: (with 20 mg) I experienced some physical
discomfort, but doesnUt that tell us about the work to be done, rather
than the property of the material?  The breakthrough I had was the
following day (and this seems to be the way MEM operates, i.e., first
the energy and expansion, next day insight) was of the highest value
and importance for me.  I was given a methodology for dealing with my
shadow parts.  No small gift.  And I did it all alone and the results
were immediate.  I am so grateful.

(with 20 mg, at 1.5 h following 120 mg MDMA) RThe transition was very
smooth, with no obvious loss of the MDMA experience.  I felt less of a
need to talk, but the intimate closeness with the others was
maintained.  The experience continues to grow more profound and
euphoric and I prayed, in the latter part of the afternoon, that it
wouldnUt stop.  It continued until midnight with marvelous feelings,
good energy, and much hilarity.  And it abated very little over the
next several days leaving me with the feeling of lasting change with
important insights still coming to mind one week later.

(with 25 mg, at 2 h following 120 mg MDMA) RI found that sounds in
general were distracting.  No, they were out-and-out annoying.  I may
have been in an introspective mood, but I really wanted to be alone.
No body problems at all.  Felt good.  I developed some color changes
and some pattern movement.  Not much, but then I didnUt explore it
much.  The wine party afterwards was certainly most pleasant.  The
soup was a great pleasure.  And that hard bread was good.  The
material was clearly not anorexic, or at least I overcame whatever
anorexia there might have been.

(with 30 mg) I was aware of this in thirty minutes and it slowly
developed from there to an almost +++ in the following hour.  There
were visual phenomena, with some color enhancement and especially a
considerable enhancement of brights and darks.  The first signs of
decline were at about six hours, but there was something still working
there after another six hours had passed.  A slow decline, certainly.

(with 50 mg) I came into the experience knowing that yesterday had
been a very fatiguing and tense day.  I felt this material within the
first ten minutes which is the fastest that I have ever felt anything.
The ascent was rapid and for the first hour I tended to an inward
fantasying with a distinct sensual tinge.  There was a persistent
queasiness that never left me, and it contrasted oddly with a good
feeling of outward articulation and lucidity which succeeded in coming
to the fore after the introverted first hour.  Sleep was difficult,
but the next day was calm and clear.

(with 50 mg) Lots of energy, best directed into activity.  Clear
imaging, thinking.  Intense yet serene.  Good feeling of pleasantness
and some euphoria.  I felt the need to keep moving.  Hard to stay
still.

(with 70 mg, in two parts) RThe effects of the 40 milligrams were
muted by another drug experiment yesterday morning, and I never got
much over a plus 1.  There is an erotic nature, tactile sensitivity
perhaps not as delicate as with 2C-B, but it is there.  At the 2 hour
point, an additional 30 milligrams increased the body impact (a
distinct tremor and sensitivity) but somehow not a lot more mental.  I
have been compromised by yesterday.

EXTENSIONS AND COMMENTARY: MEM was both a valuable and dramatic
compound, as well as a drug that played a watershed role.  The
completion of all the possible trimethoxyamphetamines (the TMAUs)
showed that only two of them combined the values of dependability of
positive psychedelic effects with a reasonably high potency.  Both
TMA-2 and TMA-6 are treasures, both active in similar dosages, and
both offer methoxyl groups that are begging to be replaced by other
things.  The first focus was on TMA-2, partly because the needed
synthetic chemistry was better known, and partly because I had
discovered its activity earlier.  But there were three entirely
different and distinct methoxyl groups to work on, in TMA-2.  There is
one at the 2-position, one at the 4-position, and one at the
5-position.  The most obvious thing to do, it seemed, was to make each
of them one carbon longer.  Replace a methoxy with an ethoxy.  And a
logical naming pattern could follow the use of M for methoxy, and E
for ethoxy, in sequence right around the ring from the 2- to the 4- to
the 5-positions.  The first group to be compared, then, would be EMM,
MEM, and MME.  And of these three, it was only MEM that was right up
there in drama and in potency.  But, by the time that became apparent,
I had already completed the diethoxy possibilities (EEM, EME, and MEE)
as well as the triethoxy homologue, EEE.  With the discovery that the
4-position was the magic leverage point, and that the homologues at
positions 2- and 5- were clearly less interesting, all emphasis was
directed at this target, and this has led to the many 4-substituted
families that are now known to be highly potent and felt by many to be
personally valuable.

Why put such emphasis on potency, I am frequently asked? Why should it
matter how much of a compound you take, as long as the effective level
is much lower than its toxic level?  Well, in a sense, that is the
very reason.  There are no guides as to what the toxic levels of any
of these many compounds might really be in man.  There is simply no
way of determining this.  Only a few have been explored in animals in
the pursuit of an LD-50 level.  Most of them are similar to
one-another, in that they are, in mice, of relatively low toxicity
and, in rat, of relatively high toxicity.  But this toxicity appears
not to be related to potency in man.  So, if one might extrapolate
that they are of more or less the same risk to man (from the toxic
point of view) then the lower the dosage, the greater the safety.
Maybe.  In the absence of anything factual, it makes a reasonable
operating hypothesis.

Many of the reports of MEM effects have been with experiments in which
an effective dose of MDMA had been taken shortly earlier.  There has
developed a concept, embraced by a number of researchers, that the
ease and quietness usually seen with the development of the MDMA
experience can mitigate some of the physically disturbing symptoms
sometimes seen with other psychedelics.  This may be partly due to a
familiar entry into a altered place, and partly due to a lessening of
dosage usually required for full effects.  MEM seems to have had more
trials using this combination than many of the other psychedelic
drugs.

 

 

 



#123 MEPEA; 3-METHOXY-4-ETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 10.0 g 3-methoxy-4-ethoxybenzaldehyde in 150
mL nitromethane was treated with 1.7 g anhydrous ammonium acetate, and
heated on the steam bath for 1 h.  The excess nitromethane was removed
under vacuum, yielding a loose, yellow crystalline mass that was
filtered and modestly washed with cold MeOH.  The 8.0 g of damp yellow
crystals thus obtained were dissolved in 50 mL of vigorously boiling
CH3CN, decanted from a small amount of insolubles (probably ammonium
acetate residues) and cooled in an ice bath.  The crystals so obtained
were removed by filtration, washed with 2x5 mL cold CH3CN, and air
dried to constant weight.  The yield of
4-ethoxy-3-methoxy-'-nitrostyrene was 6.3 g of beautiful yellow
crystals.

A solution of 2.3 g LAH in 70 mL anhydrous THF was cooled, under He to
0 !C with an external ice bath.  With good stirring there was added
2.3 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 6.2 g 3-ethoxy-4-methoxy-'-nitrostyrene in
anhydrous THF.  After a few min further stirring, the temperature was
brought up to a gentle reflux on the steam bath, and then all was
cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of IPA followed by sufficent 10% NaOH to give a
white granular character to the oxides, and to assure that the
reaction mixture was basic.  The reaction mixture was filtered and the
filter cake well washed with THF.  The filtrate and washes were
combined and stripped of solvent under vacuum.  The residue was
dissolved in dilute H2SO4.  This was washed with 2x75 mL CH2Cl2, which
removed the residual yellow color.  The remaining aqueous phase was
made basic with NaOH, and extracted with 3x75 mL CH2Cl2.  These
extracts were combined and the solvent removed under vacuum.  The
residue was distilled at 108-115 !C at 0.4 mm/Hg to give 4.2 g of a
mobile, colorless liquid.  This was dissolved in 12 mL IPA,
neutralized with 60 drops concentrated HCl, and diluted with 100 mL
anhydrous Et2O.  There was deposited a fine white crystalline product
which, after removal by filtration, ether washing, and air drying,
yielded 3.8 g of 3-methoxy-4-ethoxyphenethylamine hydrochloride
(MEPEA).

DOSAGE: 300 mg or greater.

DURATION: short.

QUALITATIVE COMMENTS: (with 120 mg) I am at perhaps a +1, a very
slight effect of lightness, without any body awareness at all.  And
then in another hour, I was completely baseline again.

(with 300 mg) Whatever changes took place were complete at the end of
an hour.  The effects were very quiet, very pleasant, and very light.
There was nothing psychedelic here, but rather a gentle lifting of
spirits.  No sensory enhancement or other expected changes.

EXTENSIONS AND COMMENTARY: This is one of the very few phenethylamines
with only two substituents that shows even a hint of central activity.
And there is an interesting story attached.  I got a call out of
absolutely nowhere, from a Stanislov Wistupkin, that he had discovered
a number of new psychedelic drugs which he would like to share with
me.  Two of them were simple phenethylamines, one with an ethoxy group
at the 4-position, and one with an allyloxy group there.  Both, he
said, were mood elevators active between 100 and 300 milligrams.  One
of them was this material, here called MEPEA, and the other one was
3-methoxy-4-allyloxyphenethylamine, or MAPEA.  When I did meet him in
person, he gave me a most remarkable publication which had been
authored some ten years earlier, by a person named Leminger, now dead.
It was all in Czech, but quite unmistakably, right there on the third
page, were the structures of MEPEA and MAPEA, and the statement that
they were active at between 100 and 300 milligrams.  I have not yet
made the allyloxy compound, but I feel that it too might be a gentle
mood elevator similar to the ethoxy.

A most appealing extension of these materials would be the amphetamine
derivatives, things with a 3-methoxy group, and something small and
terse on the 4-position.  The immediate analogies of MEPEA and MAPEA
would be 3-methoxy-4-ethoxy- (and 3-methoxy-4-allyloxy)-amphetamine.
And equally interesting would be the 4-hydroxy analogue.  This would
be an easily made compound from vanillin, one of our most enjoyable
spices in the kitchen cabinet, and it would be directly related to the
essential oils, eugenol and isoeugenol.  This amphetamine compound has
already been synthesized, but it is still unexplored in man.

Some years ago a report appeared in the forensic literature of Italy,
of the seizure of a small semitransparent capsule containing 141
milligrams of a white powder that was stated to be a new
hallucinogenic drug.  This was shown to contain an analogue of DOM,
3-methoxy-4-methylamphetamine, or MMA.  The Italian authorities made
no mention of the net weight contained in each dosage unit, but it has
been found that the active level of MMA in man is in the area of 40-60
milligrams.  The compound can apparently be quite dysphoric, and long
lived.

In the Czechoslovakian publication that presented MEPEA and MAPEA.
there were descriptions of escaline (E), proscaline (P), and the
allyloxy analogue (AL).  These are all active in man, and have been
entered elsewhere.  This is the only published material dealing with
psychedelic drugs I have ever been able to find, from the laboratory
of Otakar Leminger.  What sort of man was this chemist?  He worked for
years in industry, and only at the time of his retirement did he
publish this little gem.  He lived at Usti, directly north of Praha,
on the Labe river (which is called by the better known name, the Elbe,
as soon as it enters Germany).  Might there be other treasures that he
had discovered, and never published?  Was young Wistupkin a student of
his?  Are there unrecognized notes of Otakar Leminger sitting in some
farm house attic in Northern Czechoslovakia?  I extend my heartfelt
salute to an almost unknown explorer in the psychedelic drug area.

 

 

 



#124 META-DOB; 5-BROMO-2,4-DIMETHOXYAMPHETAMINE

SYNTHESIS: The reaction of 2,4-dimethoxyamphetamine (2,4-DMA) with
elemental bromine proceeded directly to the formation of
5-bromo-2,4-dimethoxyamphetamine which was isolated as the
hydrobromide salt with a melting point of 204.5-205.5 !C and in a 67%
yield.  A mp of 180-181 !C has also been published.

DOSAGE: 50 - 100 mg.

DURATION: 5 - 6 h.

EXTENSIONS AND COMMENTARY: There is very little synthetic information
available, and some of it is contradictory.  The initial human report
in the medical literature says only that a dosage of about 100
milligrams produced effects that were similar to those produced by
MDA.  Both the quality of the experience and the potency of the
compound have been modified in more recent publications by the
originators of this compound.  A 40 milligram dose, after an induction
period of an hour, produced a vague uneasiness that was interpreted
originally as a threshold psychedelic effect.  At doses in the 60 to
90 milligram range, there were produced feelings of anxiety and
paranoid fantasies, and distinct toxic signs such as flushing,
palpitations, and occasional nausea, vomiting and diarrhea.  Any
psychedelic effects seem to have been blurred by the more obvious
toxic actions of the drug.  I have been told that their final
conclusion was that the drug appears toxic in the 50 to 60 milligram
range.  I have not personally explored this positional isomer of DOB.

The positional isomer of DOB with the bromine in the ortho-position is
4,5-dimethoxy-2-bromoamphetamine and is called, not surprisingly,
ORTHO-DOB.  It has been made by the condensation of
2-bromo-4,5-dimethoxybenzaldehyde with nitroethane to give
1-(2-bromo-4,5-dimethoxyphenyl)-2-nitropropene with a mp of 105-106
!C.  Reduction to the amphetamine had to be conducted at a low
temperature and using only an equimolar amount of lithium aluminum
hydride, to minimize reductive removal of the bromo group.  The
hydrochloride salt of 2-bromo-4,5-dimethoxyamphetamine (ORTHO-DOB) had
a mp of 214-215.5 !C, and the hydrobromide salt a melting point of
196-197 !C or of 210 !C.  Both have been reported.  The yield from the
direct bromination of 3,4-DMA was apparently very bad.  I do not think
that the compound has ever gone into man.

There are three other dimethoxyamphetamine isomers known, and each has
been explored chemically as to its reactivity with elemental bromine.
With 2,3-DMA, a mixture of the 5-Br-2,3-DMA and 6-Br-2,3-DMA was
formed; with 2,6-DMA, 3-Br-2,6-DMA was formed; and with 3,5-DMA, a
mixture of 2-Br-3,5-DMA and the 2,6-dibromo product was produced.  The
bromination of 2,5-DMA is, of course, the preferred procedure for the
synthesis of 4-Br-2,5- DMA, or DOB, q.v.  None of these positional
isomers has evear been put into man, but 3-Br-2,6-DMA and the
iodo-counterpart have been explored as potential radio-fluorine
carriers into the brain.  This is all discussed in the 3,4-DMA recipe.

 

 

 



#125 META-DOT; 2,4-DIMETHOXY-5-METHYLTHIOAMPHETAMINE

SYNTHESIS: To 27 g 1,3-dimethoxybenzene that was being well stirred,
there was added, dropwise, 29 g concentrated H2SO4 over a period of 15
min.  Stirring was continued for 1 hour, and then the mixture was
poured slowly into 250 mL of saturated aqueous K2CO3.  The precipitate
that formed was removed by filtration, and dried at 125 !C to give
59.6 g crude potassium 2,4-dimethoxybenzenesulfonate.  This was finely
ground, and 30 g of it was treated with 35 g of POCl3 and the mixture
heated on the steam bath for 2 h.  This was cooled to room
temperature, and then poured over 300 mL crushed ice.  When all had
thawed, this was extracted with 2x150 mL Et2O.  The extracts were
pooled, washed with saturated brine, and the solvent removed under
vacuum to give a residue which solidified.  There was thus obtained
14.2 g 2,4-dimethoxybenzenesulfonyl chloride as white solids with a mp
of 69-72 !C.  Heating of a small portion with concentrated ammonium
hydroxide gave the corresponding sulfonamide which, on
recrystallization from EtOH, produced white needles with a mp of
165.5-166.5 !C.

To a stirred and gently refluxing suspension of 11 g LAH in 750 mL
anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl
chloride in an Et2O solution.  The refluxing was maintained for 48 h
then, after cooling externally with ice water, the excess hydride was
destroyed by the slow addition of 600 mL of 10% H2SO4.  The phases
were separated, and the aqueous phase extracted with 2x200 Et2O.  The
organics were pooled, washed once with 200 mL H2O, and the solvent
removed under vacuum.  The residue was dried azeotropically through
the addition and subsequent removal of CH2Cl2.  Distillation of the
residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil,
boiling at 89-92 !C at 0.5 mm/Hg.

To a solution of 7.8 g 2,4-dimethoxythiophenol in 40 mL absolute EtOH
there was added a solution of 4 g 85% KOH in 65 mL EtOH.  This was
followed by the addition of 5 mL methyl iodide, and the mixture was
held at reflux for 30 min.  This was poured into 200 mL H2O, and
extracted with 3x50 mL Et2O.  The pooled extracts were washed once
with aqueous sodium hydrosulfite, then the organic solvent was removed
under vacuum.  The residue was distilled to give 8.0 g of
2,4-dimethoxythioanisole as a colorless oil with a bp of 100-103 !C at
0.6 mm/Hg.

To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been
warmed briefly on the steam bath there was added 7.8 g of
2,4-dimethoxythioanisole.  The reaction was heated on the steam bath
for an additional 20 min and then poured into 200 mL H2O.  Stirring
was continued until the insolubles had become completely loose and
granular.  These were removed by filtration, washed with H2O, sucked
as dry as possible, and then recrystallized from boiling MeOH.  The
product, 2,4-dimethoxy-5-(methylthio)benzaldehyde, was an off-white
solid weighing 8.6 g.  It could be obtained in either of two
polymorphic forms, depending on the concentration of aldehyde in MeOH
at the time of crystal appearance.  One melted at 109-110 !C and had a
fingerprint IR spectrum including peaks at 691, 734, 819 and 994 cm-1.
The other melted at 124.5-125.5 !C and had major fingerprint peaks at
694, 731, 839 and 897 cm-1.  Anal. (C10H12O3S) C,H.

A solution of 8.2 g 2,4-dimethoxy-5-(methylthio)benzaldehyde in 30 mL
nitroethane was treated with 1.8 g anhydrous ammonium acetate and
heated on the steam bath for 4 h.  Removal of the excess nitroethane
under vacuum gave a colored residue which crystallized when diluted
with MeOH.  Recrystallization of the crude product from boiling EtOH
gave, after filtration, washing and air drying to constant weight, 8.3
g 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene with a mp of
112-113 !C.  Anal. (C12H15NO4S) C,H,N.

A suspension of 6.5 g LAH in 250 mL anhydrous THF was placed under a
N2 atmosphere and stirred magnetically and brought to reflux.  There
was added, dropwise, 8.0 g of
1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene in 50 mL THF.  The
reaction mixture was maintained at reflux for 18 h.  After being
brought to room temperature, the excess hydride was destroyed by the
addition of 6.5 mL H2O in 30 mL THF.  There was then added 6.5 mL of
3N NaOH, followed by an additional 20 mL H2O.  The loose, white,
inorganic salts were removed by filtration, and the filter cake washed
with an additional 50 mL THF.  The combined filtrate and washes were
stripped of solvent under vacuum yielding a residue that was
distilled.  The free base boiled at 125-128 !C at 0.1 mm/Hg and was a
white oil which solidified on standing.  It weighed 5.1 g and had a mp
of 47-48.5 !C.  This was dissolved in 50 mL IPA, neutralized with
concentrated HCl (until dampened universal pH paper showed a deep red
color) and diluted with anhydrous Et2O to the point of turbidity.
There was a spontaneous crystallization providing, after filtering,
washing with Et2O, and air drying,
2,4-dimethoxy-5-methylthioamphetamine hydrochloride (META-DOT) with a
mp of 140.5-142 !C.  Anal. (C12H20ClNO2S) C,H,N.

DOSAGE: greater than 35 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 35 mg) There was a vague awareness of
something all afternoon, something that might be called a thinness.
Possibly some brief cardiovascular stimulation, but nothing completely
believable.  This is a threshold level at the very most.

EXTENSIONS AND COMMENTARY: Again, as with the studies with ORTHO-DOT,
it is apparent that the activity of META-DOT is going to be way down
from the most interesting of these isomers, PARA-DOT (ALEPH-1, or just
ALEPH).  In the rectal hyperthermia assay (which calculates the
psychedelic potential of compounds by seeing how they influence the
body temperature of experimental animals in comparison to known
psychedelics) the three DOT's were compared with DOM.  And the results
fell into line in keeping with the activities (or loss of activities)
found in man.  PARA-DOT was about half as active as DOM, but both
ORTHO-DOT and the compound described here, META-DOT, were down by
factors of 50x and 30x respectively.  These animal studies certainly
seem to give results that are reasonable with a view to other known
psychedelic drugs, in that mescaline was down from DOM by a factor of
more than 1000x, and LSD was some 33x more potent than DOM.

I have a somewhat jaundiced view of this rabbit rectal hyperthermia
business.  One is presumably able to tell whether a compound is a
stimulant or a psychedelic drug by the profile of the temperature
rise, and how potent it will be by the extent of the temperature rise.
But the concept of pushing thermocouples into the rear ends of
restrained rabbits somehow does not appeal to me.  I would rather
determine both of these parameters from human studies.

 

 

 



#126 METHYL-DMA; DMMA; 2,5-DIMETHOXY-N-METHYLAMPHETAMINE

SYNTHESIS: To a stirred solution of 28.6 g methylamine hydrochloride
in 120 mL MeOH there was added 7.8 g 2,5-dimethoxyphenylacetone
followed by 2.6 g sodium cyanoborohydride.  HCL was added as needed to
maintain the pH at about 6.  The reaction was complete in 24 h, but
was allowed to stir for another 3 days.  The reaction mixture was
poured into 600 mL H2O, acidified with HCl (HCN evolution, caution)
and washed with 3x100 mL CH2Cl2.  Aqueous NaOH was added, making the
solution strongly alkaline, and this was then extracted with 3x100 mL
CH2Cl2.  Removal of the solvent from the pooled extracts under vacuum
gave 8.3 g of a clear, off-white oil that distilled at 95-105 !C. at
0.25 mm/Hg.  The 6.5 g of colorless distillate was dissolved in 25 mL
IPA, neutralized with concentrated HCl, and then diluted with
anhydrous Et2O to the point of cloudiness.  As crystals formed,
additional Et2O was added in small increments, allowing clearing
crystallization between each addition.  In all, 200 mL Et2O was used.
After filtering,Et2O washing, and air drying, there was obtained 6.2 g
of 2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DMA) as
fine white crystals with a mp of 117-118 !C.  The mixed mp with
2,5-DMA (114-116 !C) was depressed to 96-105 !C.  An alternate
synthesis gave the same overall yield of an identical product, but
started with 2,5-DMA.  It required two synthetic steps.  The free base
amine was converted to the crystalline formamide with formic acid in
benzene using a Dean Stark trap, and this intermediate was reduced to
METHYL-MDA with LAH.

DOSAGE: above 250 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 250 mg) There is a slight paresthesia at
about 45 minutes, an awareness on the surface of the skin as if I had
been touched by a cold draft of air.  But nothing more.  At three
hours, I am completely out, if I was ever in.  In the evening I
assayed 120 milligrams of MDMA, and it barely produced a threshold
effect, so the two materials might be seeing one another.

EXTENSIONS AND COMMENTARY: This is a difficult compound to pin down in
the anthology of drugs.  For some reason it has intrigued several
independent, quiet researchers, and I have accumulated a number of
interesting reports over the years.  One person told me that he had
felt nothing at up to 60 milligrams.  Another had found a threshold at
50 milligrams, and had complete and thorough experiences at both 150
and 200 milligrams.  Yet another person described two incidents
involving separate individuals, with intravenous administrations of
0.2 mg/Kg, which would be maybe 15 or 20 milligrams.  Both claimed a
real awareness in a matter of minutes, one with a tingling in the
genitalia and the other with a strange presence in the spine.  Both
subjects reported increases in body temperature and in blood pressure.
Apparently the effects were felt to persist for many hours.

There is an interesting, and potentially informative, convergence of
the metabolite of one drug with the structure of another.  Under 4-MA,
mention was made of a bronchodilator that has been widely used in the
treatment of asthma and other allergenic conditions.  This compound,
2-methoxy-N-methylamphetamine is known by the generic name of
methoxyphenamine, and a variety of trade names with Orthoxine (Upjohn)
being the best known.  The typical dosage of methoxyphenamine is
perhaps 100 milligrams, and it may be used several times a day.  It
apparently produces no changes in blood pressure and only a slight
cardiac stimulation.  And one of the major metabolites of it in man is
the analogue with a hydroxyl group at the 5-position of the molecule.
This phenolic amine, 5-hydroxy-2-methoxy-N-methylamphetamine is just a
methyl group away from METHYL-DMA; it could either be methylated to
complete the synthesis, or METHYL-DMA could be demethylated to form
this phenol.  There is plentiful precedent for both of these reactions
occuring in the body.  It is always intriguing when drugs which show
distinctly different actions can, in principle, intersect
metabolically at a single structure.  One wonders just what the
pharmacology of that common intermediate might be.

Three additional N-methylated homologues of known psychedelics warrant
mention, but do not really deserve separate recipes.  This is because
they have had only the most cursory assaying, which I have learned
about by personal correspondence.  All three were synthesized by the
reduction of the formamide of the parent primary amine with LAH.
METHYL-TMA (or N-methyl-3,4,5-trimethoxyamphetamine) had been run up
in several trials to a maximum of 240 milligrams, with some mental
disturbances mentioned only at this highest level.  METHYL-TMA-2 (or
N-methyl-2,4,5-trimethoxyamphetamine) had been tried at up to 120
milligrams without any effects.  METHYL-TMA-6 (or N-methyl-2,4,6-
trimethoxyamphetamine) had been tried at up to 30 milligrams and it,
too, was apparently without effects.  These are reports that I have
heard from others, but I have had no personal experience with them.
Those that I can describe from personal experience are entered
separately as recipes of their own.  And there are many, many other
N-methyl homologues which have been prepared and characterized in the
literature, and have yet to be tasted.  So far, however, the only
consistent thing seen is that, with N-methylation, the potency of the
psychedelics is decreased, but the potency of the stimulants appears
to be pretty much maintained.

 

 

 



#127 METHYL-DOB; 4-BROMO-2,5-DIMETHOXY-N-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 6.0 g of the free base of
2,5-dimethoxy-N-methyl-amphetamine (see recipe under METHYL-DMA) in 30
mL glacial acetic acid there was added, dropwise and with good
stirring, a solution of 5.5 g bromine in 15 mL acetic acid.  The
reaction became quite warm, and turned very dark.  After stirring an
additional 45 min, the mixture was poured into 200 mL H2O and treated
with a little sodium hydrosulfite which lightened the color of the
reaction.  There was added 20 mL concentrated HCl, and the reaction
mixture was washed with 2x100 mL CH2Cl2 which removed most of the
color.  The aqueous. phase was made basic with 25% NaOH, and extracted
with 3x100 mL CH2Cl2.  The removal of the solvent from the pooled
extracts under vacuum gave 1.8 g of an oil which was dissolved in 10
mL IPA, neutralized with concentrated HCl, and diluted with 100 mL
anhydrous Et2O.  No crystals were obtained, but rather an oily and
somewhat granular insoluble lower phase.  The Et2O was decanted, and
the residue washed by grinding up under 3x100 mL Et2O.  The original
decanted material was combined with the three washes, and allowed to
stand for several h.  The product
4-bromo-2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DOB)
separated as fine white crystals which weighed, after filtering and
air drying, 0.3 g and had a mp of 149-150 !C.  The Et2O-insoluble
residue finally set up to a pale pink mass which was finely ground
under a few mL acetone.  Filtration and air drying gave a second crop
of product as 0.9 g of pale lavender solids, with a mp of 143-145 !C.

DOSAGE: greater than 8 mg.

DURATION: probably rather long.

QUALITATIVE COMMENTS: (with 8.0 mg) At an hour and twenty minutes, I
was suddenly quite light headed.  An hour later I must say that the
effects are real, and generally good.  I am spacey Q nothing tangible.
And a couple of hours yet later I am still aware.  My teeth are
somewhat rubby, and as things have been pretty steady for the last
three hours, this will prove to be long lasting.  There are a lot of
physical effects that may be kidding me into providing myself some of
the mental.  At the sixth hour, I find that this is almost entirely
physical.  My teeth are tight, there is a general physical tenseness,
my reflexes seem exaggerated, and my eyes are quite dilated.  All of
these signs are lessened by the eighth hour, and do not interfere with
sleep at the twelfth hour.  There is no desire to proceed any further,
at least at the present time.  Mental (+) physical (++).  Next day,
slight impression of persistence of toxicity.

(with 10 mg) Nothing psychedelic, but awfully hard on the bod.  The
next day (24 hours later) I had a severe response to 5 milligrams of
psilocybin.

EXTENSIONS AND COMMENTARY: The mention above, of the 10 milligrams of
METHYL-DOB followed by 5 milligrams of psilocybin, leads to some
interesting speculation.  The usual pattern that is seen when two
psychedelic drugs are taken too closely together is that the second
experience is less effective than would have been expected.  This is
the property that is called tolerance, and it is frequently seen in
pharmacology.  The two exposures may be to a single drug, or they may
be to two different drugs which usually have some properties in
common.  It is as if the spirit of the receptor site had become a
little tired and needed a while to rest up and recuperate.  When there
is a demand for a repeat of full effectiveness, the user will
customarily increase the dosage of the drug that is used.  It is one
of the built-in protections, in the area of psychedelics that, after
one experience, you must wait for a period of time to lose the
refractoriness that has set in.

The measure of the degree of tolerance that can be shared between
different drugs, called cross-tolerance, can be used as an estimate of
the similarities of their mechanisms of action.  In other words, if A
and B are somehow seen by the body as being similar, then a normally
effective dose of A will make a next-day's normally effective dose of
B weaker than expected.  Or not active at all.  And B will do the same
job on A.  If two drugs are different in their ways of doing things in
the body, there is most often no cross-tolerance seen.  This was
described for MDMA and MDA, and is the basis of the argument that they
act by distinctly separate mechanisms.  A person who used what would
be held as an active dose of MDMA for several days lost all response
to the drug.  He was tolerant to its effects.  But an exposure to an
effective dose of MDA at the time that tolerance to MDMA was complete,
provided a normal response to the MDA.  The drugs are not
cross-tolerant and the body recognizes them as distinct individuals.

But for one drug to promote, or to exaggerate, the effect of another
is called potentiation, and can be a clue to the dynamics going on in
the brain or body.  Here, admittedly in only a single report,
METHYL-DOB had somehow sensitized the subject to a rather light dosage
of psilocybin.  But there have been other reports like this that I
have heard of, from here and there.  I have been told of an experiment
with the dextro-isomer of DOM (this is the inactive optical isomer) at
a level that was, not surprisingly, without any effects.  The
researcher had a severe reaction the following day with what was
referred to as RpoorS hashish.  A similar form of potentiation has
been commented upon under the recipe for TOMSO, where an inactive
drug, and a most modest amount of alcohol, add together to create an
unexpectedly intense intoxication.  But note that in each of these
cases, it is a phenethylamine interacting with a non-phenethylamine
(psilocybin is an indole, hashish is a non-alkaloid terpene thing, and
alcohol is, well, alcohol).

The bottom line with METHYL-DOB is, as with the other N-methylated
psychedelics, that it is way down in potency, and probably not worth
pursuing.

 

 

 



#128 METHYL-J; MBDB; EDEN;
2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;
N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

SYNTHESIS: A solution of 0.12 g mercuric chloride in 180 mL H2O was
added to 5 g aluminum foil that had been cut into 1 inch squares, and
amalgamation allowed to proceed for 0.5 h.  The gray cloudy aqueous
phase was decanted, and the resulting aluminum washed with 2x200 mL
H2O.  After shaking as dry as possible, there was added, in sequence,
a solution of 7.6 g methylamine hydrochloride in an equal weight H2O,
23 mL IPA, 18.3 mL 25% NaOH, 6.72 g
1-(3,4-methylenedioxyphenyl)-2-butanone (see under the recipe of J for
its preparation), and finally 44 mL additional IPA.  The mixture was
occasional swirled, and cooled externally as needed to keep the
temperature below 50 !C.  After the reduction was completed (no
metallic aluminum remaining, only gray sludge), it was filtered and
the residues washed with MeOH.  The combined filtrate and washes were
stripped of organic volatiles under vacuum, the residue treated with
100 mL Et2O, and this was extracted with 2x50 mL 3 N HCl.  After
washing the pooled aqueous extracts with 3x100 mL CH2Cl2, they were
made basic with an excess of 25% NaOH and extracted with 5x50 mL
CH2Cl2.  Drying of these extracts with anhydrous MgSO4 and removal of
the solvent gave a residue that was distilled at 88 !C at 0.08 mm/Hg
to give a colorless oil that was dissolved in IPA and neutralized with
concentrated HCl.  The solids that separated were removed by
filtration, Et2O washed, and air dried to provide 6.07 g
2-methylamino-1-(3,4-methylenedioxyphenyl)butane hydrochloride
(METHYL-J or MBDB) as white crystals with a mp of 156 !C.  Anal.
(C12H18ClNO2) C,H,N.  Reductive amination of the butanone with
methylamine hydrochloride in MeOH, employing sodium cyano-borohydride,
gave an identical product but in a smaller yield.

DOSAGE: 180 - 210 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS: (with 210 mg) Generally very, very friendly,
very quiet effect.  I can read easily, but looking at pictures in most
books is relatively meaningless.  Distinct de-stressing effect, to the
point where it's too much trouble to set out to do anything at all,
really.  There is just no drive, and it isnUt even bothersome to be
missing it.  Do I like it?  Yes, very much.  Feel that IUve just begun
to explore it, though.  Would I consider this material in therapy?
Well, sure, it's worth trying.  Destressing would be excellent, and
better than MDMA in some ways, but the empathy and intuition levels
have yet to be explored in a therapy setting.  I feel that they may be
somehow lower.

(with 210 mg) Onset rapid.  Alert 20 minutes, and to a +2.5 at 30 to
35 minutes.  No physical symptoms, i.e., teeth clench, no stomach
problems.  Good visual enhancement; eyes open Q bright colors Q no
visuals with eyes closed.  No 'cone of silence' that I get with MDMA
(and enjoy), otherwise IUm not sure I could tell which was which if I
took them blind.

(with 210 mg and a 50 mg supplement) RTasted perfectly rotten.
Suspect I was getting some type of alert in 5 minutes (I often get one
quickly with MDMA) and at 30 minutes, a full blown high developed
rather abruptly.  It would be difficult to describe the high.  I
suspect it is the lack of language for the phenomenon.  I would
describe it somewhat like an alcohol high without the disabling side
effects of confusion, slurring, staggering and etc.  The high never
got any more intense than at that 30 minute point and with a
noticeable drop in another hour, I took a 50 mg supplement.  I enjoyed
the high.  I relaxed with the material.  However, it did not seem to
have the same qualities as MDMA, in that it was not as stimulating,
and it had very little visual activity.  I talked with others, but
found it easy to lie down and relax.  There was some jaw-clenching
towards the end, and I had considerable nystagmus at the peak which I
could control.  After the experience, I did not want to drink alcohol
very much (sell it as a substitute for EtOH!).

(with 210 mg and a 70 mg supplement) RI begin to feel the rush at 20
minutes, increasing rapidly.  Very much like MDMA, only more intense
intoxication.  Otherwise same symptoms: intense euphoria that I call a
feeling of grace, soft skin, voices, youthful appearance, animated
discussions, feelings of great closeness to others.  I start to drop
noticeably at less than an hour and a half into it, but I delayed a
supplement until the hour and fifty minute point.  It does not get me
back to the original intoxication.  However, it is very nice, very
much like MDMA.  Only difference is that there seems to be more
quietness, less inclination to talk than with an MDMA supplement.  My
conclusion: Seems an excellent substitute for MDMA, Next time may try
somewhat lower amount, supplement sooner.

EXTENSIONS AND COMMENTARY: An observer who was familiar with the
outwardly apparent effects with groups experimenting with MDMA felt
that, although most subjects commented favorably in their comparisons
of METHYL-J with MDMA, there was lacking some of the spontaneity, the
warmth, and the clear intimacy of the latter drug.  The dosage range
explored is remarkably tight, attesting to a consistency of response.
The typical supplement used, if any, was 70 milligrams or less, just
before the two hour point.  This indicates a chronology similar to
that of MDMA, and about two thirds the potency.

The arguments that weigh the use of the code name of MBDB against the
use of METHYL-J are present in the recipe for BDB (or J).  But what is
the source of this H, I, J, K naming thing that I have called the Muni
Metro?

First, a little bit of local color.  In San Francisco, there is a
public transportation called the S.F. Municipal Metropolitan System
complex that has integrated an underground street-car system that
emerges above ground and connects with a bus network.  A number of the
street-car lines fan across the city to the outer reaches which are
called the Avenues.  These lines are named by sequential letters.
There is the J Church Street line, the K Ingelside line, the L Taraval
line, the M Ocean line, and the N Judah.  And in the pharmacological
complex that involved the lengthening of the aliphatic chain, there
were two coincidental benchmarks in the names that were proposed.
Those without an alpha-substituent (no carbon atoms at the position
alpha to the amine group, the phenethylamines) were originally called
the H compounds.  H stood for Rhomopiperonylamine.S And the first of
those with the alpha-ethyl group there (two carbon atoms at the
position alpha to the amine group) was familiarly called RJacobamineS
in recognition of a famous chemist who had set the synthetic wheels in
motion.

It is quite obvious, that with one carbon atom lying on that
alpha-position, you are precisely half-way between no carbons and two
carbons.  And there was one letter of the alphabet that lies precisely
half-way between an H and a J.  So, an natural naming pattern
developed.  The I compounds were already pretty well known by names
such as MDA and MDMA and MDE, so I, and METHYL-I, and ETHYL-I, didnUt
have any appeal.  But for the new, the alpha-ethyl compounds, why not
call them the J-compounds?  If it has a methyl on the nitrogen it will
be METHYL-J and if it has an ethyl group it will be ETHYL-J.  And in
the next longer group, the 3-carbon propyl group on the alpha-position
becomes the K family, and the 4-carbon butyl group located there, the
L family.  Each with its METHYL and ETHYL prefixes, if the nitrogen
atoms are substituted with a methyl or and ethyl group.  VUla, comme
on dit en Fran

ais.  Le systme Muni Metro.  Plus simple.

 

 

 



#129 METHYL-K; 2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)PENTANE;
N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-PENTYLAMINE

SYNTHESIS: The Grignard reagent of butyl bromide was prepared in
anhydrous Et2O by the dropwise addition of 68 g n-butyl bromide to a
well-stirred suspension of 14 g magnesium turnings in 500 mL anhydrous
Et2O.  When the exothermic reaction had stopped, there was added a
solution of 60 g piperonal in about 100 mL Et2O, over the course of 1
h.  After the exothermic addition was complete, the reaction mixture
was held at reflux for several h, then cooled and decomposed by the
addition of dilute HCl.  The phases were separated, and the aqueous
phase extracted with 2x75 mL CH2Cl2.  The organics were combined and
gave, after the removal of the solvents under vacuum, 84 g of
1-hydroxy-1-(3,4-methylenedioxyphenyl)pentane as a yellow liquid.
This was used in the following dehydration step without further
purification.

A mixture of 52 g of the crude
1-hydroxy-1-(3,4-methylenedioxyphenyl)pentane and 2 g powdered KHSO4
was heated with a flame until there was no more apparent generation of
H2O.  The resulting dark, fluid oil was distilled at 100-110 !C at 0.3
mm/Hg to give 29.5 g of 1-(3,4-methylenedioxyphenyl)-1-pentene as a
light yellow liquid.  This was employed in the following oxidation
step without further purification.

To 120 mL of 90% formic acid there was added, with good stirring, 15
mL H2O, followed by 23 mL of 35% H2O2 To this mixture, cooled with an
external ice bath, there was added a solution of 24 g crude
1-(3,4-methylenedioxyphenyl)-1-pentene in 120 mL acetone at a rate
slow enough to keep the internal temperature from exceeding 35 !C.  At
the end of the addition, the temperature was brought up to 45 !C by
heating briefly on the steam bath, and then the reaction mixture was
allowed to stand and stir at ambient temperature for several h.  All
volatiles were removed under vacuum, with a bath temperature
maintained at 45 !C.  The residue was dissolved in 30 mL MeOH, then
there was added 200 mL 15% H2SO4 and the mixture held on the steam
bath for 1.5 h.  There was then added an additional 300 mL H2O, and
this was extracted with 2x250 mL of a petroleum ether/EtOAc (5:1)
mixture.  The extracts were pooled, and the solvents removed under
vacuum to give a residue that was distilled at 115-120 !C at 0.3
mm/Hg.  This light yellow liquid weighed 13.5 g and was substantially
pure 1-(3,4-methylenedioxyphenyl)-2-pentanone by TLC.

To 5.0 g of aluminum foil cut into 1 inch squares, there was added a
solution of 150 mg HgCl2 in 200 mL H2O.  The mixture was heated
briefly until there were clear signs of active amalgamation, such as
fine bubbling for the aluminum surfaces and the beginning of the
formation of a gray, amorphous solid phase.  The HgCl2 solution was
decanted off and the aluminum was washed with 2x200 mL additional H2O.
After shaking as dry as possible, there was added, in sequence and
with good swirling agitation between each addition, 10 g methylamine
hydrochloride in 10 mL H2O, 27 mL IPA, 22 mL of 25% NaOH, 5.0 g
1-(3,4-methylenedioxyphenyl)-2-pentanone, and finally an additional 50
mL IPA.  The mixture was heated on the steam bath periodically to
maintain the reaction rate at a vigorous boil.  When all of the
aluminum had been consumed, the cooled mixture was filtered and the
solids washed with MeOH.  The combined filtrate and washings were
stripped of solvent under vacuum.  The residue was dissolved in dilute
H2SO4 and washed with 2x75 mL CH2Cl2.  After making basic again with
25% NaOH, this was extracted with 2x100 mL CH2Cl2, and the pooled
extracts were stripped of solvent under vacuum.  The residue was
distilled at 105-110 !C at 0.3 mm/Hg to give 2.7 g of a colorless
liquid.  This was dissolved in 15 mL IPA, neutralized with
concentrated HCl, and diluted with 75 mL anhydrous Et2O which allowed
a delayed appearance of a fine white crystal.  This was removed by
filtration, Et2O washed, and air dried to give 2.45 g
2-aminomethyl-1-(3,4-methylenedioxyphenyl)pentane hydrochloride
(METHYL-K) as a white product with a mp of 155-156 !C.  Anal.
(C13H20ClNO2) C,H.

DOSAGE: greater than 100 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 100 mg) There were no effects.  I was
busy and totally wound up and didnUt sleep until 3 AM, but this was
probably unrelated to the Me-K.

EXTENSIONS AND COMMENTARY: The well appears to be running dry, with a
pentane chain as a basic skeleton.  METHYL-J, at this level, was
already showing a number of hints and clues, largely physical such as
coldness in the feet and a slight mastoidal pressure, that activity
was right around the corner.  But METHYL-K gave no such hints.  The
unmethylated homologue, 2-amino-1-(3,4-methylenedioxyphenyl)pentane
(K), was also made, by the reductive amination of
1-(3,4-methylene-dioxyphenyl)-2-pentanone with ammonium acetate and
sodium cyanoborohydride in methanol.  It was a white crystalline
solid, mp 202-203 !C, but is given here in the comments only, as its
human assaying had never even been initiated.  Anal. (C12H18ClNO2)
C,H.  The N-ethyl homologue,
2-ethylamino-1-(3,4-methylene-dioxyphenyl)pentane (ETHYL-K), is
entered with its own recipe, on the other hand, since testing had been
started with it.

And the longest chain that has been explored in this Muni Metro series
is the six-carbon hexyl chain which is, quite logically, the L-series,
sort of the end of the Taraval line (see under METHYL-J for an
explanation).  The central compound for all the L-compounds was the
ketone 1-(3,4-methylenedioxyphenyl)-2-hexanone, which was prepared by
the Grignard reagent of (n)-amyl bromide with piperonal to give
1-hydroxy-1-(3,4-methylenedioxyphenyl)hexane, dehydration of this with
potassium bisulfate to the olefin, and oxidation of this with hydrogen
peroxide and formic acid to the L-ketone which was an orange-colored
liquid with a bp of 125-135 !C at 0.3 mm/Hg.  This ketone was
reductively aminated with ammonium acetate and sodium cyanoborohydride
in methanol to produce 2-amino-1-(3,4-methylenedioxyphenyl)hexane
hydrochloride (L) as a white crystalline product with a mp of 157-158
!C.  Anal. (C13H20ClNO2) C,H.  And this ketone was reductively
aminated with methylamine hydrochloride and amalgamated aluminum in
isopropanol to produce
2-methylamino-1-(3,4-methylenedioxyphenyl)hexane hydrochloride
(METHYL-L) as a white crystalline product with a mp of 139-141 !C.
Anal. (C14H22ClNO2) C,H.  The reduction of this ketone in a similar
manner with ethylamine hydrochloride produced
2-ethylamino-1-(3,4-methylenedioxyphenyl)hexane (ETHYL-L).  None of
this series has yet been explored either as psychedelic or
entactogenic materials.

 

 

 



#130 METHYL-MA; PMMA; DOONE; 4-MMA; 4-METHOXY-N-METHYLAMPHETAMINE

SYNTHESIS: A solution of 20 g methylamine hydrochloride in 150 mL hot
MeOH was treated with 10.0 g 4-methoxyphenylacetone and stirred
magnetically.  After returning to room temperature, there was added
5.0 g sodium cyanoborohydride, followed by cautious addition of HCl as
required to maintain the pH at about 6.  The reaction was complete
after a few days, and the mixture was poured into 800 mL H2O.  This
was acidified with HCl (HCN evolution!) and washed with 3x75 mL
CH2Cl2, which removed most of the yellow color.  There was 25% NaOH
added to make the reaction mixture strongly basic, and this was
extracted with 3x75 mL CH2Cl2.  The solvent was removed from the
pooled extracts under vacuum, and the 10.3 g of residue distilled at
0.3 mm/Hg.  The 9.7 g of colorless oil that distilled at 75-90 !C was
dissolved in 50 mL IPA, neutralized with 4.5 mL concentrated HCl, and
then diluted with 100 mL anhydrous Et2O.  There were generated
glistening crystals of 4-methoxy-N-methylamphetamine hydrochloride
(METHYL-MA or DOONE) that weighed, after washing with Et2O and air
drying to constant weight, 11.0 g and which had a mp of 177-178 !C.
The same base can be made by the action of ethyl chloroformate on 4-MA
in the presence of triethylamine to make the carbamate, or the action
of formic acid to make the formamide.  These can then be reduced with
LAH to this same end product.

DOSAGE: greater than 100 mg.

DURATION: short.

QUALITATIVE COMMENTS: (with 110 mg) One hour into it, my pulse was up
over 100, and I was compulsively yawning.  There was some eye muscle
disturbance, a little like the physical side of MDMA, but there was
none of its central effects.  But all the hints of the cardiovascular
are there.  By the fourth hour, I am pretty much back to baseline, but
the yawning is still very much part of it.  I might repeat this, at
the same level, but with continuous close monitoring of the body.

EXTENSIONS AND COMMENTARY: Why would there be interest in this
particular compound?  The track record from the comparison of active
compounds that are primary amines, and their N-methyl homologues, has
shown that, in general, the stimulant component might be maintained,
but the RpsychedelicS contribution is generally much reduced.  MDMA
is, of course, an exception, but then, that particular compound is a
one-of-a-kind thing which simply defies all the rules anyway, and I
drop it from this kind of reasoning.  And as 4-MA is a pretty pushy
stimulant with little if any sensory sparkle, why bother with the
N-methyl compound at all?

For a completely silly and romantic reason.  When the MDMA story
became front-page news back in mid-1985, the cartoonist-author of
Doonesbury, Gary Trudeau, did a two-week feature on it, playing it
humorous, and almost (but not quite) straight, in a hilarious sequence
of twelve strips.  On August 19, 1985 he had Duke, president of Baby
Doc College, introduce the drug design team from USC in the form of
two brilliant twins, Drs. Albie and Bunny Gorp.  They vividly
demonstrated to the enthusiastic conference that their new drug
RIntensityS was simply MDMA with one of the two oxygens removed.
RVoila,S said one of them, with a molecular model in his hands, RLegal
as sea salt.S And what is MDMA with one oxygen atom removed?  It is
4-methoxy-N-methylamphetamine or METHYL-MA which, according to the
twins, should give the illusion of substance to one's alter ego.  So,
I called it Doonesamine, or simply RDOONES for short.  Maybe that was
also a homonym for Frank Herbert's science fiction book, RDune,S
wherein the magical drug RspiceS provided a most remarkable alteration
of the user's state of consciousness.

This comic strip presentation was the first nationally distributed
allusion to the term Rdesigner drugs,S and perhaps it lent unexpected
support for the passage, just a year later, of the Controlled
Substances Analogue Enforcement Act of 1986.  This intentionally vague
piece of legislation makes the giving of, or the taking of, or even
the possession with the intent to take, any drug that in any way
alters your state of consciousness, a felony.  A shameful and
desperate effort by the governmental authorities to maintain the image
of control in a lost situation.

Enough editorial.  Back to historic technicalities.  In truth,
METHYL-MA is a well studied drug, at least in animals.  In both mice
and rats, it is an exceptionally potent agent in creating the state of
catatonia.  Animal studies, prompted by the clandestine synthesis of
METHYL-MA, have shown that there is indeed locomotor stimulation and
some central effects, but these effects are somehow different than
those of a simple amphetamine-like agent.  The experimenterUs
conclusions, based on its structural resemblance to 4-MA and its
proclivity to produce catatonia in some animal species and the
ever-present possibility that there might be unsuspected neurochemical
changes to be seen with its use, are that human experimentation should
be discouraged.  I have come to the same conclusion, but in my case
this is based on a much more succinct observation: I tried it and I
didnUt like it.

A brief comment on two of the N,N-dimethylhomologues of
methoxyamphetamine.  One was 4-methoxy-N,N-dimethylamphetamine,
4-MNNA.  This material, made by the reductive amination of
4-methoxyphenylacetone with dimethylamine, was a colorless oil, which
distilled at 70-85 !C at 0.3 mm/Hg.  The corresponding
2-methoxy-N,N-dimethylamphetamine was similarly made.  2-MNNA was also
a colorless oil and had the same bp.  Both of them were fluorinated
with 18F labelled acetyl hypofluorite (3% and 6% yields respectively)
but neither of them was pursued any further in the search for a brain
blood flow indicator.

 

 

 



#131 METHYL-MMDA-2; 2-METHOXY-N-METHYL-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A suspension of 17.4 g electrolytic elemental iron in 100 g
glacial acetic acid was heated on the steam-bath until there were the
first signs of bubbling and reaction, about 60 !C.  There was then
added, in small portions, a suspension of 9.2 g
1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene (see under
MMDA-2 for its preparation) in 40 g warm glacial acetic acid.  The
reaction was extremely exothermic.  After the color had lightened as
much as possible, there was added an additional quantity of iron
sufficient to completely discharge the residual yellow color.
Mechanical stirring was maintained as the reaction mixture was allowed
to return to room temperature.  All was poured into 800 mL H2O, and
the insolubles were removed by filtration.  These were washed
alternately with H2O and with CH2Cl2, the combined filtrate and washes
were separated, and the aqueous phase extracted with 3x100 mL CH2Cl2.
All organics were combined, washed with 2x75 mL 5% NaOH (which removed
most of the color) and the solvent removed under vacuum.  The 8.7 g
residue was distilled at 90-105 !C at 0.2 mm/Hg to give 6.7 g of
2-methoxy-4,5-methylenedioxyphenylacetone as a pale yellow oil.

To a magnetically stirred solution of 30 g methylamine hydrochloride
in 150 mL warm MeOH, there was added 6.5 g
2-methoxy-4,5-methylenedioxyphenylacetone followed by 3.0 g sodium
cyano-borohydride.  Concentrated HCl was added as was required to keep
the mixture at a pH of about 6.  When the reaction was complete, it
was added to 1 L H2O and made strongly basic with 25% NaOH.  This was
extracted with 3x100 mL CH2Cl2, and the pooled extracts were, in turn,
extracted with 2x100 mL dilute H2SO4.  This aqueous phase was washed
with CH2Cl2, made basic with NaOH, and extracted with 3x100 mL CH2Cl2.
Removal of the solvent from these pooled extracts under vacuum gave
8.7 g of an amber oil.  This was distilled at 110-125 !C at 0.25 mm/Hg
to give 5.1 g of a colorless oil.  This was dissolved in 30 mL IPA,
neutralized with about 3 mL concentrated HCl, and diluted with 60 mL
anhydrous Et2O.  The clear solution slowly deposited white crystals
which were removed by filtration and air dried to give 4.2 g
2-methoxy-N-methyl-4,5-methylenedioxyamphetamine hydrochloride
(METHYL-MMDA-2) with a mp of 168-169 !C.  Anal. (C12H18ClNO3) C,H.

DOSAGE: greater than 70 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 70 mg) Maybe a threshold Q pleasant but
not possible to characterize it.

EXTENSIONS AND COMMENTARY: With the effective dosage of the
unmethylated homologue being the range of 25 to 50 milligrams, this
N-methyl compound is, as with the other N-methylated materials
discussed here, again of reduced activity.  The highest dose yet
reported was 70 milligrams, and there is no way of estimating what
miight be an active level nor, once there, what the quality of the
effects might be.

This is the only MMDA analogue that has been explored as an N-methyl
derivative.  A more highly substituted analogue has also been made,
the N-methyl derivative of DMMDA.  Isoapiole (see its preparation
under DMMDA) was oxidized with formic acid and hydrogen peroxide to
the ketone (2,5-dimethoxy-3,4-methylenedioxyphenylacetone, a solid
with a mp of 75-76 !C from methanol) which was reductively aminated
with methylamine and amalgamated aluminum to give
2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine hydrobromide
monohydrate (METHYL-DMMDA, or DMMDMA) as a white crystalline solid
with a mp of 91-92 !C.  The hydrochloride salt was a hygroscopic
solid.  Anal. (C13H22BrNO5) C,H.  The above ketone has also been used
in the synthesis of another methylated DMMDA, on the beta-carbon.
This is described under DMMDA itself.  DMMDMA has not yet been
launched into an evaluation program, and I wouldnUt be surprised if
the needed dosage might be up there somewhere over 100 milligrams.  I
feel quite sure that the answers may be known in the near future.
There is a surprisingly large number of inconspicuous chemical
explorers out there all over the world, doing their synthetic thing in
their private laboratories.  They are truly the astronauts of inner
space.

 

 

 



#132 MMDA; 3-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: (from protocatechualdehyde) A solution of 18 g commercial
protocatechualdehyde (3,4-dihydroxybenzaldehyde) in 200 mL warm acetic
acid was filtered free of any insolubles, to provide a very dark but
clear solution.  With good stirring there was then added 20 g
elemental bromine.  The reaction spontaneously heated to about 30 !C
and solids appeared in about 5 min.  Stirring was continued for 1 h,
and then the light gray solids that had formed were removed by
filtration and lightly washed with acetic acid.  These were air dried
on the steam bath until free of acetic acid smell.  The product,
3-bromo-4,5-dihydroxybenzaldehde, weighed 11.7 g and had a mp of 222
!C.

To a solution of 11.7 g 3-bromo-4,5-dihydroxybenzaldehyde in 36 mL
DMSO there was added 29 g methylene iodide followed by 20.8 g
anhydrous K2CO3.  This was heated on the steam bath for 3 h, added to
1 L H2O, made strongly basic with NaOH, then extracted with 3x100 mL
CH2Cl2.  These extracts were pooled, washed with H2O, and the solvent
removed under vacuum.  The dark brown semi-solid residue was distilled
with the major fraction (6.0 g) coming over at 120-130 !C at 0.3
mm/Hg.  This, upon recrystallization from 35 g boiling MeOH, gave 1.3
g of 3-bromo-4,5-methylenedioxybenzaldehyde as an off white
crystalline solid with a mp of 123-124 !C.

A mixture of 2.2 g 3-bromo-4,5-methylenedioxybenzaldehyde and 3.6 mL
cyclohexylamine in a distillation flask was heated to 100 !C to effect
solution, and then with an open flame until the signs of H2O evolution
were evident.  This was then placed under a hard vacuum to remove the
generated water and excess cyclohexylamine, and the product distilled
at 120-125 !C at 0.2 mm/Hg.  There was obtained 2.4 g of the Schiff
base of the aldehyde and the amine, melting at 86-96 !C.
Recrystallization of an analytical sample from 5 volumes of MeOH gave
3-bromo-4,5-methylenedioxybenzylidine-N-cyclohexylamine as a white
solid with a mp of 97.5-98.5 !C.  Anal. (C14H16BrNO2) H; C: calcd,
54.20; found, 53.78.

A solution of 2.2 g
3-bromo-4,5-methylenedioxybenzylidine-N-cyclohexylamine (the above
Schiff base) in 50 mL anhydrous Et2O was placed in a He atmosphere,
stirred magnetically, and cooled with a dry ice/acetone bath.  A white
fine crystalline phase appeared.  There was then added 5.2 mL 1.55 M
butyllithium in hexane (the fine solids dissolved) followed by 4.0 mL
of tributyl borate.  After returning to room temperature, the reaction
was quenched with 20 mL of saturated aqueous ammonium sulfate.  The
Et2O/hexane layer was separated, washed with additional ammonium
sulfate solution, and then stripped of volatiles under vacuum.  The
residue was dissolved in 100 mL 50% MeOH, treated with 2 mL of 30%
hydrogen peroxide and, after 15 min swirling, quenched with a solution
of 10 g ammonium sulfate in 50 mL H2O.  This aqueous phase (pH about
8) was extracted with 2x50 mL CH2Cl2, the extract pooled and stripped
of solvent under vacuum, and the residue dissolved in warm, dilute
HCl.  After all the residue had dissolved (a few min heating was
sufficient), the solution was cooled to room temperature and extracted
with 2x50 mL CH2Cl2.  These organics were pooled and extracted in turn
with 2x50 mL 5% NaOH.  Acidification of the pooled aqueous fractions
with HCl, followed by extraction with 2x50 mL CH2Cl2 gave, after
evaporation of the solvent, a residue that was distilled at 140-150 !C
at 0.25 mm/Hg to give 3-hydroxy-4,5-methylenedioxybenzaldehyde.  This
was recrystallized from toluene (40 mL/g) to give 0.46 g of an
off-white product with a mp of 134-134.5 !C.  Anal. (C8H6O4) C,H.

A solution of 0.44 g 3-hydroxy-4,5-methylenedioxybenzaldehyde in 10 mL
dry acetone was treated with 0.5 g methyl iodide and 0.5 g powdered
anhydrous K2CO3, and was held at reflux for 6 h.  All volatiles were
stripped under vacuum, the residue dissolved in water, made strongly
basic with NaOH, and extracted with 3x50 mL CH2Cl2.  Removal of the
solvent gave myristicinaldehyde (mp 133-134 !C) which, on
recrystallization from hexane, gave a final yield of 0.42 g with a mp
of 134-135 !C.  Care must be taken with two sequential products that
have identical mps.  A mixed mp with the unmethylated phenol above is
strong depressed, whereas that with an authentic sample is not.

A solution of 9.8 g myristicinaldehyde in 35 mL glacial acetic acid
was treated with 5.3 mL nitroethane and 3.2 g anhydrous ammonium
acetate, and heated on the steam bath for 1.5 h.  It was removed,
treated with H2O with good stirring to just short of turbidity, seeded
with product nitrostyrene, and allowed to come slowly to room
temperature.  The bright yellow solids that formed were removed by
filtration, washed with a small amount of aqueous acetic acid, and
sucked as free of solvent as possible.  This material, pressed on a
porous plate, had a mp of 107-110 !C.  Recrystallization from 60 mL
boiling EtOH gave, after filtering and air drying, 5.1 g of
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene as light yellow
solids with a mp of 109-110 !C.

A suspension of 7.5 g LAH in 500 mL anhydrous Et2O was magnetically
stirred, and heated in an inert atmosphere to a gentle reflux.  The
condensing Et2O leached out a total of 9.8 g
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene from a Soxhlet
thimble in a shunted reflux condenser.  This, in effect, added the
nitrostyrene to the reaction medium as a warm saturated Et2O solution.
When the addition was completed, the refluxing was maintained for an
additional 5 h, then the reaction mixture was cooled and the excess
hydride destroyed by the addition of 400 mL 1.5 N H2SO4 (the first 20
mL a drop at a time and with very good stirring).  The phases were
separated, and sufficient saturated aqueous Na2CO3 was added to the
aqueous phase to bring the pH up to about 6.0.  This was heated to 80
!C and filtered through a coarse sintered glass funnel to remove some
insoluble fines.  The clear filtrate was brought up almost to a boil,
and treated with a solution of 10.2 g of 90% picric acid in 110 mL
boiling EtOH.  Crystals of the picrate formed immediately at the
edges, and as the reaction flask was cooled in an ice tub, the entire
reaction set to a yellow mass of crystals.  These were removed by
filtration, washed sparingly with 80% EtOH, and air dried to give 14.0
g of the picrate salt of MMDA, with a mp of 182-184 !C.
Recrystallization of a small sample from EtOH dropped this to 179-181
!C.  This salt was treated with 30 mL 5% NaOH, and the red solution
decanted from some insolubles.  Additional H2O and NaOH effectively
dissolved everything, and the resulting basic aqueous phase was
extracted with 3x50 mL CH2Cl2.  The pooled extracts were stripped of
solvent under vacuum, and the residue dissolved in 200 mL anhydrous
Et2O and saturated with anhydrous HCl gas.  There was a heavy
precipitation of white crystals, which were removed by filtration,
Et2O washed, and air dried to give 6.37 g
3-methoxy-4,5-methylenedioxyamphetamine hydrochloride (MMDA) with a mp
of 190-191 !C.  Anal. (C11H16ClNO3) Cl.

(from Oil of Nutmeg) The careful distillation of Oil of Nutmeg (or the
Oil of Mace) allowed the isolation of a number of compounds in varying
degrees of purity.  The fraction that boiled in the 110-115 !C range
at about 1.0 mm/Hg was myristicin
(3-methoxy-4,5-methylenedioxyallylbenzene).  It constituted some 7% of
the original oil of commerce and, in its original isolated form, was
obtained with a purity of 87%.  The major contaminant was elemicin
(3,4,5-trimethoxyallylbenzene).  A solution of 100 g myristicin in 100
g absolute EtOH was treated with 200 g solid KOH and heated on a steam
bath overnight.  Removal of the volatiles under vacuum, flooding the
residue with H2O, and extraction with 3x100 mL CH2Cl2 gave, after
removal of the solvent from the combined extracts, a residue of crude
isomyristicin (a mixture of the cis- and trans-isomers).  This product
was distilled, and the fraction boiling at 125-130 !C at 1 mm/Hg gave
63 g of isomyristicin as a pale yellow oil that spontaneously
crystallized.  The mp was 41.5-42.5 !C.  Part of the losses associated
with the purification of these solids was due to formation of the
cis-isomer of isomyristicin, which was an oil.

A solution of 50 g isomyristicin in 300 mL dry acetone containing 24 g
pyridine was vigorously stirred and cooled to 0 !C with an ice bath.
To this there was added 54 g tetranitromethane which had been
pre-cooled to 0 !C.  Stirring was continued for exactly 2 min, and
then the reaction was quenched by the addition of a cold solution of
16.8 g KOH in 300 mL H2O.  Stirring was continued until the
temperature had again been lowered to near 0 !C.  The product was
removed by filtration.  Extraction of the filtrate with CH2Cl2 and
removal of the solvent provided additional nitrostryrene, for a
combined yield of 50.7 g with a mp of 103 !C due to the presence of a
small amount of free myristicinaldehyde.  A recrystallization from
MeOH produced 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene
with a mp of 109-110 !C.  This material was completely adequate for
the above-described reduction to MMDA.  The conversion of this
nitropropene to myristicinaldehyde is an alternative to the lengthy
synthesis given above), and can be used in the preparation of
LOPHOPHINE.

A mixture of 50 g
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene and 26 g racemic
a-methylbenzylamine was heated on the steam bath.  The mixture
gradually formed a clear solution with the steady evolution of
nitroethane.  When the reaction became quiet, there was added a
mixture of 20 mL concentrated HCl in 100 mL H2O.  The reaction mixture
dissolved completely, and as the temperature continued to rise there
was the abrupt solidification as the formed myristicinaldehyde
crystallized out.  This product was removed by filtration and, when
combined with a second crop obtained by the hexane extraction of the
filtrate, gave 36.9 g of myristicinaldehyde.  The mp of 128-129 !C was
raised to 133-134 !C by recrystallization from hexane.

DOSAGE: 100 - 250 mg.

DURATION: moderate.

QUALITATIVE COMMENTS: (with 100 mg) I felt completely relaxed at one
hour.  Almost as if I was floating.  There were no obvious effects on
taste, and the relaxation and composed feeling is much like a small
dose, maybe 20 mikes, of LSD.  There was some dilation, and in the
evening I was a little restless and slightly tired.  I slept well, and
awoke refreshed and happy.

(with 100 mg) It seemed to take 45 minutes to work and then it came
on very suddenly, as if my eyeballs were being pulled out and my whole
head expanding.  Soon a cold feeling set in with shivering Q this was
not unpleasant.  My state in about two hours seemed to be one of
empathy and passivity, compassion of an impersonal sort.  The music
sounded artificial and canned and tinny, in contrast to the voices,
which sounded rich and full and finely articulated and melodious.

(with 150 mg) We are on the beach at the river mouth drying seaweed,
on split redwood.  There is a slight nausea, slight cramps, and then
my visual field starts to light up.  Still vertigo but only with my
eyes open, and heaviness and time stretches out; numbness in the chest
as when an opiate is taken.  There are geometric patterns, but the
excess light on my closed eyelids interferes with this.  A dance of
the glittering diamond studded sea waves, increasing motion and
beauty.  More landscapes appear inside.  This is a good introductory
drug to the drugs of this class, to become familiar with the drug
state in as gentle a fashion as possible.  This substance seems to
have a much gentler action than others of this class; perhaps more
like cannabis or psilocybin.  There is very little paranoia.  I note
hallucinations of two types: those which are strictly retinal and more
minute and small and influenced by light and focused on the light
ahead on the retina or lids; and the other, those deep in the visual
tract and occiput which are larger and more global and dream-like and,
when solid, are quite dramatic and unforgettable as in meditation.

(with 210 mg) MMDA tastes awful.  The bitter alkaloid taste is
followed by a distinctively chemical laboratory flavor as if from old
rubber tubing.  Nothing seems to happen for about 45 minutes when
rather suddenly an anvil seems to lower itself over your head; you
feel disoriented, and tend to withdraw from social contact a little.
The drug gives less feeling of being ill than mescaline.  The effect
definitely reaches a climax with a pleasant afterglow following.
Apparently there are no profound motor coordination problems.  MMDA
yields that 'Sunday afternoon' feeling of desiring to lie down and
enjoy life; a luxurious feeling of 'layback.'  No enhancement of
colors in visual scene (except for some greenish tinges in faces) but
upon closing eyes hallucinations appear to be quite real in 3-D, like
watching a movie.  First these dreams appear in black and white, but
later colors start appearing.  Chartreuse and magenta first appear,
then blue and finally red.  First I had visions of large numbers on
gaming tables, then people.  MMDA appears to bring dreams to the
conscious level; is a link between the subconscious and the
conscious.

(with 225 mg) I had a strange awareness of my hands in about 20
minutes Q not a feeling in them as just that I was attracted to them
somehow.  Then I began to get fearful, an acute experience of
aloneness.  I lay face down (a depressed position for me).  Next I was
talking to the kids at school (an image) or to other teachers.  This
was very vivid.  The scenes at school were more vivid that the real
scenes around me here.  Those people were much more real.  I am
actually very sleepy right now during the experiment.  Of any
experience I have had, this was most like a series of dreams easily
remembered.  When it was over, I felt as if I had had a long period of
sleeping Q I had gone to bed and had a series of dream-like states
very vivid and colorful and real.

EXTENSIONS AND COMMENTARY: The phrase that had been used by several of
the subjects in the early trials with MMDA, again and again, was
Rbrain movies.S Apparently the richest of the effects were to be had
with the eyes closed.  This is the compound that I had first completed
in 1962, and had named it MMDA, and had begun the exploring of it when
I heard that Dr. Gordon A. Alles, a professor of pharmacology at U. C.
L. A. who had his own private laboratory in Los Angeles, had also
synthesized it in 1962, had also named it MMDA, and had also begun
exploring it.  We made a date to meet and share ideas, and then he
died, at the age of 62, in 1963.

This is a material that might be a contributing factor to the
pharmacology of nutmeg.  The major essential oil from that spice is
myristicin, and it is the easiest source of MMDA.  It has been
reported that the passage of this oil through the liver of a rabbit
will generate MMDA in that animal.  The only difference between the
two molecules, structurally, are the elements of ammonia.  Myristicin
plus ammonia gives MMDA.  Another natural source of myristicin is Oil
of Parsley, which is also an excellent source of apiole, mentioned
under DMMDA.  A rumor that had currency in the 1960Us, that parsley
could get you high, probably had its origins in the reports of
myristicin being present, coupled with myristicin being the principal
source of MMDA.  The relationship to myristicin (an essential oil) led
to the classifying of MMDA as a Essential Amphetamine.  These
relationships are expanded upon, under TMA.

At the time that the FDA issued its proclamation of dangerous drugs
(in the mid-1960Us), MMDA was being talked about, and in fact it had
just become available commercially in England through the Koch Light
Industries.  But to my knowledge it had never appeared on the street,
so its having being swept into the listings of evil drugs was simply a
coincidence of bad timing.  The close resemblance of initials between
MMDA, and the currently notorious MDMA, has led to no small amount of
confusion in the popular press.  They remain totally separate and
completely different drugs.

 

 

 



#133 MMDA-2; 2-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A solution of 11.5 g pellet KOH (85%) in 75 mL EtOH was
treated with 25 g sesamol followed by 27 g methyl iodide.  This was
brought to reflux on the steam bath.  Salt formation was apparent in
20 min, and refluxing was main-tained for a total of 4 h.  The solvent
was removed under vacuum, and residue poured into 400 mL H2O.  This
was acidified with HCl and extracted with 3x150 mL CH2Cl2.  The pooled
extracts were washed with 3x100 mL 5% NaOH, which removed most of the
color.  The solvent was removed under vacuum to provide 24.0 g of
3,4-methylenedioxyanisole as a pale amber oil.

A mixture of 56.4 g POCl3 and 49.1 g N-methylformanilide was allowed
to stand for 40 min and then it was poured into a beaker containing 64
g 3,4-methylenedioxyanisole.  There was an immediate exothermic
reaction with darkening and the generation of bubbles.  This was
heated on the steam bath for 1 h, then poured into 1 L H2O with
extremely vigorous stirring.  The dark brown phase was quite opaque,
and then there was a sudden lightening of color with the generation of
a fine pale yellow solid.  Stirring was continued for 2 h, then these
crystals were removed by filtration. This crude product was
recrystallized from 400 mL boiling MeOH yielding, after filtering,
washing, and air drying to constant weight, 44.1 g
2-methoxy-4,5-methylenedioxybenzaldehyde with a mp of 110-111 !C.
Only one positional isomer was visible in the final product by GC, but
extraction of the original mother liquors with CH2Cl2 produced, after
evaporation of the solvent under vacuum, 2 g of a red oil that showed
two earlier peaks on OV-17.  These were consistent with about 1% of
each of the two alternate positional isomers that could result from
the Vilsmeier formylation reaction.

A solution of 43 g 2-methoxy-4,5-methylenedioxybenzaldehyde in 185 g
nitroethane was treated with 9.3 g anhydrous ammonium acetate and
heated on the steam bath for 4.5 h.  The excess nitroethane was
removed under vacuum to give a residue that spontaneously
crystallized.  These solids were washed out mechanically with the aid
of 200 mL cold MeOH, and the brilliant orange crystals recovered by
filtering and air drying to constant weight.  There was obtained 35.7
g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of
166-167 !C.  This was not improved by recrystallization from IPA.
Evaporation of solvent from the methanolic washes gave yellow solids
(4.6 g melting at 184-186 !C) which, on recrystallization from
THF/hexane, melted at 188-190 !C.  This showed a molecular weight of
416 by chemical ionization mass spectroscopy (isobutane at 0.5 torr)
and is the C20H20N2O8 adduct of one molecule each of nitrostyrene,
aldehyde, and ammonia that frequently appears as a very insoluble
impurity in aldehyde-nitroethane condensations that are catalyzed by
ammonium acetate.

To a refluxing suspension of 36 g LAH in 1 L anhydrous THF under an
inert atmosphere, there was added 44.3 g
1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene in hot THF.  The
solubility was very low, so that it was necessary to use a heat lamp
on the dropping funnel to maintain a clear solution for addition.  The
addition required 2 h and the reflux was maintained for 36 h.  The
reaction mixture was then cooled in an ice bath and there was added,
in sequence and commensurate with heat evolution, 36 mL H2O, 36 mL 15%
NaOH, and finally 108 mL H2O.  The granular solids were removed by
filtration and washed with THF.  The combined filtrate and washes were
stripped of solvent under vacuum yielding 58.8 g of a pale amber oil.
This was dissolved in 100 mL IPA, neutralized with con-centrated HCl
(20 mL was needed) and diluted with 500 mL anhydrous Et2O.  More IPA
was required to keep an oil phase from appearing.  After the
crystalline product was completely formed, it was removed by
filtration, washed with IPA/Et2O, and finally with Et2O.  Air drying
gave 31.1 g of 2-methoxy-4,5-methylenedioxyamphetamine hydrochloride
(MMDA-2) with a mp of 186-187 !C.

DOSAGE: 25 - 50 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 25 mg) Had some not-too-pleasant jangly
effects Q this is not the smoothest of drugs.  Duration: onset at 1
1/2 hours (dose after lunch), acute 3 to 4 hours, seconal at 11 hours
to stop residual effects so I could sleep.  Occasionally from 5 to 10
hours acute abdominal distress, resembling gas pains but unable to
defecate.  Abdominal muscles tight and hard.  This occurred for about
15 minutes every hour or so.  Rather unpleasant.

(with 30 mg) There was the first subtle note at 45 minutes, and the
slow development makes the changes easy to assimilate, but difficult
to quantitate.  My awareness is truly enhanced.  Nothing is distorted,
so there can be no misrepresentation as a result.  This would be a
good material to introduce someone to the slow-on slow-off type of
experience.  It would be impossible for any person, at this level, on
this drug, to have a bad experience.  This is very much like a slow
MDA, perhaps 80 milligrams of it, and fully as controllable.  The
N-methyl of this is a must.

(with 40 mg) The chemical is primarily a visual enhancer with only an
extremely modest amount of visual distortion.  The retinal activity
was of a minor and non-threatening nature.  The chemical seemed to
facilitate empathic communication and the emotions felt strong and
clean.  Conversation flowed easily, without inhibitions or
defensiveness.  Anorexia accompanied experience.  There was no
impotence.  There was some restless movement which dissipated with
exercise (walking and playing frisbee).  Next day woke feeling
energetic, no muscular stiffness, alert.  I would repeat this
experience.

(with 50 mg) I was coming on within 40-60 minutes, easy and slow, but
the body was +3 before the mind.  The mental was strange for the first
2-3 hours Q I called it 'High Sierras' Q realistic, dispassionate, not
kind.  Some dark areas are persistent.  Watched last half of Circus of
Dr. Lao and the whole feeling changed from pornographic to erotic.
Delightful.  Some fantasy.  On coming down, sleep was difficult.  The
body feels unexpectedly depleted.  Rubber legs and handwriting jerky.

EXTENSIONS AND COMMENTARY: A comparison of this material to MDA was
often made by subjects who were familiar with both.  But it is hard to
separate that which is intellectualized from that which is felt.  An
awareness of the chemical structure immediately shows, of course, the
close resemblance.  There is the complete MDA molecule, with the
addition of a methoxy group.  And for the non-chemist, the name itself
(MMDA-2) represents the second possible methoxy-MDA.  Certainly one
property that is shared with MDA is the broad variety of opinions as
to the quality of its action.  Some like it much, and some like it not
at all.  The N-methyl homologue was indeed made, for direct evaluation
in comparison to N-methyl MDA (which is MDMA).

The phenethylamine analog of MMDA-2 has been prepared by the
condensation of the above benzaldehyde with nitromethane (in acetic
acid with ammonium acetate catalyst, giving an equal weight of the
nitrostyrene as deep orange crystals with a mp of 166-167 !C from
ethyl acetate) followed by lithium aluminum hydride reduction (in
ether).  The product, 2-methoxy-4,5-methylenedioxyphenethylamine
hydrochloride (2C-2) melted at 218-219 !C.  There were no effects
observed at up to 2.6 milligrams, but no higher trials were made.  The
4-carbon homologue was made similarly (from the aldehyde and
nitropropane but using tert-butylammonium acetate as a reagent in 100%
excess and isopropanol as solvent, giving orange crystals melting at
98-99 !C from methanol) followed by reduction (with lithium aluminum
hydride in ether) to give
1-(2-methoxy-4,5-methylenedioxyphenyl)-2-aminobutane hydrochloride
(4C-2) with a mp of 172-174 !C.  This material has never even been
tasted.

The Tweetio homologue of MMDA-2 has been tasted, however.  This is
2-ethoxy-4,5-methylenedioxyamphetamine, or EMDA-2.  The allyl ether of
sesamol (3,4-methylenedioxy-allyloxybenzene) was rearranged to the
2-allyl phenol which was, in turn, converted to the ethyl ether.
Reaction with tetranitromethane gave the nitrostyrene intermediate
which had a mp of 120-121 !C.  The final hydrochloride salt of EMDA-2
had a mp of 188-188.5 !C.  At 135 milligrams, there have been reported
eyes-closed visual phenomena, with intense colors.  The overall
duration is similar to MMDA-2 (some 10 hours) and there are reported
sleep disturbances.  At 185 milligrams, the feelings were intensified,
there were Rmarvelous eyes-closed visuals (the colors were
incredible), good concentration, but distinct body-tingles and
rushes.S The time span was about 12 hours from start to finish, but it
proved to be impossible to sleep afterwards.  This homologue is thus
about a third the potency of MMDA-2.

 

 

 



#134 MMDA-3a; 2-METHOXY-3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: To a solution of 100 g of 2,3-dihydroxyanisole in 1 L dry
acetone there was added 110 g of powdered anhydrous K2CO3 followed by
210 g of methylene iodide.  This was brought up to a reflux on the
steam bath.  There was a sudden appearance of a solid phase, and then
a gentle reflux was maintained for three days, during which time much
of the heavy solid that initially formed had redissolved.  The
reaction mixture was filtered to remove the insoluble salts, and these
were washed with hot acetone.  The combined mother liquor and washes
were stripped of solvent under vacuum, leaving a solid residue.  This
was leached with several portions of boiling hexane.  These were
pooled, and removal of the solvent under vacuum provided 53.6 g of
2,3-methylenedioxyanisole as white crystals with a sharp spicy smell.

A mixture of 120 g N-methylformanilide and 137 g POCl3 was allowed to
incubate at ambient temperature for 0.5 h, then there was added 53 g
of crude 2,3-methylenedioxyanisole.  The dark reaction mixture was
heated on the steam bath for 2 h and then poured into a beaker filled
with shaved ice.  This was stirred until hydrolysis was complete, and
the black, almost crystalline gunk that separated was removed by
filtration.  The 53.6 g of crude product was analyzed by GC using an
ethylene glycol succinate column at 190 !C.  Three peaks were apparent
and had baseline separation.  The major peak at 7.8 min constituted
82% of the product and was 2-methoxy-3,4-methylenedioxybenzaldehyde.
A minor peak at 12.0 min represented 16% of the product and was the
positional isomer 4-methoxy-2,3-methylenedioxybenzaldehyde.  A trace
component (2%) lay intermediate (at 9.5 min) and was
myristicinaldehyde.  The mps of the two major benzaldehydes were
sufficiently different that they could serve as means of
identification.  The major product was obtained directly from the
black gunk by repeated extraction with boiling cyclohexane which, upon
removal of the solvent, gave 33.1 g of a yellow-colored product.
This, upon one additional recrystallization from boiling cyclohexane,
gave 24.4 g of 2-methoxy-3,4-methylenedioxybenzaldehyde as pale yellow
crystals with a mp of 103-105 !C.  The mother liquors were pooled and,
after removal of all volatiles under vacuum, yielded an amber-colored
solid that upon recrystallization provided a yellowish crystals.
These, after yet another crystallization from cyclohexane, gave 4.1 g
of 4-methoxy-2,3-methylenedioxybenzaldehyde with a mp of 85-86 !C.
This latter isomer was used in the synthesis of MMDA-3b.

To a solution of 3.5 g 2-methoxy-3,4-methylenedioxybenzaldehyde in 14
g acetic acid there was added 1.4 g anhydrous ammonium acetate and 2.3
mL of nitroethane.  The mixture was brought to reflux and held there
for 35 min.  It was then quenched by the addition of 40 mL H2O,
knocking out an orange, gummy solid.  This was removed by filtration,
and recrystallized from 50 mL boiling MeOH.  After cooling for a few h
in an ice bath, the bright yellow crystals were removed by filtration,
washed with MeOH and air dried to constant weight, yielding 2.15 g
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene.  The mp was
106-107 !C. Recrystallization from EtOH raised this mp to 109.5-110.5
!C.

A suspension of 2.2 g LAH in 300 mL anhydrous Et2O under an inert
atmosphere was brought to a gentle reflux.  The reflux condensate was
passed through a modified Soxhlet thimble containing 1.95 g
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene effectively
adding it, over the course of 0.5 h, to the reaction mixture as a
saturated Et2O solution.  The mixture was maintained at reflux for 16
h.  After cooling to 0 !C with an ice bath, the excess hydride was
destroyed by the addition of 1.5 N H2SO4.  The phases were separated,
and the aqueous phase washed with 2x100 mL Et2O.  To the aqueous phase
there was added 50 g potassium sodium tartrate followed by sufficient
25% NaOH to raise the pH >9.  This was then extracted with 3x100 mL
CH2Cl2, and the solvent from the pooled extracts removed under vavuum.
The residual white oil was dissolved in 250 mL anhydrous Et2O, and
saturated with anhydrous HCl gas.  There was produced a crop of white
microcrystals of 2-methoxy-3,4-methylenedioxyamphetamine hydrochloride
(MMDA-3a) which was removed by filtration, washed with Et2O, and air
dried to a constant weight of 1.2 g.  The mp was 154-155 !C.

DOSAGE: 20 - 80 mg.

DURATION: 10 - 16 h.

QUALITATIVE COMMENTS: (with 20 mg) I became aware at about an hour,
and an hour later I found myself suddenly caught up in the marvelous
world of insects.  Right alongside a pile of bricks I saw a measuring
worm, and with great tenderness and patience I picked him up, observed
his fore and aft 'feet' and finally replaced him and watched him
acclimate himself.  There was also a spider on the bricks, and I was
compelled to watch him in action.  I was grateful that I was not being
observed.  Time was moving slowly, and I felt I should intentionally
move slowly, so as not to exhaust myself.

(with 40 mg) This developed between one and two hours into it, and
there were considerable body tremors.  Talking directed the energy
outwards, and I became aware of a visually sparkling world about me.
I started dropping way too soon; it would have been interesting to
have gone higher.  By early evening I was left only with an awareness
of some residual physical hypersensitivity, and there was light
diarrhea.  I am not at all sure just what to compare this drug to.  It
is gentle.

(with 60 mg) There were visuals of a soft sort Q things moved with
eyes open, and with eyes closed the music was great.  There seemed to
be some lasting stimulation, but it didnUt get in the way of sleeping.
The next morning, however, I was still on.  A good compound.

EXTENSIONS AND COMMENTARY: The term MMDA-3a has the feel of being
complicated, but there is a reason for the code.  As had been
mentioned, MMDA was the initials for methoxy (the M) methylenedioxy
(the MD) amphetamine (the A).  And with a molecule of amphetamine
there are six ways of sticking these two groupings on the aromatic
ring.  The numbers 1-6 had already been assigned to the six ways of
sticking three methoxyl groups onto an amphetamine molecule (with the
trimethoxyamphetamines, the TMAUs) and I decided to hew to the same
convention with the methylenedioxy counterparts.  However, there are
two #3's (the methoxy and the methylenedioxy can go onto the three
oxygen atoms in a row in two different ways, whereas the three
methoxys can go on in just one way) and there can be no #6 (since a
methylenedioxy must, perforce, have two oxygens that are adjacent, and
there are none to be so found in the 2,4,6-orientation of TMA-6).  So,
with two possible MMDA-3's it becomes reasonable, in fact essential,
to name one of them RaS and the other RbS.  The RaS orientation occurs
in nature as the essential oil croweacin, or
1-allyl-2-methoxy-3,4-methylenedioxybenzene.  It thus can allow
MMDA-3a to be classified as an Essential Amphetamine, since it can
arise, in principle, by amination in the liver in vivo.  But in the
laboratory, croweacin is certainly not a practical starting material
in this synthesis.

I have been told of a number of clinical trials that have explored
MMDA-3a at considerably higher levels, but I have no explicit
quotations to give, and the details are quite sketchy.  Three trials
at 80 milligrams, and one at 100 milligrams, all made comparisons, in
both quantity and quality of the experience, to 100 micrograms of LSD.
However, two events occurred that may or may not be related to these
trials; one subject had a spontaneous peak experience five days after
the experiment, and another made a symbolic suicide attempt.

And, as with MMDA-2, both the 2-carbon RphenethylamineS analogue and
the 4-carbon RARIADNES analogue of MMDA-3a have been made.  The
phenethylamine analog was prepared by the condensation of 7.6 g of the
above benzaldehyde with nitromethane (in acetic acid with ammonium
acetate catalyst, giving 5.4 g of the nitrostyrene with a mp of
115.5-116.5 !C from methanol) followed by lithium aluminum hydride
reduction (in ether).  The product,
2-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (2C-3a)
melted at 143-145 !C.  A series of subjective evaluations were made,
and there are reports of marginal effects in the 40 to 120 milligram
range.  At 40 milligrams, perhaps the hint of a psychic energizer; at
65 milligrams, there was a pleasant mood elevation; at 80 milligrams,
there was a brief paresthetic twinge noted at about the hour and a
half point, and at 120 milligrams, about the same at one hour, and
then nothing.  The fact that there can be such a modest change of
effect over a three-fold range of dosage suggests that this compound
might have some merit as an anti-depressant.  It would be interesting
to know if it blocks serotonin reuptake!

The 4-carbon analog was made similarly (from the aldehyde and
nitropropane but using tert-butylammonium acetate as a reagent in 100%
excess and isopropanol as solvent, giving bright yellow crystals
melting at 105.5-106.5 !C from 25 volumes of boiling methanol)
followed by reduction (with lithium aluminum hydride in ether) to give
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-aminobutane hydrochloride
(4C-3a) with a mp of 183-185 !C with prior sintering at 173 !C.  This
material has been tasted at up to 3.5 milligrams with nothing noted.
There have been no trials at any higher dose.

 

 

 



#135 MMDA-3b; 4-METHOXY-2,3-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A solution of 7.0 g of 98% pure (by GC)
4-methoxy-2,3-methylenedioxybenzaldehyde (see under MMDA-3a for its
preparation) in 30 mL glacial acetic acid was treated with 5 mL
nitroethane and 3 g anhydrous ammonium acetate, and heated on the
steam bath for 3.5 h.  H2Owas added to the hot solution to the point
of turbidity, then it was allowed to cool to room temperature with
occasional stirring.  A modest crop of yellow crystals formed which
were removed by filtration, washed with aqueous acetic acid and air
dried to constant weight.  There was obtauned 4.6 g of
1-(4-methoxy-2,3-methylenedioxphenyl)-2-nitropropene, with a mp of
95-102 !C.  Recrystallization from EtOH tightened this to 97-101.5 !C.
The infra-red spectrum is completely different from that of its
positional isomer
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene.

A suspension of 7.0 g LAH in 1 L anhydrous Et2O under an inert
atmosphere was brought to a gentle reflux.  The reflux condensate was
passed through a Soxhlet thimble containing 6.15 g
1-(4-methoxy-2,3-methylenedioxyphenyl)-2-nitropropene which was
effectively adding the nitropropene as a saturated solution.  The
mixture was maintained at reflux for 16 h.  After cooling to 0 !C with
an ice bath, the excess hydride was destroyed by the addition of 800
mL of 1.5 N H2SO4.  The phases were separated, and the aqueous phase
washed with 2x100 mL Et2O.  To this phase there was added 175 g
potassium sodium tartrate followed by sufficient 25% NaOH to raise the
pH >9.  This was then extracted with 3x100 mL CH2Cl2, and the solvent
from the pooled extracts removed under vacuum.  The residual off-white
oil weighed 5.4 g and was dissolved in 250 mL anhydrous Et2O and
saturated with anhydrous HCl gas.  There was produced a crop of
slightly sticky white solids that finally became granular and loose.
These were removed by filtration, washed with Et2O, and air dried to
give 5.56 g of 4-methoxy-2,3-methylenedioxyamphetamine hydrochloride
(MMDA-3b) with a mp of 196-199 !C.  A small sample from propanol had a
mp of 199-200 !C, and a sample from nitromethane/MeOH (5:1) had a mp
of 201-202 !C.

DOSAGE: greater than 80 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 60 mg) Definitely active.  Qualitatively
like MDA; quantitatively perhaps less.

(with 80 mg) No more effective than 60 mg.

EXTENSIONS AND COMMENTARY: And that's all there is known as to the
activity of MMDA-3b in man.  Very, very little.  Nothing has ever been
tried in excess of 80 milligrams that I know of, and the above trials
were made over 20 years ago.  There can be little argument that the 3b
is less effective than the 3a, but no one can say by how much.  The
literature statement is that it is threefold less, but that was based
on the relative responses at just-above-threshold levels.  The effects
here are hand-wavingly similar to those reported for MMDA-3a at 20
milligrams, but these are difficult to compare accurately as they were
reported by different people.  There have been absolutely no animal
studies reported with MMDA-3b in the scientific literature.  And
neither the 2-carbon nor the 4-carbon analogues of MMDA-3b has even
been prepared.

The remaining MMDA-analogue that has been prepared, is the
2,3,6-isomer.  The flow diagram started with sesamol
(3,4-methylenedioxyphenol) which was methylated with methyl iodide,
converted to the aldehyde using butyllithium and N-methylformanilide
(putting the new group directly between the two oxygen atoms, giving
2,3-methylenedioxy-6-methoxybenzaldehyde), reaction with nitroethane
to the nitrostyrene, and its reduction with lithium aluminum hydride
in ether.  The product, 6-methoxy-2,3-methylenedioxyamphetamine
hydrochloride (MMDA-5) is practically unexplored in man.  I have heard
one report that 30 milligrams was modestly active, but not a
particularly pleasant experience.  Another person told me that he had
tried 15 milligrams, but he neglected to mention if there had been any
effects.  I have not tried it myself.  But, I have succumbed to the
pressure of the experimental pharmacologists to give a number for the
RY-axisS of their animal behavior studies.  So I said to myself, if
this is active at 30 milligrams, and mescaline is active at 300
milligrams, why not say that it is 10x the activity of mescaline?  So
I did.  But I have absolutely no confidence in that number.

And if the information on MMDA-5 is sparse, look at the positional
isomer, MMDA-4, which I have discussed under its analogue TMA-4.  Here
nothing is known at all, since the compound itself is unknown.  No one
has yet found a way of making it.

 

 

 



#136 MME; 2,4-DIMETHOXY-5-ETHOXYAMPHETAMINE

SYNTHESIS: A solution was made of 166 g ethylvanillin
(4-ethoxy-3-methoxybenzaldehyde) in 600 mL glacial acetic acid and
arranged so that it can be stirred continuously, magnetically, and
cooled as needed with an external ice bath.  There was then added a
total of 218 g of 40% peracetic acid in acetic acid, at a rate that
permitted the temperature to stay at 25 !C with the continuous
application of the ice bath.  The temperature should not drop below 23
!C (the reaction stops) but it absolutely cannot be allowed to exceed
29 !C (the reaction can no longer be controlled).  The addition takes
about 1.5 h.  At the end of the reaction, there was added 3 volumes of
H2O, and all acids were neutralized with solid K2CO3.  The 3 or so L
of black, gooey mess was extracted with 2x400 mL boiling Et2O which,
on pooling and evaporation, provided 60 g of a black oil which was a
mixture containing mainly the intermediate formate and the product
phenol.  This was treated with 300 mL 10% NaOH, and heated on the
steam bath for 1 h.  After cooling, this was washed with 2x150 mL
CH2Cl2 (discarded), acidified with HCl, and extracted with 3x200 mL
Et2O.  The pooled extracts were washed with 2x200 mL saturated NaHCO3,
and then the Et2O was removed under vacuum.  The residual black oil,
41.3 g, was distilled at 1.0 mm/Hg to give a fraction boiling at
140-145 !C as a pale amber oil that set up as crystals.  The weight of
the isolated 4-ethoxy-3-methoxyphenol was 29.1 g.  An analytical
sample had a mp of 45.5-46 !C.  This product can be used either for
the synthesis of MME (see below) or for the synthesis of EME (see
separate recipe).  A solution of 0.5 g of this phenol, and 0.5 g
methyl isocyanate in 10 mL hexane containing 1 mL CH2Cl2 was treated
with three drops of triethylamine.  In about 1 h, there was the
spontaneous formation of white crystals of 4-ethoxy-3-methoxyphenyl
N-methyl carbamate, with a mp of 104-105 !C.

A solution of 14 g of the distilled, solid 4-ethoxy-3-methoxyphenol in
20 mL MeOH was treated with a solution of 5.3 g KOH in 100 mL hot
MeOH.  There was then added 11.9 g methyl iodide, and the mixture was
held at reflux temperature for 2 h.  The reaction was quenched with 3
volumes H2O, made strongly basic by the addition of 1 volume of 5%
NaOH, and extracted with 2x150 mL Et2O.  Pooling the extracts and
removal of the solvent under vacuum gave 9.7 g of
2,4-dimethoxy-1-ethoxybenzene as a clear, off-white oil that showed a
single peak by GC.  An acceptable alternate synthesis of this ether is
the ethylation of 2,4-dimethoxyphenol, which is described in the
recipe for TMA-4.  The index of refraction was nD25 = 1.5210.

A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed
to stand at room temperature until a strong red color had been
generated (about 0.5 h).  There was then added 9.2 g
2,4-dimethoxy-1-ethoxybenzene and the mixture was heated on the steam
bath for 2 h.  The black, viscous product was poured onto 800 mL
cracked ice, and mechanically stirred.  The deep color gradually faded
to a yellow solution, and then yellow crystals began to form.  After
standing overnight, these were removed by filtration and sucked as dry
as possible, yielding 16 g of a wet, crude product.  This was
dissolved in 100 mL boiling MeOH which, on cooling, deposited fluffy,
white crystals of 2,4-dimethoxy-5-ethoxybenzaldehyde.  The dry weight
was 8.8 g and the mp was 107-108 !C.  The mother liquor showed no
isomeric aldehydes by GC, but there were small suggestions of isomers
seen in the CH2Cl2 extracts of the original water filtration.  A
sample of 0.7 g of the aldehyde obtained as a second crop from the
methanolic mother liquors was dissolved, along with 0.5 g
malononitrile, in 20 mL hot EtOH.  The addition of 3 drops of
triethylamine generated the almost immediate formation of brilliant
yellow crystals, 1.4 g after filtration and EtOH washing, with a mp of
134-135.5 !C.  Recrystallization from toluene gave an analytical
sample of 2,4-dimethoxy-5-ethoxybenzalmalononintrile with a mp of
135-136 !C.

A solution of 6.7 g 2,4-dimethoxy-5-ethoxybenzaldehyde in 23 g glacial
acetic acid was treated with 3.3 g nitroethane and 2.05 g anhydrous
ammonium acetate.  The mixture was heated on the steam bath for 2.5 h.
The addition of a little water to the cooled solution produced a gel
which was a mixture of starting aldehyde and product nitrostyrene.
The solvent was decanted from it, and it was triturated under MeOH, to
provide a yellow solid with a mp of 76-84 !C.  Recrystallization from
30 mL boiling MeOH gave, after filtering and air drying, 4.3 g of a
yellow solid with a mp of 90-92 !C.  There was still appreciable
aldehyde present, and this was finally removed by yet another
recrystallization from toluene.  The product,
1-(2,4-dimethoxy-5-ethoxyphenyl)-2-nitropropene, was obtained as
bright yellow crystals with a mp of 96-97 !C.  The analytical sample
was dried in vacuum for 24 h to completely dispel the tenacious
residual traces of toluene.  Anal. (C13H17NO5) C,H.

To a gently refluxing suspension of 1.6 g LAH in 120 mL anhydrous Et2O
under a He atmosphere, there was added 2.1 g
1-(2,4-dimethoxy-5-ethoxyphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added, dropwise, a warm saturated
solution of the nitrostyrene to the reaction mixture.  Refluxing was
continued for 6 h, and after cooling the reaction flask to 0 !C the
excess hydride was destroyed by the cautious addition of 1.5 N H2SO4.
When the aqueous and Et2O layers were finally clear, they were
separated, and 40 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was >9,
and this was then extracted with 3x200 mL CH2Cl2.  Evaporation of the
solvent under vacuum produced 1.6 g of an amber oil that was dissolved
in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas.  There
was an immediate white blush, then there was the generation of an oily
solid that upon further administration of HCl became a fine, loose
white powder.  This was removed by filtration, Et2O washed, and air
dried to give 1.6 g 2,4-dimethoxy-5-ethoxyamphetamine hydrochloride
(MME) with a mp of 171-172 !C.  Anal. (C13H22ClNO3) C,H,N.

DOSAGE: 40 mg and above.

DURATION : probably 6 - 10 h.

QUALITATIVE COMMENTS: (with 40 mg) At the one hour point there was a
real threshold, and at the second hour, while I was walking down 24th
Street, there was an honest 1+.  By the third hour it was at, or just
under a ++, with the earmarks of a possibly interesting collection of
effects, were it just a bit more intense.  I had unexpected diarrhea
at hour #5, and by #6 I was mending, and by #8 I was largely down.
The day was very encouraging, and this must be re-tried at 50 or 60
milligrams.

EXTENSIONS AND COMMENTARY: This is one of the very few compounds with
which I actually risked (and took) the lives of experimental animals.
I was still impressed by the scientific myth that pharmacological
research wasnUt really acceptable without animal support data.  And I
had access to an experimental mouse colony at the University.  I
injected one mouse with a dose of 300 mg/Kg., i.p.  That sounds pretty
scientific.  But what it really means is that I picked up a mouse by
the scruff of the back with my left hand, then turned my hand over so
that the mouse was belly-up.  I put the ring finger over a hind leg to
keep things relatively immobile.  Usually at this point there is a
little urine evident where there had been none before.  And I took a
syringe equipped with a very fine needle and containing about 8
milligrams of MME in a fraction of a mL of a water solution and pushed
that needle into the mouse at about where the navel would be if one
could see the mouse's navel, and then I pulled the needle back just a
little so that there should be nothing at the business end but the
loose folds of the peritoneum.  Then I pushed the syringe plunger
home, effectively squirting the water solution into the area that
surrounds the intestines.  I dropped the mouse back into his cage, and
watched.  In this case, the mouse went into a twitching series of
convulsions (known as clonic in the trade) and in five minutes he was
dead.

Fired with the lust for killing, I grabbed another mouse, and nailed
him with 175 mg/Kg.  Dead in 6 minutes.  Another one at 107 mg/Kg.
Dead in 5 minutes.  Another at 75 mg/Kg.  Well, he looked pretty sick
there for a while, and had some shakes, and then he seemed to be
pretty much OK.  One final orgy of murder.  I injected 5 mice at 100
mg/Kg i.p., and watched four of them die within 20 minutes.  I took in
my hands the sole survivor, and I went outside the laboratory and let
him loose on the hillside.  He scampered away and I never saw him
again.

And what did I learn, at the cost of seven precious lives which I can
never replace?  Not a damned thing.  Maybe there is an LD-50 somewhere
around 60 or 80 mg/Kg.  This is for mice, not for men.  I was
intending to take an initial trial dose of 300 micrograms of this
completely untested compound, and it would have made no difference to
me if the LD-50 had been 600 mg/Kg or 6 mg/Kg.  I still took my trial
dose, and had absolutely no effects, and I never killed another mouse
again.  No, that is simply out-and-out dishonest.  I had an invasion
of field mice last winter coming up through a hole in the floor behind
the garbage holder under the kitchen sink, and I blocked the hole, but
I also set some mouse traps.  And I caught a couple.  But never again
for the simple and stupid reasons of being able to say that RThis
compound has an LD-50 in the mouse of 70 mg/Kg.S Who cares?  Why kill?

But there are two very valuable things that have come out of this
simple study with MME.  One is, of course, that it is an active
compound and as such warrants additional attention.  And the other,
and even more important, is that as one of the three possible ethoxy
homologues of TMA-2, it is less active than MEM.  The third possible
ethoxy compound is EMM and, as will be found elsewhere in this book,
it is even less active.  Thus it is MEM, only, that maintains the
potency of TMA-2, and this was the initial observation that really
focused my attention on the importance of the 4-position.

 

 

 



#137 MP; METAPROSCALINE; 3,4-DIMETHOXY-5-(n)-PROPOXYPHENETHYLAMINE

SYNTHESIS: There was mixed 96 g of 5-bromovanillin and 90 mL 25% NaOH.
The solution was almost complete, when there was a sudden deposition
of a heavy precipitate.  This was diluted with 200 mL water.  There
was then added 300 mL methylene chloride, 85 g methyl iodide, and 3 g
decyltriethylammonium chloride.  The heterogenous mixture was
vigorously stirred for 2 days.  The organic phase was separated, and
the aqueous phase extracted once with 100 mL CH2Cl2.  The organic
phase and extract were pooled, washed with water and the solvent
removed under vacuum The residue weighed 46.3 g and spontaneously
crystallized.  It was recrystallized from 40 mL of MeOH to yield 34 g
of 3-bromo-4,5-dimethoxybenzaldehyde as white crystals with a mp of
60.5-61 !C.  An additional 4 g product was obtained from the mother
liquor.  Acidification of the aqueous phase above produced, after
recrystalization from IPA/acetone, 13.2 g of recovered
5-bromo-vanillin, with a mp of 166-169 !C.

A mixture of 38.7 g 3-bromo-4,5-dimethoxybenzaldehyde and 17.2 g
cyclohexylamine was heated with an open flame at about 120 !C until it
appeared to be free of H2O.  The residue was put under a vacuum (0.2
mm/Hg) and distilled at 146-160 !C yielding 44.6 g
3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine as a clear oil which
did not crystallize.  The imine stretch in the infra-red was at 1640
cm-1.  Anal. (C15H20BrNO2) C,H.

A solution of 31.6 g 3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine
in 300 mL anhydrous Et2O was placed in an atmosphere of He, stirred
magnetically, and cooled with an dry ice/acetone bath.  Then 71 mL of
a 1.55 M solution of butyllithium in hexane was added over a 2 min
period.  The reaction mixture turned cloudy and a light precipitate
formed which seemed heaviest at the half-way point.  Stirring remained
easy and was continued for 10 min.  There was then added 35 mL of
butyl borate at one time.  The precipitate dissolved, and the stirred
solution allowed to return to room temperature.  There was then added
200 mL of an aqueous solution containing 20 g ammonium sulfate.  The
Et2O layer was separated, washed with saturated ammonium sulfate
solution, and the organic solvents removed under vacuum.  The residue
was dissolved in 250 mL of 70% MeOH and 14 mL of 30% hydrogen peroxide
added in small portions.  This reaction was very exothermic, and
stirring was continued for 1 h.  The reaction mixture was then added
to 500 mL H2O, which knocked out white solids.  A small sample of this
intermediate, N-cyclohexyl-3,4-dimethoxy-5-hydroxybenzylidineimine was
recrystallized from MeOH to a white crystal with a mp of 148-149 !C
and which showed the C=N bond as a doublet at 1635 and 1645 cm-1 in
the infra-red.  These wet solids were suspended in 200 mL 5% HCl and
heated on the steam bath for 1 h.  Stirring was continued until the
reaction was again at room temperature and then it was extracted with
2x100 mL CH2Cl2.  These extracts were pooled and in turn extracted
with 2x75 mL dilute NaOH.  The aqueous extracts were reacidified with
HCl, and reextracted with 2x100 mL CH2Cl2.  These extracts were
pooled, and the solvent removed under vacuum to yield a brown viscous
oil as a residue.  This was distilled at 105-120 !C at 0.2 mm/Hg to
yield 8.8 g of 3,4-dimethoxy-5-hydroxybenzaldehyde as a distillate
that set to white crystals.  Recrystallization from toluene/hexane
gave a sample with the mp 64-65 !C.  The literature mps are several,
ranging from at about 60 !C to about 70 !C.

A solution of 4.7 g of 3,4-dimethoxy-5-hydroxybenzaldehyde in 75 mL
acetone was treated with 6.0 g powdered KI, 16 mL (21 g) propyl
bromide, and 7.0 g finely powdered anhydrous K2CO3, and this mixture
was held at reflux on a steam bath for 15 h.  The reaction mixture was
added to 1 L H2O, made strongly basic, and extracted with 3x100 mL
CH2Cl2.  The extracts were pooled, washed with 5% NaOH, and the
solvent removed under vacuum yielding 8.8 g of a yellow oil,
undoubtedly containing propyl iodide.  This residue was distilled at
133-145 !C at 0.15 mm/Hg to yield 4.5 g of
3,4-dimethoxy-5-(n)-propoxybenzaldehyde as a white oil which did not
crystallize.  There was an appreciable pot residue.  This product was
clearly impure, having a minor, slower moving component not the
starting phenol, as seen by TLC (on silica gel, with CH2Cl2 as a
developing solvent).  Fusion of a small amount of impure aldehyde with
p-anisidine produced a crystalline anil which, on hydrolysis with
dilute acid, produced an aldehyde sample free of this impurity.  But
as this sample also remained as an oil, the above crude product was
used in the following preparation.

To a solution of 3.8 g 3,4-dimethoxy-5-(n)-propoxybenzaldehyde in 50
mL nitromethane, there was added 0.5 g anhydrous ammonium acetate.
This was held at reflux for 50 min.  The excess nitromethane was
removed under vacuum and 2 volumes of boiling MeOH were added to the
residue.  The hot solution was decanted from some residual insolubles,
and on cooling spontaneously crystallized.  These solids were removed
by filtration, washed sparingly with MeOH and air dried yielding 3.3 g
yellow crystals of 3,4-dimethoxy-'-nitro-5-(n)-propoxynitrostyrene as
yellow crystals melting at 79-81 !C.  Recrystallization from MeOH or
cyclohexane neither improved the mp nor freed the product from a
residual opalescenceseen in the melt.  Anal. (C13H17NO5) C,H.

A solution of 1.5 g LAH in 30 mL anhydrous THF under He was cooled to
0 !C and vigorously stirred.  There was added, dropwise, 1.0 mL of
100% H2SO4, followed by the dropwise addition of a solution of 2.3 g
3,4-dimethoxy-'-nitro-5-(n)-propoxynitrostyrene in 10 mL anhydrous
THF, over the course of 5 min.  The mixture was stirred at 0 !C for a
while, and then brought to a reflux on the steam bath.  After cooling
again, the excess hydride was destroyed with IPA added dropwise,
followed by the addition of about 10 mL of 10% NaOH which was
sufficient to covert the solids to a white, granular form.  These were
removed by filtration, the filter cake washed with IPA, the mother
liquor and filtrates were combined, and the solvents were removed
under vacuum to yield an amber oil.  This residue was added to 75 mL
dilute H2SO4 which produced a gummy insoluble phase which was
physically removed with a spatula.  The aqueous phase was washed with
3x50 mL CH2Cl2.  It was then made basic with 25% NaOH, and extracted
with 2x75 mL CH2Cl2.  The solvent was removed from these pooled
extracts and the residue distilled at 106-116 !C at 0.2 mm/Hg to
provide 1.3 g of the product as a colorless liquid.  This was
dissolved in 4 mL IPA, neutralized with about 20 drops of concentrated
HCl, and diluted with 4 volumes of anhydrous Et2O added slowly with
continuous stirring.  A white crystalline salt crystallized out
spontaneously and was isolated by filtration, washed first with IPA,
then with Et2O, and air dried giving 1.3 g
3,4-dimethoxy-5-(n)-propoxyphenethylamine hydrochloride (MP) with a mp
of 170-171 !C. Anal. (C13H22ClNO3) C,H.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) There might have been some
disturbance at the three to four hour point, but it was extremely
light if at all.

(with 240 mg) No effects whatsoever.

EXTENSIONS AND EXTRAPOLATIONS: The loss of activity on lengthening the
carbon chain on the meta-oxygen from two to three (from metaescaline
to metaproscaline) discouraged any further exploration at this
specific point of the molecule.  The isopropyl analog
(3,4-dimethoxy-5-(i)-propoxyphenethylamine, metaisoproscaline, MIP)
was started and carried along as far as the aldehyde, and abandoned
with the discovery that metaproscaline was without activity.  There
were other fish to fry.

 

 

 



#138 MPM; 2,5-DIMETHOXY-4-(n)-PROPOXYAMPHETAMINE

SYNTHESIS: To a solution of 68 g 2,5-dimethoxybenzaldehyde in 250 mL
glacial acetic acid that had been warmed to 25 !C and well stirred,
there was added, dropwise, 86 g of a 40% peracetic acid solution (in
acetic acid).  The reaction was exothermic, and the rate of addition
was dictated by the need to maintain the internal temperature within a
few degrees of 28 !C.  External cooling was used as needed.  The
addition took 1 h, and when the reaction had clearly been completed
(there was no further temperature rise) the entire reaction mixture
was added to 3 volumes of H2O.  The excess acid was neutralized with
solid K2CO3.  The dark solution was extracted with 3x100 mL Et2O, the
extracts pooled, and stripped of solvent under vacuum to give 59 g of
crude 2,4-dimethoxyphenyl formate.  This was suspended in 200 mL 10%
NaOH, and the mixture heated on the steam bath for 1 h.  On cooling,
the reaction mixture was washed with 2x200 mL methylene chloride,
acidified with HCl, and extracted with 3x200 mL CH2Cl2.  The extracts
were pooled and the solvent removed under vacuum.  There remained as
residue, 47.4 g 2,5-dimethoxyphenol which was deep amber in color, but
clear and fluid.  It was homogenous by GC and completely correct by
NMR.  It was used without further purification.

To a solution of 3.08 g 2,5-dimethoxyphenol in 20 g MeOH, there was
added a solution of 1.26 g flaked KOH in 20 g hot MeOH.  There was
then added 2.46 g n-propyl bromide, and the mixture held at reflux for
2 h on the steam bath.  This was quenched in 5 volumes H2O, made
strongly basic with 10% NaOH, and extracted with 3x100 mL CH2Cl2.
Removal of the solvent from the pooled extracts left 2.0 g of
1,4-dimethoxy-2-(n)-propoxybenzene as a clear, amber oil.  The IR
spectrum was appropriate, no phenol was present, and this residue was
used in the following reaction without further purification or
characterization.

A mixture of 3.5 g N-methylformanilide and 4.0 g POCl3 was held at
room temperature for 0.5 h producing a deep red color.  To this there
was added 2.0 g 1,4-dimethoxy-2-(n)-propoxybenzene, and the mixture
was held on the steam bath for 1.75 h.  It was then poured over 400 mL
shaved ice, and vigorous stirring was maintained until the dark
complex had completely broken up.  This aqueous mixture was allowed to
stand overnight, and the crude aldehyde solids that had formed were
removed by filtration, water washed, and sucked as dry as possible.
This 2.0 g damp material was crystallized from 20 mL boiling MeOH
giving, after filtering and drying to constant weight, 1.4 g
2,5-dimethoxy-4-(n)-propoxybenzaldehyde as reddish-tan solids, with a
mp of 97-98 !C.  To the methanolic mother liquors of this
crystallization there was added a gram of malononitrile and a few
drops of triethylamine.  The eventual addition of a little H2O
encouraged the separation of crystals which were removed, and had a mp
of 150-152 !C.  Recrystallization from toluene gave gold-colored
crystals of the benzalmalononitrile with a mp of 153.5-155 !C, but the
melt remained slightly cloudy.

To a solution of 1.4 g 2,5-dimethoxy-4-(n)-propoxybenzaldehyde and
0.65 g nitroethane in 4.4 g glacial acetic acid there was added 0.4 g
anhydrous ammonium acetate, and the mixture was heated on the steam
bath for 5 h.  The addition of a modest amount of H2O and scratching
with a glass rod produced crystal seed.  The reaction was diluted with
about 5 mL H2O, seeded, and allowed to stand at room temperature
overnight.  There was generated a crystalline product which was
removed by filtration and air dried.  There was thus obtained 0.6 g
1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene as yellow-orange
crystals, with a mp of 83-84 !C.  The addition of H2O to the mother
liquors provided an additional 0.3 g of an orange solid which proved
to be largely unreacted starting aldehyde.

To a stirred, warm suspension of 0.5 g LAH in 20 mL anhydrous Et2O
under a He atmosphere, there was added 0.6 g
1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene dissolved in a
little anhydrous Et2O.  The mixture was heated and stirred for a few
h, and the excess hydride decomposed with 30 mL 1.5 N H2SO4.  The two
layers were separated, and 15 g potassium sodium tartrate was
dissolved in the aqueous fraction.  Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x50 mL CH2Cl2.
Removal of the solvent under vacuum gave 0.7 g of an amber oil that
was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.
No crystals formed, and so the ether was removed under vacuum, leaving
a residue that set up to crystals that were then no longer soluble in
ether.  They were, however, very soluble in chloroform.  These were
ground under dry Et2O, removed by filtration, and air dried giving
0.35 g 2,5-dimethoxy-4-(n)-propoxyamphetamine hydrochloride (MPM) with
a mp of 123 - 125 !C.

DOSAGE: 30 mg or more.

DURATION: probably short.

QUALITATIVE COMMENTS: (with 15 mg) This is just barely threshold.  A
marginal intoxication at best.  This level is producing less response
that the 11 mg. trial of MEM, so the propoxy is off in potency.  At
four and a half hours I am out of whatever little there was.

(with 30 mg) By the mid-second hour, I am at a valid plus one.  I
cannot identify the nature Q with eyes closed it would be lost, as it
would also be if I were watching a play or movie.  It would have been
interesting to see where it could have gone.  Seventh hour, completely
clear.

EXTENSIONS AND COMMENTARY: The 4-propoxy homologue of TMA-2 and MEM is
clearly less active, and this has discouraged me from putting too much
more effort in this direction.  Three additional materials of this
pattern were prepared and either shown to be even less active, or
simply were not assayed at all.  These are the 4-isopropoxy isomer
(MIPM), the (n)-butoxy homologue (MBM), and the (n)-amyl homologue
(MAM).  They scarcely warrant separate recipes as they were all made
in a manner similar to this one describing MPM.

For the preparation of MIPM, the above phenol, 2,5-dimethoxyphenol was
isopropylated with isopropyl bromide in methanolic KOH giving
2,5-dimethoxy-1-(i)-propoxybenzene as an oil.  This formed the
benzaldehyde with the standard Vilsmeier conditions, which melted at
77-78 !C from hexane and which gave a yellow malononitrile derivative
melting at 171.5-173 !C.  The nitrostyrene, from nitroethane in acetic
acid was orange colored and melted at 100-101 !C from either methanol
or hexane.  This was reduced with lithium aluminum hydride in ether to
give 2,5-dimethoxy-4-(i)-propoxyamphetamine hydrochloride (MIPM).  The
properties of the isolated salt were strange (soluble in acetone but
not in water) and the microanalysis was low in the carbon value.  The
molecular structure had a pleasant appeal to it, with a complete
reflection symmetry shown by the atoms of the amphetamine side chain
and the isopropoxy side chain.  But the nature of the actual product
in hand had no appeal at all, and no assay was ever started.

For the preparation of MBM, the starting phenol was alkylated to
2-(n)-butoxy-1,4-dimethoxybenzene in methanolic KOH with n-butyl
bromide.  The benzaldehyde melted at 79.5-81 !C from methanol, and
formed a malononitrile derivative that had a melting point of
134.5-135 C.  The nitrostyrene from the aldehyde and nitroethane in
acetic acid crystallized from methanol with a mp of 71-72 !C.  Lithium
aluminum hydride reduction in ether gave the ether-insoluble
chloroform-soluble product 4-(n)-butoxy-2,5-dimethoxyamphetamine
hydrochloride (MBM) with a melting point of 128-130 !C.  This product
met all tests for structural integrity, and assays were started.  At
levels of up to 12.0 milligrams, there were no effects noted.

As to the preparation of MAM, the exact same sequence was used, except
for the employment of n-amyl bromide.  The benzaldehyde crystallized
from methanol with a mp of 79-80 !C, and formed a malononitrile
derivative which was bright yellow and melted at 103-104 !C.  The
nitrostyrene, when pure, melted at 57-58.5 !C but proved very
difficult to separate from the aldehyde.  The final product,
4-(n)-amyl-2,5-dimethoxyamphetamine hydrochloride (MAM) was obtained
by lithium aluminum hydride reduction in ether and melted at 125-127
!C.  It was assayed at up to 16 milligrams, at which level there was
noted a heaviness in the chest and head at the 2-hour point, but no
cardiovascular disturbance and no mydriasis.  This was called an
inactive level, and no higher one has yet been tried.

 

 

 



#139 ORTHO-DOT; 4,5-DIMETHOXY-2-METHYLTHIOAMPHETAMINE

SYNTHESIS: To 26.4 g veratrol that was being magnetically stirred
without any solvent, there was added 50 g chlorosulfonic acid a bit at
a time over the course of 20 min.  The reaction was exothermic, and
evolved considerable HCl.  The deeply colored mixture that resulted
was poured over 400 mL crushed ice and when all had thawed, it was
extracted with 2x150 mL CH2Cl2.  Removal of the solvent under vacuum
gave a residue that set up as a crystalline mass.  The weight of the
crude 3,4-dimethoxybenzenesulfonyl chloride was 37.1 g and it had a mp
of 63-66 !C.  Recrystallization raised this to 72-73 !C.  Reaction
with ammonium hydroxide gave the sulfonamide as colorless needles from
EtOH, with a mp of 132-133 !C.

The finely pulverized 3,4-dimethoxybenzenesulfonyl chloride (33 g) was
added to 900 mL of crushed ice in a 2 L round-bottomed flask equipped
with a heating mantle and reflux condenser.  There was then added 55
mL concentrated H2SO4 and, with vigorous mechanical stirring, there
was added 50 g of zinc dust in small portions.  This mixture was
heated until a vigorous reaction ensued and refluxing was continued
for 1.5 h.  After cooling to room temperature and decantation from
unreacted metallic zinc, the aqueous phase was extracted with 3x150 mL
Et2O.  The pooled extracts were washed once with saturated brine and
the solvent was removed under vacuum.  The residue was distilled to
give 20.8 g of 3,4-dimethoxythiophenol boiling at 86-88 !C at 0.4
mm/Hg.

A solution of 10 g 3,4-dimethoxythiophenol in 50 mL absolute EtOH was
protected from the air by an atmosphere of N2.  There was added a
solution of 5 g 85% KOH in 80 mL EtOH.  This was followed by the
addition of 6 mL methyl iodide, and the mixture was held at reflux for
30 min.  This was poured into 200 mL H2O and extracted with 3x50 mL
Et2O.  The pooled extracts were washed once with aqueous sodium
hydrosulfite, then the organic solvent was removed under vacuum.  The
residue was distilled to give 10.3 g of 3,4-dimethoxythioanisole with
a bp of 94-95 !C at 0.4 mm/Hg.  The product was a colorless oil that
crystallized on standing.  Its mp was 31-32 !C.

To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been
warmed briefly on the steam bath there was added 8.2 g of
3,4-dimethoxythioanisole, the exothermic reaction was heated on the
steam bath for an additional 20 min, and then poured into 200 mL H2O.
Stirring was continued until the insolubles had become completely
loose and granular.  These were removed by filtration, washed with
H2O, sucked as dry as possible, and then recrystallized from 100 mL
boiling EtOH.  The product, 4,5-dimethoxy-2-(methylthio)benzaldehyde,
was an off-white solid, weighing 8.05 g and having a mp of 112-113 !C.
Anal. (C10H12O3S) C,H.

A solution of 2.0 g 4,5-dimethoxy-2-(methylthio)benzaldehyde in 8 mL
nitroethane was treated with 0.45 g anhydrous ammonium acetate and
heated on the steam bath for 4.5 h.  Removal of the excess solvent
under vacuum gave a red residue which was dissolved in 5 mL boiling
MeOH.  There was the spontaneous formation of a crystalline product
which was recrystallized from 25 mL boiling MeOH to give, after
cooling, filtering and air drying, 1.85 g of
1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene as bright orange
crystals with a mp of 104-105 !C.  Anal. (C12H15NO4S) C,H,N.

A suspension of 1.3 g LAH in 50 mL anhydrous THF was placed under an
inert atmosphere and stirred magnetically.  When this had been brought
to reflux conditions, there was added, dropwise, 1.65 g of
1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF.  The
reaction mixture was maintained at reflux for 18 h.  After being
brought back to room temperature, the excess hydride was destroyed by
the addition of 1.3 mL H2O in 10 mL THF.  There was then added 1.3 mL
of 3N NaOH followed by an additional 3.9 mL H2O.  The loose, inorganic
salts were removed by filtration, and the filter cake washed with
additional 20 mL THF.  The combined filtrate and washes were stripped
of solvent under vacuum yielding a light yellow oil as a residue.
This was dissolved in 20 mL IPA, neutralized with 0.9 mL concentrated
HCl, and diluted with 200 mL anhydrous Et2O.  There was thus formed
1.20 g of 4,5-dimethoxy-2-methylthioamphetamine hydrochloride
(ORTHO-DOT) as a pale yellow crystalline product.  This melted at
218-219.5 !C, and recrystallization from EtOH yielded a white product
and increased the mp to 222-223 !C with decomposition Anal.
(C12H20ClNO2S) C,H,N.

DOSAGE: greater than 25 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 25 mg) Vague awareness, with the feeling
of an impending something.  Light food sat uncomfortably.  By the late
afternoon there was absolutely nothing.  Threshold at best.

EXTENSIONS AND COMMENTARY: This material, ORTHO-DOT, can be looked at
as the sulfur homologue of TMA-2 with the sulfur atom located in place
of the oxygen at the 2-position of the molecule.  At what level this
compound might show activity is completely unknown, but wherever that
might be, it is at a dosage greater than that for the PARA-DOT isomer,
ALEPH-1 (or ALEPH), which was fully active at 10 milligrams (ALEPH can
be looked at as TMA-2 with the sulfur atom located in place of the
oxygen at the 4-position of the molecule).  A lot of variations are
easily makable based on this structure, but why bother?  ALEPH is the
much more appealing candidate for structural manipulation.

 

 

 



#140 P; PROSCALINE; 3,5-DIMETHOXY-4-(n)-PROPOXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for
its synthesis), 100 mg decyltriethylammonium iodide, and 10 g n-propyl
bromide in 50 mL anhydrous acetone was treated with 6.9 g finely
powdered anhydrous K2CO3 and held at reflux for 10 h.  An additional 5
g of n-propyl bromide was added to the mixture, and the refluxing
continued for another 48 h.  The mixture was filtered, the solids
washed with acetone, and the combined filtrate and washes stripped of
solvent under vacuum.  The residue was suspended in acidified H2O, and
extracted 3x175 mL CH2Cl2.  The pooled extracts were washed with 2x50
mL 5% NaOH, once with dilute HCl (which lightened the color of the
extract) and then stripped of solvent under vacuum giving 9.0 g of a
deep yellow oil.  This was distilled at 132-142 !C at 0.3 mm/Hg to
yield 4.8 g of 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile as a
clear yellow oil.  Anal. (C13H17NO3) C H N.

A solution of 4.7 g 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile in
20 mL THF was treated with 2.4 g powdered sodium borohydride.  To this
well-stirred suspension there was added, dropwise, 1.5 mL
trifluoroacetic acid.  There was a vigorous gas evolution from the
exothermic reaction.  Stirring was continued for 1 h, then all was
poured into 300 mL H2O.  This was acidified cautiously with dilute
H2SO4, and washed with 2x75 mL CH2Cl2.  The aqueous phase was made
basic with dilute NaOH, extracted with 2x75 mL CH2Cl2, the extracts
pooled, and the solvent removed under vacuum.  The residue was
distilled at 115-125 !C at 0.3 mm/Hg to give 1.5 mL of a colorless oil
which upon dissolving in 5 mL IPA, neutralizing with 27 drops
concentrated HCl, and dilution with 25 mL anhydrous Et2O yielded 1.5 g
3,5-dimethoxy-4-(n)-propoxyphenethylamine hydrochloride (P) as
spectacular white crystals.  The catalytic hydrogenation process for
reducing the nitrile (see under E) also succeeded with this material.
The mp was 170-172 !C.  Anal. (C13H22ClNO3) C,H,N.

DOSAGE: 30 - 60 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 30 mg) Proscaline dulled my sense of pain
and made the other senses really sharp.  Everything felt really soft,
and clean and clear.  I could feel every hair my hand was touching.  I
felt so relaxed and at ease.  I know that under the appropriate
circumstances, this material would lead to uninhibited eroticism.

(with 35 mg) The whole experiment was very quiet.  There was no
nystagmus, no anorexia, and insignificant visuals with the eyes
closed.  I was restless with a bit of tremor for the first couple of
hours, and then became drowsy.  Would I do this again?  Probably not.
It doesnUt seem to offer anything except speculation about the nature
of the high.  The high was pleasant, but quite uneventful.

(with 40 mg) For me there was a deep feeling of peace and
contentment.  The euphoria grows in intensity for several hours and
remains for the rest of the day making this one of the most enjoyable
experiences I have ever had.  It was marvel-ous talking and joking
with the others.  However, I was a little disappointed that there was
no enhanced clarity and no deep realizations.  There was not a problem
to be found.  There were no motivations to discuss anything serious.
If I had any objection, it would be with the name, not the
pharmacology.

(with 60 mg) The development of the intoxication was complete in a
couple of hours.  I feel that there is more physical effect than
mental, in that there is considerable irritability.  This should
probably be the maximum dose.  Despite feeling quite drunk, my
thinking seems straight.  The effects were already waning by the fifth
hour, but sleep was not possible until after the twelth hour.  There
was no hangover the next day.

EXTENSIONS AND COMMENTARY: There is a very early report describing the
human use of proscaline tucked away in the Czechoslovakian literature
that describes experiments at up to 80 milligrams.  At these dosages,
there were reported some difficulty with dreams, and the residual
effects were still apparent even after 12 hours.

The amphetamine homologue of proscaline,
3,5-dimethoxy-4-(n)-propoxy-amphetamine is an unexplored compound.
Its synthesis could not be achieved in parallel to the description
given for P.  Rather, the propylation of syringaldehyde to give
3,5-dimethoxy-4-(n)-propoxybenzaldehyde, followed by coupling with
nitroethane and the reduction of the formed nitrostyrene with lithium
aluminum hydride would be the logical process.  Following the
reasoning given under E, the initials for this base would be 3C-P, and
I would guess it would be active, and a psychedelic, in the 20 to 40
milligram range.

 

 

 



#141 PE; PHENESCALINE; 3,5-DIMETHOXY-4-PHENETHYLOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for
its preparation) in 50 mL of acetone containing 100 mg
decyltriethylammonium iodide, there was added 14.8 g
'-phenethylbromide and 6.9 g of finely powdered anhydrous K2CO3.  The
greenish mixture was refluxed for 3 days, with two additional 4 g
batches of anhydrous K2CO3 being added at 24 h intervals.  After
addition to aqueous base, the product was extracted with CH2Cl2, the
pooled extracts were washed with dilute base (the organic phase
remained a deep purple color) and then finally with dilute HCl (the
organic phase became a pale yellow).  The solvent was removed giving
15.6 g crude 3,5-dimethoxy-4-phenethyloxyphenylacetonitrile which
distilled at 165-185 !C at 0.3 mm/Hg to yield
3,5-dimethoxy-4-phenethyloxyphenylacetonitrile as a reddish viscous
oil weighing 8.1 g.  Anal. (C18H19NO3) C,H.

A solution of 7.9 g of distilled
3,5-dimethoxy-4-phenethyloxyphenylacetonitrile in 15 mL dry THF was
added to a 0 !C solution of AH prepared from a vigorously stirred
solution of 4.6 g LAH in 160 ml THF which had been treated, at 0 !C
with 3.6 mL 100% H2SO4 under an atmosphere of He.  The gelatinaceous
reaction mixture was brought to a brief reflux on the steam bath, then
cooled again.  It was treated with 5 mL IPA which destroyed the
unreacted hydride, followed by sufficient 15% NaOH to give loose,
white filterable solids.  These were removed by filtration and washed
with THF.  The filtrate and the washes were combined and, after
removal of the solvent under vacuum, there remained 7.8 g of the
product as a crude base which crystallized spontaneously.
Distillation of this product at 170-180 !C at 0.35 mm/Hg gave 5.1 g
white solids, with a mp of 85-86 !C from hexane.  This base was
dissolved in 20 mL warm IPA and treated with 1.6 mL concentrated HCl.
To the resulting clear solution, there was added 75 mL anhydrous Et2O
which gave, after a few moments of stirring, a spontaneous
crystallization of 3,5-di-methoxy-4-phenethyloxyphenethylamine
hydrochloride (PE) as beautiful white crystals.  The weight was 5.4 g
after air drying, and the mp was 151-152 !C.  Anal. (C18H24ClNO3) C,H.

DOSAGE: greater than 150 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 150 mg) At most, there was a bare
threshold over the course of the afternoon.  A vague unreal feeling,
as if I had not had quite enough sleep last night.  By late afternoon,
even this had disappeared and I was left with an uncertainty that
anything at all had occurred.

EXTENSIONS AND COMMENTARY: There is not much there, so there is not
much to make commentary on.  This response is called a RthreshholdS
effect, and cannot be used to predict with any confidence just what
level (if any) would produce psychological effects.

A similar chain on the 4-position, but with one less carbon atom,
deserves special comment.  Rather than a phenethyloxy group, this
would be benzyloxy group (which in this day and age of Chemical
Abstracts purity should probably be called a phenylmethoxy group).  If
one were to follow the naming philosophy of Rproscaline equals P and
buscaline equals BS convention, one would call it 4-benzescaline, and
give it the code name BZ.  The nomenclature purist would probably call
the compound PM (for phenylmescaline or, more likely
phenylmethoxydimethoxyphenethylamine), since the term BZ is awkward
and misleading.  It is a code name that has been given to a potent CNS
agent known as quinuclidin-3-yl benzilate, which is a chemical and
biological warfare (CBW) incapacitating agent currently being stored
by the military to the extent of 20,000 pounds.  And, BZ has also
recently become the jargon name given to benzodiazepine receptors.
They have been called the BZ-receptors.

However, let's be awkward and misleading, and call this benzyloxy-base
BZ.  For one thing, the three-carbon analogue 3C-BZ has already been
described in its own recipe using this code.  And the 4-fluoroanalogue
of it, 3C-FBZ, is also mentioned there.  And BZ has already been
described synthetically, having been made in exactly the procedure
given for escaline, except that the reduction of the nitrile was not
done by catalytic hydrogenation but rather by sodium borohydride in
the presence of cobalt chloride.  It has been shown to be a effective
serotonin agonist, and may warrant human experimentation.  The
serotonin activity suggests that it might be active at the same levels
found for proscaline.

All of this says very little about PE.  But then, there is very little
to say about PE except that it may be active at very high levels, and
I am not sure just how to get there safely.

 

 

 



#142 PEA; PHENETHYLAMINE

SYNTHESIS: This compound has been made industrially by a number of
routes, the motant being the reduction of benzyl cyanide and the
decarboxylation of phenylanaline.  It is offered in the catalogs of
all the major chemical supply houses for a few pennies per gram.  It
is a very strong base with a fishy smell, and rapidly forms a solid
carbonate salt upon exposure to the air.  It is a natural biochemical
in both plants and animals.

DOSAGE: greater than 1600 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 200, 400, 800 and 1600 mg) No effects.

(with 500 mg) No effects.

(with 800 and 1600 mg) No effects.

(with 25 and 50 mg i.v.)  RNo effects.

EXTENSIONS AND COMMENTARY: Here is the chemical that is central to
this entire book.  This is the structural point of departure for every
compound that is discussed here.  It is the RPS in PIHKAL.  It is
without activity in man!  Certainly not for the lack of trying, as
some of the dosage trials that are tucked away in the literature (as
abstracted in the RQualitative CommentsS given above) are pretty heavy
duty.  Actually, I truly doubt that all of the experimenters used
exactly that phrase, RNo effects,S but it is patently obvious that no
effects were found.  It happened to be the phrase I had used in my own
notes.

This, the simplest of all phenethylamines, has always been the darling
of the psychopharmacologists in that it is structurally clean, it is
naturally present in various human fluids and tissues, and because of
its close chemical relationship to amphetamine and to the
neurotransmitters.  These facts continuously encourage theories that
involve PEA in mental illness.  Its levels in urine may be decreased
in people diagnosed as being depressed.  Its levels may be increased
in people diagnosed as being paranoid schizophrenics.  Maybe it is
also increased in people under extreme stress.  The human trials were
initially an attempt to provoke some psychological change, and indeed
some clinicians have reported intense headaches generated in
depressives following PEA administration.  But then, others have seen
nothing.  The studies evolved into searches for metabolic difference
that might be of some diagnostic value.  And even here, the jury is
still out.

Phenethylamine is found throughout nature, in both plants and animals.
It is the end product of phenylalanine in the putrefaction of tissue.
One of its most popularized occurrences has been as a major component
of chocolate, and it has hit the Sunday Supplements as the
love-sickness chemical.  Those falling out of love are compulsive
chocolate eaters, trying to replenish and repair the body's loss of
this compound Q or so the myth goes.  But this amine is voraciously
metabolized to the apparently inactive compound phenylacetic acid, and
to some tyramine as well.  Both of these products are also normal
components in the body.  And, as a wry side-comment, phenylacetic acid
is a major precursor in the illicit synthesis of amphetamine and
methamphetamine.

Phenethylamine is intrinsically a stimulant, although it doesnUt last
long enough to express this property.  In other words, it is rapidly
and completely destroyed in the human body.  It is only when a number
of substituent groups are placed here or there on the molecule that
this metabolic fate is avoided and pharmacological activity becomes
apparent.

	To a large measure, this book has emphasized the RphenylS end
of the phenethylamine molecule, and the Rwhat,S the where,S and the
Rhow manyS of the substituent groups involved.  There is a broad
variety of chemical groups that can be attached to the benzene ring,
at one or more of the five available positions, and in an unending
number of combinations.  And, in any given molecule, the greater the
number of substituents on the benzene ring, the greater the likelihood
that there will be psychedelic action rather that stimulant action.

	But what can be said about the RethylamineS end of the
phenethylamine molecule?  This is the veritable backbone that holds
everything together, and simple changes here can produce new
prototypes that can serve as starting points for the substituent game
on the benzene ring.  Thus, just as there is a RfamilyS of compounds
based on the foundation of phenethylamine itself, there is an equally
varied and rich RfamiliesS of other compounds that might be based on
some phenethylamine with a small modification to its backbone.

	So, for the moment, leave the aromatic ring alone, and let us
explore simple changes in the ethylamine chain itself.  And the
simplest structural unit of change is a single carbon atom, called the
methyl group.  Where can it be placed?

The adding of a methyl group adjacent to the amine produces
phenylisopropylamine, or amphetamine.  This has been exploited already
as one of the richest families of psychedelic drugs; and over half of
the recipes in Book II are specifically for amphetamine analogues with
various substituents on the aromatic ring.  The further methylation of
amphetamine with yet another methyl group, this time on the nitrogen
atom, yields methamphetamine.  Here the track record with various
substituents on the aromatic ring is not nearly as good.  Many have
been explored and, with one exception, the quality and potency of
human activity is down.  But the one exception, the N-methyl analogue
of MDA, proved to be the most remarkable MDMA.

The placement of the methyl group between the two carbons (so to
speak) produces a cyclopropyl system.  The simplest example is
2-phenylcyclopropylamine, a drug with the generic name of
tranylcypromine and the trade name Parnate.  It is a mono-amine
oxidase inhibitor and has been marketed as an antidepressant, but the
compound is also a mild stimulant causing insomnia, restlessness and
photophobia.  Substitutions on the benzene ring of this system have
not been too promising.  The DOM analogue,
2,5-dimethoxy-4-methyltranylcypromine is active in man, and is
discussed in its own recipe under DMCPA.  The inactive mescaline
analogue TMT is also mentioned there.

The dropping of one carbon from the phenethylamine chain gives a
benzyl amine, basically an inactive nucleus.  Two families deserve
mention, however.  The phencylidine area, phenylcyclohexylpiperidine
or PCP, is represented by a number of benzyl amines.  Ketamine is also
a benzyl amine.  These are all analgesics and anesthetics with central
properties far removed from the stimulant area, and are not really
part of this book.  There is a benzyl amine that is a pure stimulant,
which has been closely compared to amphetamine in its action This is
benzylpiperazine, a base that is active in the 20 to 100 milligram
range, but which has an acceptability similar to amphetamine.  If this
is a valid stimulant, I think that much magic might be found in and
around compounds such as (1) the MDMA analogue,
N-(3,4-methylenedioxybenzyl)piperazine (or its N-methyl-counterpart
N-(3,4-methylenedioxybenzyl)-NU-methylpiperazine) or (2) the DOM
analogue, 2,5-dimethoxy-4-methylbenzylpiperazine.  The benzyl amine
that results by the relocation of the amine group of MDA from the
beta-carbon atom to the alpha-carbon atom is known, and is active.
It, and its N-methyl homologue, are described and discussed in the
commentary under MDA.  Dropping another carbon atom gives a yet
shorter chain (no carbons at all!) and this is to be found in the
phenylpiperazine analogue 3-trifluoromethylphenylpiperazine.  I have
been told that this base is an active hallucinogen as the
dihydrobromide salt at 50 milligrams sublingually, or at 15 milligrams
intravenously in man.  The corresponding 3-chloro analogue at 20 to 40
milligrams orally in man or at 8 milligrams intravenously, led to
panic attacks in some 10% of the experimental subjects, but not to any
observed psychedelic or stimulant responses.

What happens if you extend the chain to a third carbon?  The parent
system is called the phenyl-(n)-propylamine, and the parent chain
structure, either as the primary amine or as its alpha-methyl
counterpart, represents compounds that are inactive as stimulants.
The DOM-analogues have been made and are, at least in the rabbit
rectal hyperthermia assay, uninteresting.  A commercially available
fine chemical known as piperonylacetone has been offered as either of
two materials.  One, correctly called 3,4-methylenedioxyphenylacetone
or 3,4-methylenedioxybenzyl methyl ketone, gives rise upon reductive
amination to MDA (using ammonia) or MDMA (using methylamine).  This is
an aromatic compound with a three-carbon side-chain and the
amine-nitrogen on the beta-carbon.  The other so-called
piperonylacetone is really 3,4-methylenedioxybenzylacetone, an
aromatic compound with a four-carbon side-chain.  It produces, on
reductive amination with ammonia or methylamine, the corresponding
alpha-methyl-(n)-propylamines, with a four-carbon side-chain and the
amine-nitrogen on the gamma-carbon.  They are completely unexplored in
man and so it is not known whether they are or are not psychedelic.
As possible mis-synthesized products, they may appear quite
unintentionally and must be evaluated as totally new materials.  The
gamma-amine analogue of MDA, a methylenedioxy substituted three carbon
side-chain with the amine-nitrogen on the gamma carbon, has indeed
been made and evaluated, and is discussed under MDA.  The extension of
the chain of mescaline to three atoms, by the inclusion of an oxygen
atom, has produced two compounds that have also been assayed.  They
are mentioned in the recipe for mescaline.

The chain that reaches out to the amine group can be tied back in
again to the ring, with a second chain.  There are 2-aminobenzoindanes
which are phenethylamines with a one-carbon link tying the
alpha-position of the chain back to the aromatic ring.  And there are
2-aminotetralines which are phenethylamines which have a two-carbon
link tying the alpha-position of the chain back to the aromatic ring.
Both unsubstituted ring systems are known and both are fair
stimulants.  Both systems have been modified with the DOM substituent
patterns (called DOM-AI and DOM-AT respectively), but neither of these
has been tried in man.  And the analogues with the MDA substitution
pattern are discussed elsewhere in this book.

And there is one more obvious remaining methylation pattern.  What
about phenethylamine or amphetamine compounds with two methyl groups
on the nitrogen?  The parent amphetamine example,
N,N-dimethylamphetamine, has received much notoriety lately in that it
has become a scheduled drug in the United States.  Ephedrine is a
major precursor in the illicit synthesis of methamphetamine, and with
the increased law-enforcement attention being paid to this process,
there has been increasing promotion of the unrestricted homologue,
N-methylephedrine, to the methamphetamine chemist.  This starting
material gives rise to N,N-dimethylamphetamine which is a material of
dubious stimulant properties.  A number of N,N-dimethylamphetamine
derivatives, with RpsychedelicS ring substituents, have been explored
as iodinated brain-flow indicators, and they are explicitly named
within the appropriate recipes.  But none of them have shown any
psychedelic action.

This is as good a place as any to discuss two or three simple
compounds, phenethylamines, with only one substituent on the benzene
ring.  The 2-carbon analog of 4-MA, is 4-methoxyphenethylamine, or
MPEA.  This is a kissing cousin to DMPEA, of such fame in the search
for a urine factor that could be related to schizophrenia.  And the
end results of the search for this compound in the urine of mentally
ill patients are as controversial as they were for DMPEA.  There has
been no confirmed relationship to the diagnosis.  And efforts to see
if it is centrally active were failures Q at dosages of up to 400
milligrams in man, there was no activity.  The 4-chloro-analogue is
4-chlorophenethylamine (4-Cl-PEA) and it has actually been pushed up
to even higher levels (to 500 milligrams dosage, orally) and it is
also without activity.  A passing bit of charming trivia.  A
positional isomer of MPEA is 3-methoxyphenethylamine (3-MPEA) and,
although there are no reported human trials with this, it has been
graced with an Edgewood Arsenal code number, vis., EA-1302.

 

 

 



#143 PROPYNYL; 3,5-DIMETHOXY-4-(2-PROPYNYLOXY)PHENETHYLAMINE

SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for
its preparation) in 50 mL acetone containing 100 mg
decyltriethylammonium iodide, there was added 12 g of an 80% solution
of propargyl bromide in toluene and 6.9 g of finely powdered anhydrous
K2CO3.  This mixture was held at reflux on the steam bath for 12 h,
after which the solvent was removed under vacuum.  The residues were
added to 0.5 L H2O, acidified, and extracted with 3x75 mL CH2Cl2.  The
extracts were pooled, washed with 5% NaOH, and then with dilute HCl
which discharged the deep color.  Removal of the organic solvent under
vacuum yielded 6.6 g of crude product.  This was distilled at 138-148
!C at 0.25 mm/Hg, yielding 4.3 g
3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile which spontaneously
crystallized.  A small sample from MeOH had a mp of 94-95 !C. Anal.
(C13H13NO3) C,H.

A suspension of 2.8 g LAH in 70 mL anhydrous THF was cooled to 0 !C
with good stirring under He, and treated with 2.0 g 100% H2SO4.  To
this, a solution of 4.2 g
3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile in 30 mL anhydrous
THF was added very slowly.  After the addition had been completed, the
reaction mixture was held at reflux on the steam bath for 0.5 h,
cooled to room temperature, treated with IPA to decompose the excess
hydride, and finally with 15% NaOH to convert the solids to a white
filterable mass.  The solids were separated by filtration, the filter
cake was washed with THF, and the filtrate and washes were pooled.
After removal of the solvent, the residue was added to 100 mL dilute
H2SO4, and washed with 3x75 mL CH2Cl2.  The aqueous phase was made
basic with dilute NaOH, and the product extracted with 2x75 mL CH2Cl2.
After removal of the solvent under vacuum, the residue was distilled
at 125-155 !C at 0.3 mm/Hg to provide 2.4 g of a light amber viscous
liquid.  This was dissolved in 10 mL IPA, acidified with concentrated
HCl until a droplet produced a red color on dampened, external
universal pH paper, and then diluted with 40 mL anhydrous Et2O with
good stirring.  After a short delay,
3,5-dimethoxy-4-(2-propynyloxy)phenethylamine hydrochloride (PROPYNYL)
spontaneously crystallized.  The product was removed by filtration,
washed first with an IPA/Et2O mixture, and finally with Et2O.  The
yield was 3.0 g of white needles.

DOSAGE: 80 mg or more.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 55 mg) I have cold feet Q literally Q I
donUt mean that in the spiritual or adventurous sense.  But also I am
somewhat physically fuzzy.  I feel that if I were in public my
behavior would be such that someone would notice me.  Everything was
OK without any question at the ninth hour.  I could walk abroad
again.

(with 80 mg) There is a body load.  The flow of people around me all
day has demanded my attention, and when I had purposefully retreated
to be by myself, there was no particular reward as to visuals or
anything with eyes closed, either.  Sleep was easy at midnight (the
twelth hour of the experiment) but the morning was sluggish, and on
recalling the day, I am not sure of the events that had taken place.
Higher might be all right, but watch the status of the body.  There
certainly wasnUt that much mental stuff.

EXTENSIONS AND COMMENTARY: No experiments have been performed that
describe the action of this drug at full level.  This compound does
not seem to have the magic that would encourage exploration at higher
levels.

 

 

 



#144 SB; SYMBESCALINE; 3,5-DIETHOXY-4-METHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 15 g 1,3-diethoxybenzene and 15 mL of
N,N,NU,NU-tetramethylethylenediamine in 200 mL anhydrous Et2O was
placed in a He atmosphere, magnetically stirred, and cooled to 0 !C
with an ice bath.  Over the course of 10 min there was added 63 mL of
a 1.6 M solution of butyllithium in hexane, which produced a fine
white precipitate.  After an additional 15 min stirring, 20 mL of
tributyl borate was added which dissolved the precipitate.  The
stirring was continued for an additional 15 min.  The reaction was
quenched by the addition of 50 mL of a concentrated aqueous solution
of ammonium sulfate.  The resulting Rcottage cheeseS mass was
transferred to a beaker, treated with an additional 300 mL of the
ammonium sulfate solution, and allowed to stir until the solids had
dispersed to a fine texture.  The organic phase was separated and the
aqueous phase extracted with 2x100 mL Et2O.  The organic phases were
combined, evaporated under vacuum, and the off-white residue dissolved
in 100 mL MeOH.  This cloudy solution was cooled (ice bath) and, with
stirring, 20 mL of 35% hydrogen peroxide was added portionwise, .  The
reaction was allowed to continue stirring for 15 min, and then with
the addition of 600 mL H2O, crystalline solids were formed.  These
were removed, washed with H2O, and upon drying yielded 15.4 g of
2,6-diethoxyphenol with a mp of 79.5-81.5 !C.  Efforts to diethylate
pyrogallol produced mixtures of 2,6-diethoxyphenol and the isomer,
2,3-diethoxyphenol, and these proved difficult to separate.  The pure
2,3-isomer was synthesized from ortho-diethoxybenzene by the process
used above, and the product was an oil.  Both phenols yielded
crystalline 3,5-dinitrobenzoates.  This derivative of
2,6-diethoxyphenol, upon recrystallization from CH3CN had a mp of
161-162 !C.  The derivative from 2,3-diethoxyphenol, also upon
recrystallization from CH3CN, melted at 167-168 !C.  The mixed mp was
appropriately depressed (mp 137-140 !C.).

A solution of 7.6 g 2,6-diethoxyphenol in 40 mL MeOH was treated with
4.9 g of a 40% aqueous solution of dimethylamine followed by 3.6 g of
a 40% aqueous solution of formaldehyde.  The mixture was heated 1 h on
the steam bath, and all volatiles were removed under vacuum.  The
residual dark oil was dissolved in 36 mL IPA and 10.3 g of methyl
iodide was added.  There was spontaneous heating, and the deposition
of fine white solids.  After standing for 10 min, these were removed
by filtration, and the filter cake washed with more IPA.  The crude
product was freed from solvent (air dried weight, 1.7 g) and dissolved
in 7 mL hot H2O.  To this hot solution there was added 1.7 g sodium
cyanide which slowly discharged the color and again deposited
flocculant white solids.  After cooling, these were removed by
filtration, washed with H2O, and after thorough drying the isolated
3,5-diethoxy-4-hydroxyphenylacetonitrile weighed 0.5 g and had a mp of
107.5-108.5 !C.  Anal. (C12H15NO3) C,H.

To a solution of 2.1 g 3,5-diethoxy-4-hydroxyphenylacetonitrile in 20
mL anhydrous acetone, there was added 30 mg triethyldecylammonium
iodide, 4.6 g methyl iodide, and finally 2.3 g powdered anhydrous
K2CO3.  This mixture was held at reflux for 5 h.  The reaction mixture
was quenched with 200 mL acidified H2O and extracted with 3x75 mL
CH2Cl2.  The extracts were pooled, washed with 2x75 mL 5% NaOH, and
finally once with dilute HCl. The solvent was removed under vacuum,
and the residue distilled at 110-115 !C at 0.3 mm/Hg to provide
3,5-diethoxy-4-methoxyphenylacetonitrile as a solid.  This weighed 1.3
g and had a mp of 58-59 !C.  Anal. (C13H17NO3) C,H.

To 30 mL of a 1 M solution LAH in THF that had been cooled to 0 !C
with vigorous stirring, under a He atmosphere, there was added
dropwise 0.78 mL of 100% H2SO4.  When the addition was complete, there
was added dropwise a solution of 1.3 g of
3,5-diethoxy-4-methoxyphenylacetonitrile in 10 mL anhydrous THF.  The
reaction mixture was brought to room temperature and stirred an
additional 10 min, then refluxed on a steam bath for 1.5 h.  After
cooling to room temperature the excess hydride was destroyed by the
addition of about 2 mL IPA, followed by sufficient 15% NaOH to make
the reaction basic to external pH paper and to render the aluminum
oxides white and filterable.  These were removed by filtration, the
filter cake was washed with IPA, then the filtrate and washes were
combined.  The solvents were removed under vacuum and the residue
dissolved in dilute H2SO4.  This was washed with 2x75 mL CH2Cl2, the
aqueous phase made basic with 5% NaOH, and extracted with 3x75 mL
CH2Cl2.  The extracts were pooled, the solvent removed under vacuum,
and the residue distilled at 120-140 !C at 0.3 mm/Hg to yield 0.9 g of
a white oil.  This was dissolved in 4 mL of IPA and neutralized with
concentrated HCl to an end-point determined by damp external pH paper.
There was the immediate formation of solids which were removed by
filtration and washed first with IPA and then with Et2O.  This
provided 1.0 g of 3,5-diethoxy-4-methoxyphenethylamine hydrochloride
(SB) as white crystals, with a mp of 186-187 !C.  Anal. (C13H22ClNO3)
C,H.

DOSAGE: above 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 120 mg) There were no effects.  Sleep
that evening was strange, however, and I was fully awake at 4:00 AM,
alert, and mentally restless.  And there was a strange outburst of
anger in the mid-morning.  Might these be related to the material the
previous day?S

(with 240 mg) There was a slight chill that reminded me that I had
taken symbescaline a half hour earlier.  There was what might be
called a vague threshold for about three hours, then nothing more.
This material had a God-awful taste that lingers in the mouth far too
long.  If ever again, it will be in a gelatin capsule.

EXTENSIONS AND COMMENTARY: It must be concluded that SB is RprobablyS
not active.  There was no convincing evidence for much effect at
levels that would clearly be active for mescaline.  This is the kind
of result that puts some potentially ambiguous numbers in the
literature.  One cannot say that it is inactive, for there might well
be something at 400 or 800 or 1200 milligrams.  But since it has been
tried only up to 240 milligrams, I have used the phrase that the
activity is greater than 240 milligrams.  This will be interpreted by
some people as saying that it is active, but only at dosages higher
than 240 milligrams.  What is meant, is that there was no activity
observed at the highest level tried, and so if it is active, the
active dose will be greater than 240 milligrams, and so the potency
will be less than that of mescaline.  However you phrase it, someone
will misinterpret it.

 

 

 



#145 TA; 2,3,4,5-TETRAMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 50 g 2,3,4-trimethoxybenzaldehyde in 157
mL glacial acetic acid which was well stirred and preheated to 25 !C
there was added 55.6 g 40% peracetic acid in acetic acid.  The rate of
addition was adjusted to allow the evolved heat of the exothermic
reaction to be removed by an external ice bath at a rate that kept the
internal temperature within a degree of 25 !C.  When the addition was
complete and there was no more heat being evolved, the reaction
mixture was diluted with 3 volumes of H2O, and neutralized with solid
K2CO3.  All was extracted with 3x250 mL Et2O, and the removal of the
solvent from the pooled extracts under vacuum gave 42 g of residue
that appeared to be mainly phenol, with a little formate and aldehyde.
This was dissolved in 200 mL of 10% NaOH, allowed to stand for 2 h at
ambient temperature, washed with 2x75 mL CH2Cl2, acidified with HCl,
and extracted with 3x100 mL Et2O.  The pooled extracts were washed
with saturated NaHCO3, and the solvent removed to give 34.7 g of
2,3,4-trimethoxyphenol as an amber oil which was used without further
purification.  The infra-red spectrum showed no carbonyl group, of
either the formate or the starting aldehyde.

A solution of 11.4 g flaked KOH in 100 g EtOH was treated with 33.3 g
2,3,4-trimethoxyphenol and 21.9 g allyl bromide.  The mixture was held
at reflux for 1.5 h, then poured into 5 volumes of H2O, made basic
with the addition of 25% NaOH, and extracted with 3x200 mL CH2Cl2.
Removal of the solvent from the pooled extracts gave about 40 g of a
crude 2,3,4-trimethoxy-1-allyloxybenzene that clearly had unreacted
allyl bromide as a contaminant.

A 39 g sample of crude 2,3,4-trimethoxy-1-allyloxybenzene in a
round-bottomed flask with an immersion thermometer was heated with a
soft flame.  At 225 !C there was a light effervescence and at 240 !C
an exothermic reaction set in that raised the temperature immediately
to 265 !C.  It was held there for 5 min, and then the reaction was
allowed to cool to room temperature.  GC and IR analysis showed the
starting ether to be gone, and that the product was largely
2,3,4-trimethoxy-6-allylphenol.  It weighed 34.4 g.

To a solution of 9.4 g KOH in 100 mL MeOH, there was added 33.3 g of
2,3,4-trimethoxy-6-allylphenol and 21.2 g methyl iodide and the
mixture was held on the steam bath for 2 h.  This was poured into
aqueous base, and extracted with 3x100 mL CH2Cl2.  Removal of the
solvent from the pooled extracts gave 30 g of an amber oil residue
that was distilled at 100-125 !C at 0.5 mm/Hg to provide 23.3 g of
nearly colorless 2,3,4,5-tetramethoxyallylbenzene.

The total distillation fraction, 23.3 g
2,3,4,5-tetramethoxyallylbenzene, was dissolved in a solution of 25 g
flaked KOH in 25 mL EtOH and heated at 100 !C for 24 h.  The reaction
mixture was poured into 500 mL H2O, and extracted with 2x100 mL
CH2Cl2.  The aqueous phase was saved.  The pooled organic extracts
were stripped of solvent under vacuum to give 13.8 g of a fluid oil
that was surprising pure 2,3,4,5-tetramethoxypropenylbenzene by both
GC and NMR analysis.  The basic aqueous phase was acidified, extracted
with 2x100 mL CH2Cl2, and the solvent stripped to give 7.5 g of an oil
that was phenolic, totally propenyl (as opposed to allyl), and by
infra-red the phenolic hydroxyl group was adjacent to the olefin
chain.  This crude 2-hydroxy-3,4,5-trimethoxypropenylbenzene was
methylated with methyl iodide in alcoholic KOH to give an additional
5.6 g of the target 2,3,4,5-tetramethoxypropenylbenzene.  This was
identical to the original isolate above.  The distilled material had
an index of refraction, nD24 = 1.5409.

A well stirred solution of 17.9 g 2,3,4,5-tetramethoxypropenylbenzene
in 80 mL distilled acetone was treated with 6.9 g pyridine, and cooled
to 0 !C with an external ice bath.  There was then added 14 g
tetranitromethane over the course of a 0.5 min, and the reaction was
quenched by the addition of a solution of 4.6 g KOH in 80 mL H2O.  As
the reaction mixture stood, there was a slow deposition of yellow
crystals, but beware, this is not the product.  This solid weighed 4.0
g and was the potassium salt of trinitromethane.  This isolate was
dried and sealed in a small vial.  After a few days standing, it
detonated spontaneously.  The filtrate was extracted with 3x75 mL
CH2Cl2, and the removal of the solvent from these extracts gave a
residue of 20.8 g of crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene which did not
crystallize.

A solution was made of 20.3 g of the crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene in 200 mL anhydrous
Et2O, and this was filtered to remove some 2.7 g of insoluble material
which appeared to be the potassium salt of trinitromethane by
infra-red analysis.  A suspension of 14 g LAH in 1 L anhydrous Et2O
was stirred, placed under an inert atmosphere, and brought up to a
gentle reflux.  The above clarified ether solution of the propene was
added over the course of 1 h, and the mixture was held at reflux for
24 h.  After cooling, the excess hydride was destroyed by the cautious
addition of 1 L 1.5 N H2SO4 (initially a drop or two at a time) and
when the two phases were complete clear, they were separated.  The
aqueous phase was treated with 350 g potassium sodium tartrate, and
brought to a pH >9 with base.  This was extracted with 3x150 mL
CH2Cl2, and the removal of the solvent from the pooled extracts gave a
residue that was dissolved in 200 mL anhydrous Et2O, and saturated
with anhydrous HCl gas.  An Et2O-insoluble oil was deposited and,
after repeated scratching with fresh Et2O, finally gave a granular
white solid.  This product was recrystallized from acetic anhydride,
giving white crystals that were removed by filtration, Et2O washed,
and air dried.  The yield of 2,3,4,5-tetramethoxyamphetamine
hydrochloride (TA) was 1.9 g and had a mp of 135.5-136.5 !C.

DOSAGE: probably above 50 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 30 mg) Definite threshold.  There was eye
dilation, and some unusual humor Q a completely wild day with
chi-square calculations on the PDP-7 that were on the edge of bad
taste.  But I was definitely baseline in the afternoon during the
Motor Vehicle Department interactions.

(with 35 mg) I had some gastric upset, but nonetheless there was a
distinct intoxication.  The next morning I had a foul headache.

EXTENSIONS AND COMMENTARY: This is pretty thin stuff from which to go
out into a world that is populated by pharmacological sharks and stake
out claims as to psychedelic potency.  The structure of this molecule
has everything going for it.  It is an overlay of TMA (active) and
TMA-2 (even more active) so it is completely reasonable that it should
be doing something at a rational dosage.  But that dosage might well
be in the many tens of milligrams.

Tens of milligrams.  Now there is a truly wishy-washy phrase.  There
is an art to the assignment of an exact number or, as is sometimes
desperately needed, a fuzzy number, to a collection of things.  In my
youth (somewhere way back yonder in the early part of the century) I
had been taught rules of grammer that were unquestionably expected of
any well-educated person.  If you used a Latin stem, you used a Latin
prefix.  And if you used a Greek stem, you used a Greek prefix.
Consider a collection of things with simple geometric sides (a side is
a latus in Latin).  One would speak of a one-sided object as being
unilateral, and a bilateral object has two sides.  A trilateral, and
quadrilateral, and way up there to multilateral objects, are referred
to as having three or four or a lot of sides, respectively.  Just the
opposite occurs with geometric objects with faces.  A face is a hedra
in Greek, so one really should use the Greek structure.  If one has
just one face, one has a monohedron, a dihedron has two faces, and
there are trihedron, tetrahedron, and polyhedron for things that have
three, four, or a lot of faces.  Actually, the prefix RpolyS swings
both ways.  It was initially a Greek term, but as was the fate of many
Greek words, it wandered its way from East to West, and ended up as a
Latin term as well.

But back to the problem of how to refer to something that is more than
one or two, but not as much as a lot?  If you know exactly how many,
you should use the proper prefix.  But what if you donUt know how
many?  There are terms such as Rsome.S And there is Rseveral.S There
is a RfewS and a Rnumber ofS and RnumerousS and Ra hand full.S One
desperately looks for a term that is a collective, but which carries
the meaning of an undefined number.  There are English gems such as a
pride of lions and a host of daffodils.  But without a specific animal
or plant of reference, one must have a target collective that is
appropriate, to let the term RmanyS or RfewS imply the proper size.
There were many hundreds of persons (a few thousands of persons) at
the rally.  Several dozen hunters (a few score hunters) were gathered
at the lake.  A wonderful prefix is RoligoS which means a few, not a
lot, and it means that I am not sure just how many are meant.  Say,
for example, that you have synthesized something in a biochemical
mixture that contains three or four peptides.  Di-and tri- and
tetrapeptides are exact terms, but they do not describe what you have
done.  Polypeptide is way too big.  However, an oligopeptide means
that there are a few peptide units, IUm not sure how many.  This may
well be the most accurate description of just what you have.

I love the British modesty that is shown by hiding a person's physical
weight by referring to it with the dimension known as the stone.  This
is, as I remember, something like 14 pounds.  So, if stones were the
weight equivalent of 10 milligrams, the activity of TA would be
several stone.  And since the synthetic intermediate
1-allyl-2,3,4,5-tetramethoxybenzene is one of the ten essential oils,
the amination step from our hypothetical reaction in the human liver
would make TA one of the so-called Ten Essential Amphetamines.

 

 

 



#146 3-TASB; 3-THIOASYMBESCALINE;
4-ETHOXY-3-ETHYLTHIO-5-METHOXYPHENETHYLAMINE

SYNTHESIS: Without any solvent, there was combined 21.7 g of solid
5-bromovanillin and 11.4 mL cyclohexylamine.  There was the immediate
generation of a yellow color and the evolution of heat.  The largely
solid mass was ground up under 50 mL of boiling IPA to an apparently
homogeneous yellow solid which was removed by filtration and washed
with IPA.  There was thus obtained about 27 g of
3-bromo-N-cyclohexyl-4-hydroxy-5-methoxybenzylidenimine with a mp of
229-231 !C and which proved to be insoluble in most solvents (EtOH,
CH2Cl2, acetone).  A solution in dilute NaOH was unstable with the
immediate deposition of opalescent white solids of the phenol sodium
salt.  A small scale recrystallization from boiling cyclohexanone
yielded a fine yellow solid with a lowered mp (210-215 !C).  Anal.
(C14H18BrNO2) C,H.

A solution of 32.5 g
3-bromo-N-cyclohexyl-4-hydroxy-5-methoxybenzylidenimine in 60 mL of
hot DMF was cooled to near room temperature, treated with 24.5 g ethyl
iodide and followed by 14.0 g of flake KOH.  This mixture was held at
reflux for 1 h, cooled, and added to 1 L H2O.  Additional base was
added and the product was extracted with 3x150 mL CH2Cl2.  These
pooled extracts were washed with dilute NaOH, then with H2O, and
finally the solvent was removed under vacuum.  The crude amber-colored
residue was distilled.  The fraction coming over at 118-135 !C at 0.4
mm/Hg weighed 8.7 g, spontaneously crystallized, and proved to be
3-bromo-4-ethoxy-5-methoxybenzaldehyde, melting at 59-60 !C after
recrystallization from MeOH.  Anal. (C10H11BrO3) C,H.  The fraction
that came over at 135-155 !C at 0.2 mm/Hg weighed 10.5 g and also
solidified in the receiver.  This product was
3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine which, upon
recrystallization from two volumes MeOH, was a white crystalline
material with a mp of 60-61 !C.  Anal. (C16H22BrNO2) C,H.  The two
materials have identical mps, but can be easily distinguished by their
infra-red spectra.  The aldehyde has a carbonyl stretch at 1692 cm-1,
and the Schiff base a C=N stretch at 1641 cm-1.

A solution of 20.5 g
3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine in about 300 mL
anhydrous Et2O was placed in a He atmosphere, well stirred, and cooled
in an external dry ice acetone bath to -80 !C.  There was then added
50 mL of 1.6 N butyllithium in hexane.  The mixture became yellow and
very viscous with the generation of solids.  These loosened up with
continuing stirring.  This was followed by the addition of 10.7 g
diethyldisulfide.  The reaction became extremely viscous again, and
stirring was continued while the reaction was allowed to warm to room
temperature.  After an additional 0.5 h stirring, the reaction mixture
was added to 800 mL of dilute HCl.  The Et2O phase was separated and
the solvent removed under vacuum.  The residue was returned to the
original aqueous phase, and the entire mixture heated on the steam
bath for 2 h.  The bright yellow color faded and there was the
formation of a yellowish phase on the surface of the H2O.  The aqueous
solution was cooled to room temperature, extracted with 3x100 mL
CH2Cl2, the extracts pooled, washed first with dilute HCl, then with
saturated brine, and the solvent removed under vacuum.  The residue
was an amber oil weighing 20.4 g, and was distilled at 130-140 !C at
0.3 mm/Hg to yield 12.9 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde as a straw colored oil that
did not crystallize.  Anal. (C12H16O3S) C,H.

A solution of 1.0 g 4-ethoxy-3-ethylthio-5-methoxybenzaldehyde in 20 g
nitromethane was treated with about 0.2 g of anhydrous ammonium
acetate and heated on the steam bath.  TLC analysis showed that the
aldehyde was substantially gone within 20 min and that, in addition to
the expected nitrostyrene, there were four scrudge products (see the
discussion of scrudge in the extensions and commentary section under
3-TSB).  Removal of the excess nitromethane under vacuum gave an
orange oil which was diluted with 5 mL cold MeOH but which could not
be induced to crystallize.  A seed was obtained by using a preparative
TLC plate (20x20 cm) and removing the fastest moving spot (development
was with CH2Cl2).  Placing this in the above MeOH solution of the
crude nitrostyrene allowed crystallization to occur.  After filtering
and washing with MeOH, 0.20 g of fine yellow crystals were obtained
which melted at 75-77 !C.  Recrystallization from MeOH gave a bad
recovery of yellow crystals of
4-ethoxy-3-ethylthio-5-methoxy-'-nitrostyrene that now melted at
78.5-79 !C.  Anal. (C13H17NO4S) C,H.  This route was discarded in
favor of the Wittig reaction described below.

A mixture of 27 g methyltriphenylphosphonium bromide in 150 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled to 0 !C with an external ice water bath.  There was then slowly
added 50 mL of 1.6 N butyllithium in hexane which resulted in the
initial generation of solids that largely redissolved by the
completion of the addition of the butyllithium and after allowing the
mixture to return to room temperature.  There was then added 11.7 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde without any solvent.  There
was the immediate formation of an unstirrable solid, which partially
broke up into a gum that still wouldnUt stir.  This was moved about,
as well as possible, with a glass rod, and then all was added to 400
mL H2O.  The two phases were separated and the lower, aqueous, phase
extracted with 2x75 mL of petroleum ether.  The organic fractions were
combined and the solvents removed under vacuum to give the crude
4-ethoxy-3-ethylthio-5-methoxystyrene as a pale yellow fluid liquid.

A solution of 10 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 75 mL THF was placed in a He atmosphere, cooled to
0 !C, treated with 21 mL of 2-methylbutene, and stirred for 1 h while
returning to room temperature.  This was added directly to the crude
4-ethoxy-3-ethylthio-5-methoxystyrene.  The slightly exothermic
reaction was allowed to stir for 1 h, and then the excess borane was
destroyed with a few mL of MeOH (in the absence of air to avoid the
formation of the dialkylboric acid).  There was then added 19 g of
elemental iodine followed, over the course of about 10 min, by a
solution of 4 g NaOH in 50 mL hot MeOH.  The color did not fade.
Addition of another 4 mL 25% NaOH lightened the color a bit, but it
remained pretty ugly.  This was added to 500 mL H2O containing 5 g
sodium thiosulfate and extracted with 3x100 mL petroleum ether.  The
extracts were pooled, and the solvent removed under vacuum to provide
crude 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane as a
residue.

To this crude 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane
there was added a solution of 20 g potassium phthalimide in 150 mL
anhydrous DMF, and all was held at reflux overnight.  After adding to
500 mL of dilute NaOH, some 1.4 g of a white solid was generated and
removed by filtration.  The aqueous filtrate was extracted with 2x75
mL Et2O.  These extracts were combined, washed with dilute HCl, and
the solvent removed under vacuum providing 23.6 g of a
terpene-smelling amber oil.  This was stripped of all volatiles by
heating to 170 !C at 0.4 mm/Hg providing 5.4 g of a sticky brown
residue.  This consisted largely of the desired phthalimide.  The
solids proved to be a purer form of
1-(4-ethoxy-3-ethylthio-5-methoxy)-2-phthalimidoethane and was
recrystallized from a very small amount of MeOH to give fine white
crystals with a mp of 107.5-108.5 !C.  Anal. (C21H23NO4S) C,H.  The
white solids and the brown impure phthalimide were separately
converted to the final product, 3-TASB.

A solution of 1.2 g of the crystalline
1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-phthalimidoethane in 40 mL
of warm n-butanol was treated with 3 mL of 66% hydrazine, and the
mixture was heated on the steam bath for 40 min.  The reaction mixture
was added to 800 mL dilute H2SO4.  The solids were removed by
filtration, and the filtrate was washed with 2x75 mL CH2Cl2.  The
aqueous phase was made basic with 25% NaOH, extracted with 3x75 mL
CH2Cl2, and the solvent from these pooled extracts removed under
vacuum yielding 6.2 g of a residue that was obviously rich in butanol.
This residue was distilled at 138-144 C. at 0.3 mm/Hg to give 0.6 g of
a colorless oil.  This was dissolved in 2.4 mL IPA, neutralized with
concentrated HCl, and diluted with 25 mL anhydrous Et2O.  The solution
remained clear for about 10 seconds, and then deposited white
crystals.  These were removed by filtration, washed with additional
Et2O, and air dried to give 0.4 g
4-ethoxy-3-ethylthio-5-methoxyphenethylamine hydrochloride (3-TASB)
with a mp of 140-141 !C.  Anal. (C13H22ClNO2S) C,H.  The amber-colored
impure phthalimide, following the same procedure, provided another 0.9
g of the hydrochloride salt with a mp of 138-139 !C.

DOSAGE: about 160 mg.

DURATION: 10 - 18 h.

QUALITATIVE COMMENTS: (with 120 mg) This is no more than a plus one,
and it didnUt really get there until about the third hour.  By a
couple of hours later, I feel that the mental effects are pretty much
dissipated, but there is some real physical residue.  Up with some
caution.

(with 160 mg) The taste is completely foul.  During the first couple
of hours, there was a conscious effort to avoid nausea.  Then I
noticed that people's faces looked like marvelous parodies of
themselves and that there was considerable time slowing.  There was no
desire to eat at all.  Between the eighth and twelth hour, the mental
things drifted away, but the body was still wound up. Sleep was
impossible until about 3:00 AM (the 18th hour of the experiment) and
even the next day I was extremely active, anorexic, alert, excited,
and plagued with occasional diarrhea.  This is certainly a potent
stimulant.  The next night I felt the tensions drop, and finally got
an honest and easy sleep.  There is a lot of adrenergic push to this
material.

EXTENSIONS AND COMMENTARY: No pharmacological agent has an action that
is pure this or pure that.  Some pain-killing narcotics can produce
reverie and some sedatives can produce paranoia.  And just as surely,
some psychedelics can produce stimulation.  With 3-TASB we may be
seeing the shift from sensory effects over to out-and-out stimulation.
It would be an interesting challenge to take these polyethylated
phenethylamines and assay them strictly for their amphetamine-like
action.  Sadly, the potencies are by and large so low, that the human
animal canUt be used, and any sub-human experimental animal would not
enable the psychedelic part of the equation to be acknowledged.  If an
order of magnitude of increased potency could be bought by some minor
structural change, this question could be addressed.  Maybe as the
three-carbon amphetamine homologs, or as the 2,4,5- or 2,4,6-
substitution patterns, rather than the 3,4,5-pattern used in this set.

 

 

 



#147 4-TASB; 4-THIOASYMBESCALINE;
3-ETHOXY-4-ETHYLTHIO-5-METHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 20.5 g N,N,NU,NU-tetramethylethylenediamine
and 22.3 g of 3-ethoxyanisole was made in 100 mL hexane under a He
atmosphere with good stirring.  There was added 125 mL 1.6 M
butyllithium in hexane, which formed a white granular precipitate.
This was cooled in an ice bath, and there was added 24.4 g of
diethyldisulfide which produced an exothermic reaction and changed the
precipitate to a creamy phase.  After being held for a few min at
reflux temperature, the reaction mixture was added to 500 mL dilute
H2SO4 which produced two clear phases. The hexane phase was separated,
and the aqueous phase extracted with 2x75 mL methylcyclopentane.  The
organics were combined, and the solvents removed under vacuum.  There
was obtained a residue which was distilled under a vacuum.  At 0.3
mm/Hg the fraction boiling at 95-105 !C was a yellow liquid weighing
28.5 g which was largely 3-ethoxy-2-(ethylthio)anisole which seemed to
be reasonably pure chromatographically.  It was used as such in the
bromination step below.

To a stirred solution of 15.0 g of 3-ethoxy-2-(ethylthio)anisole in
100 mL CH2Cl2 there was added 12 g elemental bromine dissolved in 25
mL CH2Cl2.  There was the copious evolution of HBr.  After stirring at
ambient temperature for 3 h, the dark solution was added to 300 mL H2O
containing sodium dithionite.  Shaking immediately discharged the
residual bromine color, and the organic phase was separated, The
aqueous phase was extracted once with 100 mL CH2Cl2, the pooled
extracts washed with dilute base, and then the solvent was removed
under vacuum to give a light brown oil.  This wet product was
distilled at 112-122 !C at 0.3 mm/Hg to yield 4-bromo (and/or
6-bromo)-3-ethoxy-2-(ethylthio)anisole as a light orange oil.  This
was used in the following benzyne step without separation into its
components.

To a solution of 36 mL diisopropylamine in 150 mL anhydrous THF under
a He atmosphere, and which had been cooled to -10 !C with an external
ice/MeOH bath, there was added 105 mL of a 1.6 M solution of
butylithium in hexane.  There was then added 5.1 mL of dry CH3CN
followed by the dropwise addition of 15.0 g 4-bromo-(and/or
6-bromo)-3-ethoxy-2-(ethylthio)anisole diluted with a little anhydrous
THF. There was an immediate development of a dark red-brown color.
The reaction was warmed to room temperature and stirred for 0.5 h.
This was then poured into 600 mL of dilute H2SO4.  The organic phase
was separated, and the aqueous fraction extracted with 2x50 mL CH2Cl2.
These extracts were pooled and the solvent removed under vacuum.  The
residue was a dark oil and quite complex as seen by thin layer
chromatography.  This material was distilled at 0.3 mm/Hg yielding two
fractions The first boiled at 112-125 !C and weighed 3.9 g.  It was
largely starting bromo compound with a little nitrile, and was
discarded.  The second fraction distilled at 130-175 !C and also
weighed 3.9 g.  This fraction was rich in the product
3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile, but it also
contained several additional components as seen by thin layer
chromatographic analysis.  On standing for two months, a small amount
of solid was laid down which weighed 0.5 g after cleanup with hexane.
But even it consisted of three components by TLC, none of them the
desired nitrile.  The crude fraction was used for the final step
without further purification or microanalysis.

A solution of LAH in anhydrous THF under N2 (15 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred.  There was added,
dropwise, 0.40 mL 100% H2SO4, followed by about 3 g of the crude
3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile diluted with a little
anhydrous THF.  The reaction mixture was stirred until it came to room
temperature, and then held at reflux on the steam bath for 2 h.  After
cooling to room temperature, there was added IPA to destroy the excess
hydride (there was quite a bit of it) and then 15% NaOH to bring the
reaction to a basic pH and convert the aluminum oxide to a loose,
white, filterable consistency.  This was removed by filtration, and
washed first with THF followed by IPA.  The filtrate and washes were
stripped of solvent under vacuum, the residue added to 100 mL dilute
H2SO4.  This was washed with 2x75 mL CH2Cl2, made basic with 25% NaOH,
and extracted with 2x50 mL CH2Cl2.  After combining, the solvent was
removed under vacuum providing a residue that was distilled.  A
fraction boiling at 122-140 !C at 0.3 mm/Hg weighed 1.0 g and was a
colorless oil.  This was dissolved in 10 mL of IPA, and neutralized
with 20 drops of concentrated HCl and diluted, with stirring, with 40
mL anhydrous Et2O.  There was the slow formation of a fine white
crystalline salt, which was removed by filtration, washed with Et2O,
and air dried.  The product
3-ethoxy-4-ethylthio-5-methoxyphenethylamine hydrochloride (4-TASB),
weighed 0.5 g, and had a mp 139-140 !C.  Gas chromatographic analysis
by capillary column chromatography of the free base (in butyl acetate
solution on silica SE-54) showed a single peak at a reasonable
retention time, verifying isomeric purity of the product.  Anal.
(C13H22ClNO2S) C,H.

DOSAGE: 60 - 100 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 60 mg) The compound has a
petroleum-refinery type taste.  There was a looseness of the bowels as
I got into it.  Here we have another of these 'What is it' or 'What
isnUt it' compounds.  Somehow I seemed to have to push the erotic, the
visual, the whole psychedelic shmeer, to document that this was indeed
effective.  I am not impressed.

(with 100 mg) There were some trivial physical problems during the
early stages of this experiment.  But there was fantasy stuff to
music, and some jumpy stuff to music.  Is there a neurological
hyperreflexia?  I was able to sleep at the 12 hour point but I felt
quite irritable.  I am agitated.  I am twitchy.  This has been very
intense, and I am not completely comfortable yet.  Let's wait for a
while.

(with 100 mg) Music was lovely during the experiment, but pictures
were not particularly exciting.  I had feelings that my nerve-endings
were raw and active.  There was water retention.  There was heartbeat
wrongness, and respiration wrongness.  During my attempts to sleep, my
eyes-closed fantasies became extremely negative.  I could actually
feel the continuous electrical impulses travelling between my nerve
endings.  Disturbing.  There was continuous erotic arousability, and
this seemed to be part of the same over-sensitivity of the nervous
system; orgasm didnUt soothe or smooth out the feeling of
vulnerability.  This is a very threatening material.  DO NOT REPEAT.

EXTENSIONS AND COMMENTARY: Again, another drug with more physical
problems than psychic virtue, but with no obvious structural feature
to hang it all onto.  Some day this will all make sense!

 

 

 



#148 5-TASB; 5-THIOASYMBESCALINE;
3,4-DIETHOXY-5-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 11.5 g
3-bromo-N-cyclohexyl-4,5-diethoxybenzylidinimine (see under ASB for
its preparation) in 150 mL anhydrous Et2O was placed in a He
atmosphere, well stirred, and cooled in an external dry ice/acetone
bath to -80 !C.  There was light formation of fine crystals.  There
was then added 25 mL of 1.6 N butyllithium in hexane and the mixture
stirred for 15 min.  This was followed by the addition of 4.3 mL
dimethyldisulfide over the course of 20 min, during which time the
solution became increasingly cloudy and then thinned out again.  The
mixture was allowed to come to room temperature over the course of an
additional h, and then added to 400 mL of dilute HCl.  There was the
generation of a lot of yellow solids, and the Et2O phase was almost
colorless.  This was separated, the solvent removed under vacuum, and
the residue combined with the original aqueous phase.  This phase was
then heated on the steam bath for 2 h.  The aqueous solution was
cooled to room temperature, extracted with 3x100 mL CH2Cl2, the
extracts pooled, washed with H2O, and the solvent removed under vacuum
to yield 9.4 g of an amber oil which spontaneously crystallized.  This
was distilled at 125-132 !C at 0.2 mm/Hg to yield 7.1 g of
3,4-diethoxy-5-(methylthio)benzaldehyde as a white oil that
spontaneously crystallized.  The crude product had a mp of 73-74 !C
that actually decreased to 72-73 !C after recrystallization from MeOH.
Anal. (C12H16O3S) C,H.

A solution of 16.2 g methyltriphenylphosphonium bromide in 200 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled to 0 !C with an external ice water bath.  There was then added
30 mL of 1.6 N butyllithium in hexane which resulted in the generation
of a clear yellow solution.  The reaction mixture was brought up to
room temperature, and 7.0 g 3,4-diethoxy-5-(methylthio)benzaldehyde in
50 mL THF was added dropwise, dispelling the color, and the mixture
was held at reflux on the steam bath for 1 h.  The reaction was
quenched in 800 mL H2O, the top hexane layer separated, and the
aqueous phase extracted with 2x75 mL of petroleum ether.  The organic
fractions were combined and the solvents removed under vacuum to give
12.0 g of the crude 3,4-diethoxy-5-methylthiostyrene as a pale
amber-colored oil.

A solution of 6.0 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 45 mL THF was placed in a He atmosphere, cooled to
0 !C, treated with 12.6 g of 2-methylbutene, and stirred for 1 h while
returning to room temperature.  To this there was added a solution of
the impure 3,4-diethoxy-5-methylthiostyrene in 25 mL THF.  This was
stirred for 1 h during which time the color deepened to a dark yellow.
The excess borane was destroyed with about 2 mL MeOH (all this still
in the absence of air).  There was then added 11.4 g elemental iodine
followed by a solution of 2.4 g NaOH in 30 mL of boiling MeOH, added
over the course of 10 min.  This was followed by sufficient 25% NaOH
to discharge the residual iodine color (about 4 mL was required). The
reaction mixture was added to 500 mL water, and sodium hydrosulfite
was added to discharge the remaining iodine color (about 4 g).  This
was extracted with 3x100 mL petroleum ether, the extracts pooled, and
the solvent removed under vacuum to provide 25.9 g of crude
1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane as a pale yellow
fluid oil.  Thin layer chromatographic analysis of this material on
silica gel plates (using a 90:10 mixture of CH2Cl2/methylcyclopentane
as solvent) showed largely the iodo-product (Rf 0.9) with no visible
starting aldehyde (Rf 0.7).

To this crude 1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane there
was added a solution of 12 g potassium phthalimide in 90 mL anhydrous
DMF, and all was held at reflux in a heating mantle.  The reaction
progress was followed by TLC, and at 1.5 h it was substantially
complete.  After adding to 500 mL 5% NaOH, the organic phase was
separated, and the aqueous phase was extracted with 2x75 mL Et2O.  The
organic fractions were combined, and the solvent removed under vacuum
providing 19.3 g of an amber oil.  The residual volatiles were removed
by distillation up to 170 !C at 0.2 mm/Hg.  The distillate weighed 7.0
g and contained little if any phthalimide by TLC.  The pot residue was
a viscous amber oil, and also weighed 7.0 g.  About half of this was
employed in the following hydrolysis step, and the rest was rubbed
under an equal volume of MeOH providing
1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane as a white
solid.  A small sample was recrystallized from an equal volume of MeOH
to give white crystals with a mp of 79.5-81 !C.  Re-recrystallization
from MeOH produced an analytical sample with a mp of 83-84 !C.  Anal.
(C21H23NO4S) C,H.

A solution of 3.2 g of the impure
1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane in 150 mL of
n-butanol there was added 20 mL of 66% hydrazine, and the mixture was
heated on the steam bath for 2 h.  This was added to 600 mL of dilute
H2SO4, and the two layers were separated.  The butanol layer was
extracted with 2x100 mL dilute H2SO4.  These extracts were added to
the original aqueous phase, and this was washed with 3x75 mL CH2Cl2.
This was then made basic with 5% NaOH, extracted with 3x75 mL CH2Cl2,
and the solvent from these pooled extracts removed under vacuum.  The
residue (which weighed 9.7 g and contained much butanol) was distilled
at 140-145 !C at 0.3 mm/Hg to give 0.7 g of a colorless oil.  This was
dissolved in 3.0 mL IPA, neutralized with concentrated HCl, and
diluted with 12 mL anhydrous Et2O to give a solution that immediately
crystallized to provide white crystals of
3,4-diethoxy-5-methylthiophenethylamine hydrochloride (5-TASB).  These
weighed 0.7 g after washing with Et2O and drying to constant weight.
The mp was 182-183 !C, and an analytical sample was dried at 100 !C
for 24 h.  Anal. (C13H22ClNO2S) C,H.

DOSAGE: about 160 mg.

DURATION: about 8 h.

QUALITATIVE COMMENTS: (with 120 mg) Maybe there is something at about
hour 5.  My talking with innocent people had hints of strangeness.
And there was the slightest suggestion of some physical effect.  Call
it an overall (+).

(with 160 mg) I am immediately warm at the extremities. An awareness
grows upon me for a couple of hours.  I am a little light-headed, and
I feel that there is more physical than there is mental, and it is not
all entirely nice.  I am slightly hyperreflexive, and there is a touch
of diarrhea.  I am happy that I held this at 160 milligrams.  I am
mentally flat at the eighth hour, although there are some physical
residues.  The effects are real, but I donUt want to go higher.  Some
trace physical memory seems to stay with me as a constant companion.

EXTENSIONS AND COMMENTARY: There is a ponderousness about adding a
couple of ethyl groups and a sulfur that seems to say, Rno fun.
5-TASB has something going for it (but not much) and 3-TASB is quite a
bit more peppy and, actually, 4-TASB has quite a bit of life.  But
there is a sense of Rwhy bother?S There were a couple of bouts of
light-headedness, but there was no unexpected excitement discovered in
this methodical study.  No surprises.  Keep the chain lengths down.

 

 

 



#149 TB; 4-THIOBUSCALINE; 3,5-DIMETHOXY-4-(n)-BUTYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution was made of 12.1 g
N,N,NU,NU-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 butyl lithium in
hexane which produced a white granular precipitate.  The reaction
mixture was brought up to room temperature for a few minutes, and then
cooled again to 0 !C.  There was then added 18.7 g of di-(n)-butyl
disulfide (this reagent was quite yellow, but was used without any
purification) which changed the granular precipitate to a strange
salmon color.  Stirring was continued while the reaction mixture was
brought up to room temperature 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 weighed 33.0 g and was a dark yellow oil.  Efforts to
remove this color by reductive extraction of a CH2Cl2 solution with
aqueous sodium hydrosulfite were futile.  The residue was distilled at
0.3 mm/Hg to give two fractions.  The first boiled at 95-115 !C,
weighed 4.1 g and was largely recovered dibutyl disulfide.  The
product 2-(n)-butylthio-1,3-dimethoxybenzene boiled at 115-135 !C and
weighed 19.5 g.  It was a pale amber oil that could not be induced to
crystallize.  Anal. (C12H18O2S) C,H.

To a stirred solution of 19.5 g of
2-(n)-butylthio-1,3-dimethoxybenzene in 75 mL CH2Cl2 there was added
14.5 g elemental bromine dissolved in 75 mL CH2Cl2.  The evolution of
HBr was evident, but the reaction was not exothermic.  The reaction
was allowed to stir for 1 h and then heated briefly to a reflux on the
steam bath.  It was then washed with H2O containing sodium
hydrosulfite which discharged the residual color.  After washing with
saturated brine, the solvent was removed under vacuum leaving 26.0 g
of a pale amber oil.  This was distilled at 120-140 !C at 0.4 mm/Hg
yielding 4-bromo-2-(n)-butylthio-1,3-dimethoxybenzene as a
yellow-orange oil.  It could not be crystallized.  Anal. (C12H17BrO2S)
C,H.

To a solution of 11.5 mL diisopropylamine in 50 mL hexane that was
stirred under N2 there was added 50 mL of 1.6 M butyllithium.  After
15 min stirring, the reaction mixture became very viscous, and it was
diluted with 150 mL anhydrous THF.  After cooling in an ice bath there
was added 2.0 mL CH3CN followed in 1 min with 6.0 g of
4-bromo-2-(n)-butylthio-1,3-dimethoxyanisole a bit at a time over the
course of 1 min.  There was the immediate formation of a deep red
color.  After stirring for 0.5 h, the mixture was poured into dilute
H2SO4.  The organic layer was separated, and the aqueous layer
extracted with 3x75 mL CH2Cl2.  These extracts were pooled, dried with
anhydrous K2CO3, and the solvent was removed under vacuum.  The
residue was distilled at 0.25 mm/Hg and yielded two fractions.  The
first fraction boiled at 125-145 !C, weighed 0.8 g and was discarded.
The second fraction came over at 145-175 !C as a light yellow oil and
weighed 2.2 g.  This product,
4-(n)-butylthio-3,5-dimethoxyphenylacetonitrile, was reduced as such
without further purification or analysis.

A solution of LAH under N2 (20 mL of a 1 M solution in anhydrous THF)
was cooled to 0 !C and vigorously stirred.  There was added, dropwise,
0.53 mL 100% H2SO4, followed by 2.0 g
4-(n)-butylthio-3,5-dimethoxyphenylacetonitrile in 10 mL anhydrous
THF.  The reaction mixture was stirred at 0 !C for a few min, then
brought to room temperature for 1 h, and finally to a reflux for 1 h
on the steam bath.  After cooling back to room temperature, there was
added IPA (to destroy the excess hydride) followed by 10% NaOH which
brought the reaction to a basic pH and converted the aluminum oxides
to a loose, white, filterable consistency.  These were removed by
filtration, and washed with THF and IPA.  The filtrate and washes were
stripped of solvent under vacuum, the residue was suspended in 150 mL
of dilute NaOH and extracted with 3x100 CH2Cl2.  These extracts were
pooled and extracted with 2x75 mL diluteH2SO4.  Emulsions required
that a considerable additional quantity of H2O be added.  The aqueous
phase was made basic, and extracted with 2x100 mL CH2Cl2.  After
combining these extracts, the solvent was removed under vacuum
providing a residue that was distilled.  The product distilled at
138-168 !C at 0.4 mm/Hg as a white oil weighing 0.7 g.  This was
dissolved in a small amount of IPA, neutralized with concentrated HCl
and, with continuous stirring, diluted with several volumes of
anhydrous Et2O.  After filtering, Et2O washing, and air drying,
4-(n)-butylthio-3,5-dimethoxyphenethylamine hydrochloride (TB) was
obtained, weighed 0.6 g, and had a mp of 154-155 !C.  Anal.
(C14H24ClNO2S) C,H.

DOSAGE: 60 - 120 mg.

DURATION: about 8 h.

QUALITATIVE COMMENTS: (with 35 mg) I was aware of something at about
an hour, and it developed into a benign and beautiful experience which
never quite popped into anything psychedelic.  At the fifth hour there
was a distinct drop, and I made what might be thought of as a foolish
effort to rekindle the state with an additional 20 milligrams but it
was too little and too late.  There was no regeneration of anything
additional.

(with 60 mg) A very subtle threshold, probably, and six hours into it
there seems to have been little if any effect.  My memory of it is not
that certain and now I am not sure that there had been anything at
all.

(with 80 mg) I am vaguely aware of something.  The body discomfort
may reflect the use of sardines in tomato sauce for lunch, but still
things are not quite right.  Five hours into it I am still in a
wonderful place spiritually, but there seem to be some dark edges.  I
might be neurologically sensitive to this.

(with 120 mg) The course of the action of this is extremely clear.
The development was from 5 PM to 7 PM [the experiment started at 4 PM]
and by 10 PM I was dropping and by midnight I went to bed and slept
well.  Food was not too interesting, and a glass of wine before
sleeping produced no noticeable effect.  This was an uneventful
experience that never really made it off the ground.  It was pleasant,
but certainly not psychedelic.

EXTENSIONS AND COMMENTARY: There is a term Rdose-dependentS in
pharmacology.  When there is a complex action produced by a drug, then
each of the components of this mixture of effects should be expected
to become more intense following a bigger dose of the drug.  This is
certainly true with most of the actions of psychoactive drugs.

As to the psychedelic aspects of some drugs, there can be visual
effects, eyes-open (edge-ripples or colors or retinal games) or
eyes-closed (images of the elaborately decorated doors of the mosque,
or of an orchestra floating suspended by its music) or fantasy (you
are moving beyond the confines of your body and invading someone
else's space).  The same applies to tactile enhancement, to the
anaesthetic component, to the depth of insight realized from a drug.
The more the drug, as a rule, the more the effect, up to the point
that new and disruptive effects are realized.  This latter is called
toxicity.

As to the stimulant component, the same is true.  The person gets
wired up, and there is no sleep because there is no hiding from a
cascade of images and meanings, and the body lies there unwilling to
yield guard since both the pounding heart and the interpretive psyche
are demanding attention.  These aspects also intensify with
increasingly higher doses.

But an exception to this is the euphoria-producing aspect of a drug.
One sees with increasing doses a continuing RthresholdS that makes you
aware, that fluffs the senses, but which seems not, at any level, to
take over or to command the ship.  It is truly a catalytic on or off.
You are or you are not.  In the RTomsoS effect, this action is
produced by alcohol.  There is disinhibition with alcohol which allows
a central intoxication from the drug TOMSO regardless of the amount of
drug used (see under TOMSO).  One sees again, here with TB, the case
of a perpetual series of Rthresholds.S Never the psychedelic or the
stimulant action that increases with increased dose.  Always the
simple and ephemeral catalyst of euphoria without substance and
without body.  It is a compound that can never be pinned and labeled
in the butterfly collection since it defies an accepted
classification.

This action was seen first with the compound called ARIADNE and when
it was called an anti-depressant, it proved to be commercially
interesting.  It is fully possible that TB would be of value to
certain depressed people in exactly the same way.