SYNTHESIS: A suspension of 285 g mossy zinc in 285 mL H2O containing
5.7 g mercuric chloride was treated with 285 mL concentrated HCl and
shaken as needed to effect amalgamation. The H2O was then drained
off, the zinc washed with fresh water and drained again. There was
added a solution of 74 g 2,5-dimethoxypropiophenone (from the reaction
of propionic acid and p-dimethoxybenzene in the presence of
polyphosphoric acid, see under DOAM for an effective general
procedure) in 140 g EtOH. The reaction mixture was held at reflux for
24 h with the periodic addition of concentrated HCl. It was then
cooled, diluted with H2O and CH2Cl2, and the organic phase separated.
The aqueous phase was extracted with 2x100 mL additional CH2Cl2. The
combined organic phases were washed with 5% NaOH until the washes
remained basic, once with H2O, and then the solvent was removed under
vacuum. The residue was distilled at the water pump, giving an early
fraction quite rich in starting p-dimethoxybenzene, and a second
fraction (61 g, bp 140-160 °C) which was free of carbonyl group by
infra-red, and which was largely 2,5-dimethoxypropylbenzene. It was
used without further purification in the following aldehyde synthetic
step.
A mixture of 124 g N-methylformanilide and 140 g POCl3 was allowed to
stand until there was the development of a strong red color. There
was then added 60 g of the above 2,5-dimethoxypropylbenzene and the
mixture was held on the steam bath for 2 h. The mixture was added to
2 L H2O and stirred until the excess acid chloride had completely
decomposed. The mixture was extracted with 3x100 mL CH2Cl2 and, after
the removal of the solvent from the combined extracts, the residue was
extracted with 3x100 mL boiling hexane. Removal of the solvent gave
the product 2,5-dimethoxy-4-propylbenzaldehyde as an oil, 23 g, which
was characterized as its malononitrile derivative. Equal weights of
the product and malononitrile in EtOH with a catalytic amount of
triethylamine gave yellow crystals which, on recrystallization from
toluene, had a mp of 113-114 °C.
A solution of 21.5 g of the above crude
2,5-dimethoxy-4-propylbenzaldehyde in 75 g acetic acid, was treated
with 10.4 g nitroethane and 6.6 g anhydrous ammonium acetate. This
was heated on the steam bath for 1.75 h, then cooled and diluted with
H2O to the point of turbidity. With long standing and scratching,
there finally was the deposition of crystals which were removed by
filtration and sucked as dry as possible. This 23 g of crude product
cake was triturated under MeOH, filtered again, and air dried to give
11 g of dull orange crystals. Recrystallization from boiling MeOH
gave 1-(2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene as fine
orange crystals which weighed, after filtering, washing, and drying,
7.4 g, and which had a mp of 94-96 °C.
To a suspension of 6.0 g LAH in 500 mL anhydrous Et2O, which was being
stirred and also held as a gentle reflux, there was added a saturated
solution of (2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene in warm
THF. The reaction mixture was held at reflux for 24 h, then cooled to
room temperature. The excess hydride was destroyed by the cautious
addition of 500 mL dilute H2SO4. The phases were separated, and the
aqueous phase washed with additional Et2O. There was then added 150 g
potassium sodium tartrate, and the pH was brought to >9 with aqueous
NaOH. The product was extracted with Et2O and, after removal of the
solvent, the residue was dissolved in 200 mL anhydrous Et2O and
saturated with anhydrous HCl gas. The solids that formed were removed
by filtration, giving 6.15 g 2,5-dimethoxy-4-(n)-propylamphetamine
hydrochloride (DOPR) as an electrostatic, white crystalline powder,
with a mp of 182.5-183 °C. This was not improved by recrystallization
from either IPA or CH3CN.
DOSAGE: 2.5 - 5.0 mg.
DURATION: 20 - 30 h.
QUALITATIVE COMMENTS: (with 2.0 mg) The onset is slower than any
other thing I can think of. There was nothing at all at the end of an
hour, and only a threshold a half hour later. By the middle of the
third hour, I was up to 1+, and that seemed to be about as high as it
intended to take me. Attempts to sleep at the ninth hour were not
successful, as there were strange patterns of not-quite logical
thinking going on. Stuff like: `The block events (like a baby's
rectangular building blocks) that were gotten, along with other
things, from the full octaves of the left hand in Listz's Hungarian
Rhapsody, events that allowed an easy recognition of the odds of
achieving successful re-entry from any of several erotic codes.'
Clearly this was not a baseline state. After six hours of successful
sleep, I was still off-baseline , and on into the following day. Go
on up with curiosity but with caution.
(with 3.6 mg) Imagery that was constructed in response to the music
turned out to be necessary to organize and contain it. The trio is the
nucleus that transforms the written to the heard, but it has created
its own bubble without connections to the real world, and must play on
and on and on to keep itself afloat and never touching the stage
again.
(with 5.0 mg) I am now at midnight, and still strongly +++. This is
certainly maximum dosage, at least for a long time. There are faint
intimations of nervous system scrungies. You know, the kind of thing
that makes you figure it's going to be a while before you'll try to
relax into sleep. This material, like all the other DO's, is a heavy
duty psychedelic, the kind that says to you, 'Forget all that stuff
about screening out visuals,' and then proceeds to prove it. Sort of
indole-like in that way. Your body as well as your mind tells you
you're into it, baby, and better relax and enjoy the trip, because
you've left the shore way behind. When it was time for bed, I got to
sleep with surprising ease, and slept for only about six hours. My
dreams were excellent, balancing, and good humored. But the next day
I realized I was still carrying the DOPR in me, and that baseline was
definitely not there. But it was OK. No problems except for
sleepiness. The next evening I went to bed at unheard-of hour of 9 PM
and slept for 13 hours, give or take. Fascinating compound, but I
won't go out of my way to take it again soon.
EXTENSIONS AND COMMENTARY: There is a thread of disconnection and of
inconsistent reference that pervades most of the reports that I have
received concerning the use of DOPR. The word that comes to mind is
hypnogogic. There is a drifting into that place that lies between a
not-quite-awake and a not-quite-asleep state seems to characterize
this compound. There is no question but that it is very potent, and
that it is very long-lived. But there is a nagging suggestion of the
out-of-body, out-of-center character that is the hallmark of the
anesthetic and delusional drugs such as scopolamine or ketamine. With
them, the psychedelic effects become clouded with touches of amnesia.
If DOPR shows this with it's three carbon alkyl group, thereis every
reason to pay close attention as the chain becomes longer.
There had been quite a bit of speculation in the literature that the
metabolic attack on DOM was at the 4-position, and this was an
oxidation process. In a moment of inspiration, I decided to explore a
similar oxidation step in DOPR, since it is probably the most potent
of the DO-series. Why not make the compound which would be the first
step in this oxidation, the 1-hydroxypropyl analogue? This I did, by
using the phthalimide derivative of 2,5-dimethoxyamphetamine
(described in the synthesis of DOI) and making the propiophenone using
propionic acid as both reagent and solvent, and polyphosphoric acid as
the condensing agent. The ketone product (a white crystalline solid
from methanol) was dissolved in warm methanol and reduced to the
alcohol with sodium borohydride. This product, also a white
crystalline solid, was stripped of the phthalimide blocking group with
overnight refluxing with hydrazine in ethanol. The product,
2,5-dimethoxy-4-(1-hydroxypropyl)-amphetamine (hydroxy-DOPR) had a mp
of 148-150 °C from IPA. Its activity is not yet known, but there were
no effects at all at trials, orally, of up to 200 micrograms.
But this is all with the normal-propyl compound. There is a rich
collection of misinformation and potential discovery that is
associated with the isopropyl isomer. This structural isomer,
2,5-dimethoxyl-4-(i)-propylamphetamine is properly called DOIP for
des-oxy-iso-propyl. It has been synthesized and explored in animals
and, to a modest extent, in man. The synthesis has proceeded from
2,5-dimethoxyacetophenone by the addition of a methyl group to the
carbonyl followed by reduction to the hydrocarbon. Aldehyde
formation, nitropropene synthesis with nitroethane, and lithium
aluminum hydride reduction are uneventful, providing the hydrochloride
salt DOIP, which has a mp of 183-184 °C as an analytical sample.
Animal tests (such as rabbit hyperthermia assays), have indicated that
the isopropyl compound DOIP is less potent than the propyl prototype,
DOPR, by between one and two orders of magnitude. In man, a dose of
four milligrams, a rousing dose of DOPR, is without any effects. At
10 milligrams, there is some disturbance but substantially no effects.
I have been told that with doses in the 20 to 30 milligram range there
are valid changes in mental state, but I have not been told the nature
of these changes.
A fascinating red herring had been drawn across all of these exacting
lines by a strange visitor to this research project. An olive-faced
M.D., Ph.D., passed through this confusing scene briefly, and when he
left, a small supply of DOPR left with him. He promptly published in
an obscure journal some animal behavioral responses which he ascribed
to the isopropyl analogue, DOIP. But what he had studied could only
have been DOPR since DOIP, at that time, had not yet been synthesized
either by me, or by either of the other two active synthesists of that
moment. It was not yet a known material. We all made it some time
later, but by that time our olive-face had disappeared. There is a
magnificent French phrase that applies here as nowhere else; Il a
foutu le camp. Its idiomatic meaning is equivalent to our, "He took
off," or "He split the scene," but the literal translation is, "He
fucked the camp."
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