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#22 2C-C
2,5-DIMETHOXY-4-CHLOROPHENETHYLAMINE
SYNTHESIS: (from
2C-H) The free base of
2,5-dimethoxyphenethylamine
was generated from its salt (see recipe for
2C-H for the preparation
of this compound) by treating a
solution of 16.2 g of the
hydrochloride salt in 300 mL H2O with aqueous
NaOH, extraction with
3x75 mL
CH2Cl2, and removal of the
solvent from the pooled extracts
under vacuum. The colorless residue was
dissolved in 75 mL glacial
acetic acid (the solids that initially formed re
dissolved completely)
and this was cooled to 0 °C with an external ice bath. With vigorous
stirring, there was added 4.0 mL of liquid
chlorine, a little bit at a
time with a Pasteur
pipette. The theoretical volume was 3.4 mL, but
some was lost in pipetting, some on contact with the 0 °C acetic acid,
and some was lost by
chlorination of the acetic acid. The reaction
turned a dark amber color, was allowed to stir for an additional 10
min, then quenched with 400 mL H2O. This was washed with 3x100 mL
CH2Cl2 (which removed some of the color) then brought to neutrality
with dilute aqueous
NaOH and treated with a small amount of
sodium
dithionite which discharged most of the color (from deep brown to pale
yellow). The reaction was made strongly basic with aqueous KOH, and
extracted with 3x75 mL
CH2Cl2. The pooled extracts were washed once
with H2O and the
solvent was removed under vacuum leaving about 10 mL
of a deep amber oil as residue. This was
dissolved in 75 mL IPA and
neutralized with concentrated HCl which allowed spontaneous
crystallization. These crystals were removed by filtration, washed
with an additional 20 mL IPA, and air-dried to constant weight. There
was thus obtained 4.2 g
2,5-dimethoxy-4-chlorophenethylamine
hydrochloride (2C-C) with a mp of 218-221 °C. Re
crystallization from
IPA increased this to 220-222 °C. The position of
chlorination on the
aromatic ring was verified by the presence of two para-protons in the
NMR, at 7.12 and 7.20 ppm from external TMS, in a D2O
solution of the
hydrochloride salt.
Synthesis from
2C-B. To a
solution of 7.24 g
2,5-dimethoxy-4-bromophenethylamine (
2C-B) and 4.5 g
phthalic
anhydride in 100 mL
anhydrous DMF there was added
molecular sieves.
After 16 h reflux, the reaction mixture was cooled and the sieves
removed by filtration. The addition of a little
CH2Cl2 prompted the
deposition of yellow
crystals which were re
crystallized from
EtOH.
The resulting
1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane
weighed 7.57 g and had a mp of 141-142 °C. Anal. (
C18H16BrNO4)
C,H,N,Br.
A
solution of 14.94 g of
1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane and 4.5 g
cuprous
chloride in 300 mL
anhydrous DMF was heated for 5 h at reflux.
The cooled mixture was poured into 20 mL H2O that contained 13 g
hydrated ferric
chloride and 3 mL concentrated HCl. The mixture was
maintained at about 70 °C for 20 min, and then extracted with
CH2Cl2.
After washing the pooled organic extracts with dilute HCl and drying
with
anhydrous MgSO4, the
volatiles were removed under vacuum to
provide a solid residue. This was re
crystallized from
EtOH to provide
12.18 g of
1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane as
yellow needles that had a mp of 138-140 °C. Anal. (
C18H16ClNO4)
C,H,N,Cl.
To 60 mL absolute
EtOH there was added 12.2 g
1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane and 2.9 mL of
100%
hydrazine. The
solution was held at reflux for 15 min. After
cooling, the
cyclic hydrazone by-product was removed by filtration,
and the
alcoholic mother liquors taken to dryness under vacuum. The
residue was
distilled at 145-155 °C at 0.05 mm/
Hg to give 5.16 g of a
clear, colorless oil. This was
dissolved in
anhydrous Et2O and
treated with hydrogen
chloride gas, producing
2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) as white
crystals with a mp of 220-221 °C. Anal. (
C10H15Cl2NO2) C,H,N.
DOSAGE: 20 - 40 mg.
DURATION: 4 - 8 h.
QUALITATIVE COMMENTS: (with 20 mg) This is longer lived than
2C-B,
and there is a longer latency in coming on. It took an hour and a
half, or even two hours to get there. It had a slight
metallic
overtone.
(with 24 mg) I was at a moderately high and thoroughly favorable
place, for several hours. It seemed to be a very sensual place, but
without too much in the way of visual distraction.
(with 40 mg) There were a lot of visuals--something that I had noted
at lower levels. There seems to be less stimulation than with
2C-B,
and in some ways it is actually sedating. And yet I was up all night.
It was like a very intense form of relaxation.
EXTENSIONS AND COMMENTARY: Other reports mention usage of up to 50
milligrams which seems to increase yet further the intensity and the
duration. I have one report of an intravenous administration of 20
milligrams, and the response was described as overwhelming. The
effects peaked at about 5 minutes and lasted for perhaps 15 minutes.
The
halogens represent a small group of atoms that are unique for a
couple of reasons. They are all located in a single column of the
periodic table, being monovalent and negative. That means that they
can be reasonably stable things when attached to an aromatic nucleus.
But, being monovalent, they cannot be modified or extended in any way.
Thus, they are kind of a dead end, at least as far as the 2C-X series
is considered. The heaviest,
iodine, was explored as the
phen-ethylamine, as
2C-I, and as the
amphetamine as DOI. These are
the most potent. The next lighter is
bromine, where the
phenethylamine is
2C-B and the
amphetamine is DOB. These two are a
bit less potent, and are by far the most broadly explored of all the
halides. Here, in the above recipe, we have the
chlorine counterpart,
2C-C. There is also the corresponding
amphetamine DOC. These are
less potent still, and much less explored. Why? Perhaps because
chlorine is a gas and troublesome to handle (
bromine is a liquid, and
iodine is a solid). The
fluorine analogue is yet harder to make, and
requires procedures that are indirect, because
fluorine (the lightest
of all the
halides) is not only a gas, but is dangerous to handle and
does not react in the usual
halogen way. There will be mention made
of
2C-F, but DOF is still unexplored.
The treatment of the
2C-B phthalimide described above, with cuprous
cyanide rather than cuprous
chloride, gave rise to the cyano
analog
which, on hydrolysis with
hydrazine, yielded
2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with
hot, strong base gave the corresponding acid,
2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of
either of these compounds has been made in the human animal, as far as
I know.
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