SYNTHESIS: To a solution of 72.3 g 2,6-dimethoxyphenol in 400 mL MeOH,
there was added 53.3 g of a 40% solution of aqueous dimethylamine
folowed by 40 g of a 40% aqueous solution of formaldehyde. The dark
solution was heated under reflux for 1.5 h on a steambath. The
volatiles were then removed under vacuum yielding a dark oily residue
of 2,6-dimethoxy-4-dimethylaminomethylphenol. This residue was
dissolved in 400 mL of IPA, to which there was added 50 mL of methyl
iodide. The spontaneously exothermic reaction deposited crystals
within 3 min, and was allowed to return to room temperature and
occasionally stirred over the course of 4 h. The solids were removed
by filtration, washed with cold IPA, and allowed to air dry yielding
160 g of the methiodide of 2,6-dimethoxy-4-dimethylaminomethylphenol
as a cream-colored crystalline solid.
A suspension of 155 g of the above methiodide of
2,6-dimethoxy-4-dimethylaminophenol in 600 mL H2O was treated with a
solution of 130 g KCN in 300 mL H2O. The reaction mixture was heated
on a steam bath for 6 h during which time there was a complete
dissolving, the development of a brownish color with a bright blue
film on the surface and the walls of the flask, and the gentle
evolution of fine gas bubbles. The hot reaction mixture was poured
into 1.2 L H2O and acidified with concentrated HCl (careful, HCN
evolution). The aqueous solution was extracted with 3x150 mL CH2Cl2,
the extracts pooled, washed with saturated NaHCO3 which removed much
of the color. The solvent was removed under vacuum yielding about 70
g of a viscous black oil. This was distilled at 0.4 mm/Hg at 150-160
°C to provide 52.4 g of homosyringonitrile
(3,5-dimethoxy-4-hydroxyphenylacetonitrile) as a white oil that
spontaneously crystallized to lustrous white crystals that melted at
57-58 °C.
A solution of 5.75 g of homosyringonitrile and 12.1 g ethyl iodide in
50 mL dry acetone was treated with 6.9 g finely powdered anhydrous
K2CO3 and held at reflux for 18 h. The mixture was diluted with 100
mL Et2O, filtered, and the filtrate solvent removed under vacuum The
residue was recrystallized from Et2O/hexane to yield 5.7 g
3,5-dimethoxy-4-ethoxyphenylacetonitrile with a mp 57-58 °C. Anal.
(C12H15NO3) C,H,N.
A solution of 2.21 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile in 25 mL
EtOH containing 2.5 mL concentrated HCl and 400 mg 10% palladium on
charcoal, was shaken in a 50 lb/sq.in. atmosphere of hydrogen for 24
h. Celite was added to the reaction suspension and, following
filtration, the solvents were removed under vacuum. The residue was
recrystallized from IPA/Et2O to yield 2.14 g
3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) with a mp of
166-167 °C.
Synthesis from syringaldehyde: A well-stirred suspension of 21.9 g
syringaldehyde in 45 mL H2O was heated to reflux in a heating mantle.
There was then added a solution of 15 g NaOH in 60 mL H2O. The
heating and stirring was continued until the generated solids
redissolved. Over a period of 10 min, there was added 23 g diethyl
sulfate, then refluxing was continued for 1 h. Four additional
portions each of 5 g diethyl sulfate and of 6 mL 20% NaOH were
alternately added to the boiling solution over the course of 2 h. The
cooled reaction mixture was extracted with Et2O, the extracts pooled
and dried over anhydrous MgSO4, decolorized with Norite, and stripped
of solvent. The crude 3,5-dimethoxy-4-ethoxy-benzaldehyde weighed
21.8 g and melted at 51-52 °C.
A solution of 14.7 g 3,5-dimethoxy-4-ethoxybenzaldehyde and 7.2 mL
nitromethane in 50 mL glacial acetic acid was treated with 4.4 g
anhydrous am-monium acetate and held at reflux for 30 min. Cooling
the reaction allowed the formation of yellow crystals which were
removed by filtration and washed sparingly with cold acetic acid. The
dried 3,5-dimethoxy-4-ethoxy-beta-nitrostyrene weighed 11.5 g and melted
at 108-109 °C after recrystallization from EtOH Anal. (C12H15NO5) C,H.
Alternately, this product may be prepared from 3.9 g.
3,5-dimethoxy-4-ethoxybenzaldehyde in 60 mL nitromethane containing
0.7 g ammonium acetate and heated on a steam bath for 1 h. The
solvent was removed under vacuum, and the residue dissolved in a
minimum of hot MeOH. Cooling provided, after filtration and air
drying, 2.3 g of bright yellow crystals of
3,5-dimethoxy-4-ethoxy-beta-nitrostyrene, with a mp of 105-107 °C.
A solution of 2.25 g LAH in 45 mL anhydrous THF was vigorously stirred
and cooled to 0 °C under He. There was added 1.5 mL 100% H2SO4
dropwise, followed by 2.3 g 3,5-dimethoxy-4-ethoxy-beta-nitrostyrene in
anhydrous THF. After the addition was complete, the mixture was
allowed to stir for 30 min, and then brought to room temperature. The
unreacted hydride was decomposed with 2.3 mL H2O in THF, followed by
the addition of 9.2 mL of 15% NaOH. The white suspension was
filtered, the filter cake was washed with THF, the filtrate and
washings combined, and the solvent removed under vacuum. The residue
was dissolved in 300 mL dilute H2SO4, washed with 2x75 mL CH2Cl2, made
basic with 25% NaOH, and the product extracted with 3x75 mL CH2Cl2.
After removal of the solvent, the residue was distilled at 110-120 °C
at 0.3 mm/Hg yielding 1.4 g of a colorless oil. A solution of this
oil in 20 mL IPA was neutralized with 17 drops of concentrated HCl and
diluted with 100 mL anhydrous Et2O. After a few minutes there was the
spontaneous formation of white crystals of
3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) which was
recrystallized from 40 mL boiling EtOAc containing 1 mL MeOH. The mp
was 165-166 °C.
DOSAGE: 40 - 60 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 40 mg) This is a powerful and complex
intoxicant--I could not have coordinated any rational muscular
activity. I could not walk; I could not tie my shoe-laces. There is
analgesia and an incoordination that I cannot shake. My menstrual
flow started a bit ahead of time, but it was light.
(with 50 mg) I felt that the body tensions outweighed the
psychological and sensory rewards, in that I had a lot of dehydration
and my sleep had a nightmare quality. This pretty much offset the few
virtues that I felt I had obtained.
(with 60 mg) There is a quality of rational analysis and insight that
is totally impressive. Many subtle factors in my life can be viewed
with insight, and usefully dissected. I got into a deep discussion,
but I was not argumentative or even defensive and I remained detached
and kept a tone of cool impersonality. I had a good appetite. But I
also had some tachycardia and muscular tension. There was
unquestionable sensory enhancement, but without an intellectual
component. Overall it was most pleasant.
EXTENSIONS AND COMMENTARY: In an isolated situation, there is easy
fantasy, but little synthesis of external sensory inputs such as music
or visual stimulae. A gradual decline brings the subject back to a
restful baseline somewhere before the 12th hour. The following day is
often seen as one of tiredness and low energy. An anonymous flyer
appeared in the California drug community in 1984 stating an effective
range to be 50 to 100 milligrams, but it described the drug as the
sulfate. The above data all pertain to the hydrochloride salt.
The replacement of that one methyl group with an ethyl group leads to
a nice jeu de mots. The play on words depends on a remarkable
coincidence. The name of the alkaloid mescaline stems from an ancient
Nahuatl word for a drink (Mexcalli) which also provided the source of
the term Mescal (an Agave of entirely different pharmacology). The
prefix for the simplest, the one carbon organic radical, is methyl.
This is from the Greek word "methy" and represents wine from wood.
Such is, indeed, methyl alcohol, or methanol, or wood alcohol, the
simplest one-carbon drink and a rather dangerous one for the human
animal. And this is the group that is on the central oxygen of
mescaline.
It is customary to refer to homologs (bigger-by-one) of methanol by
their classical chemical names, so the natural extension of methyl is
ethyl, and that of mescaline would be escaline. One carbon-chain on
the 4-position oxygen becoming a two-carbon chain. This is all
entymologically appealing, but there is no botanical support for any
of it. The ethyl group is much more rare in nature. It is just a
happy coincidence that mescaline (the plant), and methyl (the alkyl
group involved), and methoxy (the group on the 4-position of the
aromatic ring) all happen to start with the letter RMS.
Very few of the homomescaline phenethylamines have been synthesized as
their three-carbon chain counterparts, the corresponding analogues of
amphetamine. And only three of them have been explored in man (four,
if you count the amphetamine analogue of mescaline itself, TMA). The
obvious names for these compounds have, unfortunately, already been
used. It would be logical to use the letter M for a methoxy, and the
letter E for ethoxy, etc. and simply read the groups from around the
ring. But this is the naming system for the 2,4,5-trisubstituted
amphetamines. MEM is, for example, 2,5-dimethoxy-4-ethoxyamphetamine
(in sequence, methoxy, ethoxy, methoxy reading around the ring, and a
fascinating compound talked about at length in this book), so this
term cannot represent 3,5-dimethoxy-4-ethoxyamphetamine.
A truly simple code employs the length of the carbon chain. The
phenethylamine chain is two carbons long, and the amphetamine chain is
three carbons long.
If a drug has been initially developed (and initially named) as an
amphetamine derivative (three carbon chain) then the two-carbon chain
analogue will use the original name (or a symbolic part of it) with
the term 2C ahead of it. The two-carbon analogue of DOB (a
three-carbon chain compound) will become 2C-B. DOI becomes 2C-I, DON
becomes 2C-N, and DOET becomes 2C-E. Each of these is a substituted
amphetamine derivative lacking one carbon atom, thus becoming a
phenethylamine derivative. Most of these have 2,4,5-substitution
patterns.
And if a drug has been initially developed (and initially named) as a
phenethylamine derivative (two carbon chain) then the three-carbon
chain analogue will use the original name with the term 3C ahead of
it. The three carbon analogue of E (escaline, a two-carbon chain
compound) will become 3C-E. P becomes 3C-P and CPM becomes 3C-CPM.
Most of these have 3,4,5-substitution patterns.
Thus, R2-CS implies that a known amphetamine drug has been shortened
to a phenethylamine, and R3-CS inplies that a known phenethylamine has
been lengthened to an amphetamine. A great number of the former have
been made and have proven to be most rewarding. Only a few of the
latter are known, but most of them will eventually prove to be potent
psychedelics.
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