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#56 DMCPA
2-(2,5-DIMETHOXY-4-METHYLPHENYL)CYCLOPROPYLAMINE
SYNTHESIS: To a
solution of 25 g
2,5-dimethoxy-4-methylbenzaldehyde
(see the recipe for
2C-D for the preparation) and 29.2 g
malonic acid
in 50 mL
anhydrous pyridine, there was added 2 mL
piperidine and this
was heated on the steam bath for several h. The mixture was added to
a
solution of 125 mL concentrated HCl in 500 mL H2O at 0 °C, and the
solid product that was formed was removed by filtration, and washed
with H2O. Re
crystallization from aqueous
EtOH yielded 31 g
2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 °C. Anal.
(
C12H14O4) C,H.
In a cooled high-pressure reaction vessel there was placed a
suspension of 30 g
2,5-dimethoxy-4-methylcinnamic acid in 150 mL
liquid
isobutene. This was treated dropwise with 0.6 mL concentrated
H2SO4, then sealed and brought to room tem
perature. After 48 h
shaking, the vessel was cooled again to -10 °C, opened, and poured
into 200 mL of 10%
Na2CO3. This was extracted with hexane, the pooled
extracts washed with H2O, and the
solvent removed to yield 17.0 g of
(t)-butyl
2,5-dimethoxy-4-methylcinnamate as an amber oil. Anal.
(
C16H22O4) C,H.
The
cyclopropane ester was prepared by the reaction between 16 g
(t)-butyl
2,5-dimethoxy-4-methylcinnamate and
dimethylsulfoxonium
methylide, prepared as described in the Kaiser reference in the
acknowledgements. Hydrolysis of this ester gave 53%
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid
which, after re
crystallization from a MeOH/H2O mixture, had a mp of
136 °C. Anal. (
C13H16O4) C,H.
A suspension of 4 g of
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid in
an equal volume of H2O, was treated with sufficient
acetone to effect
complete
solution. This was cooled to 0 °C and there was added,
first, 2.0 g
triethylamine in 35 mL
acetone, followed by the slow
addition of 2.5 g
ethyl chloroformate in 10 mL
acetone. This was
stirred for 0.5 h, and then there was added a
solution of 1.7 g NaN3
in 6 mL H2O, dropwise. After 1 h stirring at 0 °C, the mixture was
quenched by pouring into H2O at 0 °C. The separated oil was extracted
with
Et2O, and extracts dried with
anhydrous MgSO4. Removal of the
solvent under vacuum gave a residue of the azide, which was
dissolved
in 10 mL
anhydrous toluene. This
solution was heated on the steam
bath until the
nitrogen evolution was complete, and the removal of the
solvent under vacuum gave a residue of crude
isocyanate as an amber
oil. This intermediate
isocyanate was
dissolved in 5.4 g
benzyl
alcohol and the reaction mixture was heated on the steam bath for 6 h.
The excess
benzyl alcohol was removed by
distillation, yielding
trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane as
a
crystalline residue. This was re
crystallized from an
EtOAc/hexane
mixture to give 6.13 g of a
crystalline product with a mp of 107-108
°C. Anal. (
C20H23NO4) C,H,N.
A
solution of 1.5 g
trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane in
120 mL MeOH containing 200 mg 10% Pd/C was shaken under hydrogen gas
at 35 psig for 45 min. The
solution was filtered through celite, and
a sufficient amount of a
solution of 5% HCl in
EtOH was added to the
filtrate to make it acidic. Removal of all
volatiles under vacuum
gave a solid residue that was re
crystallized from an
EtOH/
ether
mixture to give 0.98 g of
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine hydrochloride
(DMCPA) as white
crystals with a mp of 210-211 °C.
DOSAGE: 15 - 20 mg.
DURATION: 4 - 8 h.
QUALITATIVE COMMENTS: (with 10 mg) The effects were quite real at an
hour, but very hard to define. Nothing left at four hours, but my
sleep was filled with bizarre and colorful dreams. Something was
still working somewhere, at some level.
(with 20 mg) I found myself lightheaded, and the thinness seemed to
be, rather remarkably, on the left side of my brain. The experience
was flighty. I was reminded of the aura that has been described
preceding a convulsion. I was decoupled from my experience and from
my environment. Not all of the control is there, and I am
uncomfortable. But in an hour, there is complete control again, and I
can relax my conscious guard which allows an easy plus three. With
this, there was easy fantasy, erotic, quite a bit of movement in the
visual field, and mild
anorexia. The
residual hyperreflexive thinness
is largely gone, and not at all worrisome. This stuff is complicated,
with a little too much of the physical. The next day was without any
residues at all.
EXTENSIONS AND COMMENTARY: Most of the human trials took place in the
fifteen to twenty milligram range. Several reports describe some
muscular tremor, especially in the earliest part of the experience,
but this never seemed to be a concern. The efforts to lock imagery to
music were not too successful. All of these clinical studies were
conducted on the trans-compound, but on the racemic mixture. This has
been resolved into the two optical
isomers, but they have not been
compared in man. The cis-mixture is unknown.
This material is intimately related to
tranylcypromine, a clinically
proven anti
depressant. This drug is a known
monoamine oxidase
inhibitor, and it is certainly possible that some of this
pharmacological property might be found in DMCPA if it were to be
looked for. The hints of physical toxicity at the higher doses
assayed might suggest some such activity.
This compound, DMCPA, was modeled directly after the structure of DOM,
with the
2,5-dimethoxy-4-methyl substitution pattern. Another
analogue of
tranylcypromine, similarly modeled, is
3,4,5-trimethoxytranylcypromine, or
trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT). It has been
evaluated at levels of only 13 milligrams orally, and at this dose
there were no hints of central activity.
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