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 wasn't 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 "This
compound has an LD-50 in the mouse of 70 mg/Kg." 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.
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