SYNTHESIS: A well stirred suspension of 140 g anhydrous AlCl3 in 400
mL CH2Cl2 was treated with 102 g butyryl chloride. This mixture was
added in small portions, over the course of 20 min, to a well-stirred
solution of 110.4 g p-dimethoxybenzene in 300 mL CH2Cl2. After an
additional 1 h stirring, the mixture was poured into 1 L H2O, and the
two phases separated. The aqueous phase was extracted with 2x100 mL
CH2Cl2, and the organic fractions pooled. These were washed with
4x125 mL 5% NaOH which removed both unreacted butyric acid as well as
a small amount of 2-hydroxy-4-methoxybutyrophenone. Removal of the
CH2Cl2 under vacuum gave 156.7 g of a residue that was distilled at
170-178 °C at the water pump. The isolated 2,5-dimethoxybutyrophenone
was a pale yellow oil that weighed 146 g and was about 85% pure by GC
analysis. The principal impurity was unreacted dimethoxybenzene. The
identical preparation with CS2 as a solvent, rather than CH2Cl2 gave a
somewhat smaller yield of product.
To 150 g mossy zinc there was added a solution of 3 g mercuric
chloride in 60 mL H2O, and this was swirled periodically for 2 h. The
H2O was drained off, and the amalgamated zinc added to a 1 L
three-neck round-bottomed flask, treated with 80 mL concentrated HCl,
and heated on the steam bath. A solution of 20.8 g of
2,5-dimethoxybutyrophenone in 45 mL EtOH containing 10 mL concentrated
HCl was added in increments over a 4 h period. During this period an
additional 140 mL of concentrated HCl was added periodically to the
ketone solution. Heating was maintained for an additional 4 h. After
cooling, the aqueous filtrate was extracted with 3x100 mL CH2Cl2 and
these pooled extracts washed with 2x200 mL 5% NaOH to remove a small
amount of phenolic impurity. After removal of the solvent under
vacuum, the residual 16.1 g of clear oil was distilled over the
100-160 °C range (largely at 141-145 °C) at the water pump to give 10
g of 2,5-dimethoxy-(n)-butylbenzene as a white oil. This was about
90% pure by GC analysis, and was used without further purification in
the next step.
A mixture of 98 mL POCl3 and 108 mL N-methylformanilide was allowed to
incubate for 0.5 h. To this there was then added 47.3 g of
2,5-dimethoxy-(n)-butylbenzene and the mixture heated on the steam
bath for 1.5 h. This mixture was poured into 1 L H2O and stirred
overnight. The H2O was drained from the extremely gooey black
crystals that were formed, and extracted with 2x100 mL portions of
hexane. The black residue was diluted with these extracts and, on
slow evaporation there was deposited 26.4 g of oily amber crystals.
Filtering these through a medium porous funnel and sucking the oily
phase away from the solids yielded 14.8 g of yellow crystals that
could be recrystallized from 50 mL MeOH to give, after filtration and
air drying to constant weight, 6.4 g of
2,5-dimethoxy-4-(n)-butylbenzaldehyde as pale yellow crystals with a
mp of 47-48 °C. The recovery of all organic soluble things from the
above process gave, after removal of the extraction solvents and
making boiling hexane extractions of the residues, a second crop of
aldehyde of equal weight and of identical mp. An analytical sample,
from hexane, had the same mp. Anal. (C13H18O3) C,H.
A solution of 13.2 g 2,5-dimethoxy-4-(n)-butylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g anhydrous ammonium acetate and 10
mL nitroethane. This mixture was heated on the steam bath for 4 h,
then poured into a large quantity of H2O. This was extracted with
2x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed
to give 19 g of a deep red oil. This was dissolved in 35 mL hot MeOH
and slowly cooled, depositing yellow-orange crystals. These were
removed by filtration, washed with cold MeOH, and air-dried to
constant weight. Thus there was obtained 11.8 g of
1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene with a mp of 54-56
°C. Recrystallization of an analytical sample from MeOH tightened the
mp to 55-56 °C. Anal. (C15H21NO4) C,H,N.
To a gently refluxing suspension of 8.5 g LAH in 300 mL anhydrous Et2O
under a He atmosphere, there was added 11.0 g
1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene by allowing the
condensing ether to drip into a Soxhlet thimble containing the
nitrostyrene, thus effectively adding a warm saturated solution of it
dropwise. Refluxing was maintained overnight, and the cooled reaction
flask stirred for several additional days. The excess hydride was
destroyed by the cautious addition of 600 mL H2O containing 55 g
H2SO4. When the aqueous and Et2O layers were finally clear, they were
separated, and 250 g of potassium sodium tartrate was dissolved in the
aqueous fraction. Aqueous NaOH was then added until the pH was above
9, and this was then extracted with 3x200 mL CH2Cl2. Evaporation of
the solvent produced 12 g of an amber oil that gelatinized to a waxy,
amorphous mass. This was leached as thoroughly as possible with
anhydrous Et2O which was clarified by filtration, then saturated with
anhydrous HCl gas. After a few minutes delay, there commenced the
separation of fine white crystals of
2,5-dimethoxy-4-(n)-butylamphetamine hydrochloride (DOBU). These
weighed, after filtration, Et2O washing, and air drying to constant
weight, 5.8 g. Recrystallization from boiling CH3CN (this is an
unusually exothermic crystallization) yielded 5.4 g of a fluffy white
product with mp 151-152 °C. Anal. (C15H26ClNO2) C,H,N.
DOSAGE: uncertain.
DURATION: very long.
QUALITATIVE COMMENTS: (with 2.2 mg) It was almost the fourth hour
before I noticed something. Then I felt an increasing manic
intoxication, winding up tighter and tighter. Sleep was impossible
until some 18 hours after the start of the trial. There was some
paresthesia, but no mydriasis. This might be a stimulant, but it is
not a psychedelic, at least at this level. Go up slowly.
(with 2.8 mg) Nothing for over seven hours. Then there was what
seemed to be an irritability and shortness of temper. Mentally I am
completely clear, but no more alert than usual. There was no sleep
that evening, and the next day there was a feeling of overall
depression. Perhaps that was due to the lack of sleep, but there were
no signs of residual sleepiness.
EXTENSIONS AND COMMENTARY: It is not possible to give a dosage range
for DOBU. There is no question but that whatever is occurring is slow
of onset, and very long lived. In general, the effects resemble
stimulation more that anything else.
A butyl group has four carbons, and they can be interconnected in four
ways (as long as you don't connect them in rings). If all four of
them are in a straight chain, you have the so-called normal butyl (or
n-butyl) group, and this is the exact arrangement that is found in the
DOBU. The atoms can be numbered #1 through #4, going outwards from
the point of attachment. The chain can, however, be only three
carbons long, and the fourth or extra carbon attached on the #2 carbon
atom; this is called the iso-butyl (or i-butyl) group. Or the extra
left-over carbon can be attached to the #1 carbon atom; this is called
the secondary butyl (or sec-butyl or s-butyl) group. Or lastly, the
atoms can be all scrunched up, with the chain only two carbons long,
and the other two left-over methyl carbons attached to the #1 carbon
atom. This isomer is called the tertiary butyl (or tert-butyl or
t-butyl) group. In animal studies, and in preliminary human studies,
the activity of these compounds drops as the butyl group gets more and
more scrunched.
The isomer with the iso-butyl group has been synthesized by the
Friedel- Crafts reaction of isobutyryl chloride with
p-dimethoxybenzene, followed by reduction of the ketone to an alcohol,
dehydration to a dimethylstyrene, and final hydrogenation to a
hydrocarbon. The formation of the benzaldehyde, reaction with
nitroethane, and final lithium aluminum hydride reduction to
2,5-dimethoxy-4-(2-methylpropyl)-amphetamine hydrochloride (DOIB, mp
164-166 °C) were completely conventional. In drug discrimination
studies in rats, DOIB was only a third as active as DOM, and in humans
the activity falls in the 10 to 15 milligram area. The isomer with
the sec-butyl group was made in a somewhat similar manner, from
2,5-dimeth-oxyacetophenone. The addition of ethyl magnesium bromide
gave an alcohol which with dehydration yielded a pair of
dimethylstyrenes isomeric to the compound mentioned above. From there
an identical sequence of steps (hydrogenation, benzaldehyde synthesis,
nitrostyrene, and lithium aluminum hydride reduction) produced
2,5-dimethoxy-4-(1-methylpropyl)amphetamine hydrochloride (DOSB, mp
168-170 °C.). In the rat studies it was only a twelfth the potency of
DOM, and in man the active dose is in the 25 to 30 milligram area. As
with the normal butyl compound, there is a strong stimulation factor,
with real and long-lasting sleep disturbance.
The last of the butyl isomers, the tert-butyl compound, was made from
a much more obvious starting material. This is the commercially
available tert-butyl hydroquinone. It was methylated in sodium
hydroxide with methyl iodide, and then carried through the above
sequence (benzaldehyde. mp 124 °C from cyclohexane, nitrostyrene,
yellow crystals from methanol, mp 95-96.5 °C, and lithium aluminum
hydride reduction) to give
2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp
168 °C). Rats trained in a process called the Sidman Avoidance
Schedule gave behavior that suggested that DOTB had no activity at
all, and in human trials, doses of up to 25 milligrams were totally
without effect.
An effort was made to prepare a butyl analogue containing a ring, but
it was never completed. This was the cyclopropylmethyl isomer,
2,5-dimethoxy-4-cyclo-propylmethylamphetamine hydrochloride, DOCPM.
Only the first step of its synthesis was complete (the reaction of
cyclopropylcarboxylic acid chloride with p-dimethoxybenzene) and even
it went badly. The desired ketone (2,5-dimethoxyphenyl cyclopropyl
ketone) was most difficult to separate from the recovered starting
ether. A promising approach would be the isolation of the phenol
(2-hydroxy-5-methoxyphenyl cyclopropyl ketone) which is a beautiful
yellow solid with a melting point of 99-100 °C from methanol. Anal.
(C11H12O3) C,H. It then could be methylated to the wanted
intermediate. It is the major product when the reaction is conducted
with anhydrous aluminum chloride in methylene chloride.
The 2-carbon phenethylamine homologues of these compounds could all,
in principle be easily made by using nitromethane instead of
nitroethane with the intermediary benzaldehydes. But, as of the
present time, none of them have been made, so their pharmacology
remains completely unknown.
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