9, and the clear solution was extracted with 3x100 mL CH2Cl2.
Remo-val of the solvent from the combined extracts under vacuum gave 5.2 g of a pale yellow oil. This was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas, giving 5.0 g of a slightly sticky off-white solid. This was recrystallized from 75 mL of boiling CH3CN to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride (DMPEA) as beautiful white crystals.
DOSAGE: greater than 1000 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 500 mg) Nothing.
(with 1000 mg) Nothing.
(with 10 mg i.v.) RNothing.
(with 1000 mg of 3,4-dimethoxyphenylacetic acid, a major human metabolite of DMPEA) RNothing.
(with 500 mg of N-acetyl-3,4-dimethoxyphenethylamine, a major human metabolite of DMPEA) RNothing.
EXTENSIONS AND COMMENTARY: Why all the interest? Why keep pursuing a compound that is so obviously without activity? Or a metabolite that is also without activity? The answer is that these are totally fascinating compounds just because they have no activity! By the way, in this instance, I actually made up most of the quotations. I am not sure that the subjects actually said, RNothing,S but they did report that there were no effects. In my own experiments, my notes record the phrase, RNo effects whatsoever.
A little background: one of the transmitter heavyweights in the brain is dopamine. Dopamine is called dopamine because it is an amine that comes from an amino acid that is 3,4-dihydroxyphenylalanine and this, in German, is Di-Oxo-Phenyl-Alanine, or DOPA. The levo-optical (or L-) isomer of DOPA has rather cutely been called the punch-drunk Spanish matador, or El Dopa. But that is not part of the story.
The story is really about the RPink Spot of Schizophrenia.S Many years ago, an observation was made in a biochemical laboratory on the East Coast that stirred up a rolling controversy. It had been found that if the urines of schizophrenic patients (sloppily called Rschizophrenic urinesS) were extracted in such and such a way, and the extracts chromatographed, a pink spot would develop at a particular place on the chromatogram. Well, if this proved to be true with urines of a sick population, and were this proved to be different from the urines of a healthy population, it would constitute an objective diagnosis of schizophrenia. A simple chemical test to confirm a pathology that had defied all efforts to achieve consensus amongst the psychiatrists of the world.
The literature was suddenly filled with dozens of papers. Researcher A confirmed that the pink spot was found with schizophrenics, and not with normal controls. Researcher B found the pink spot in all urines, regardless of pathology. Researcher C found it in no urines at all.
Researcher D argued that it was a factor from the hospital diet.
Researcher E found that the pink spot reflected the time of day that the urine sample was collected. Researcher F drew a conclusion about where truth might lie by tallying the number of papers that supported argument A, B, C, D, or E.
The only confirmable fact that endured was that the pink spot was due to DMPEA. So a bright spotlight was directed towards its possible role in mental illness. And this expressed itself in the simple question: would it produce schizophrenia in a normal subject? No.
And in a way I am comforted that that did not evolve into a simple litmus test for a schizophrenic diagnosis. There are so many cultural, political, and social factors that come to bear on the assignment of a diagnosis of mental illness, that I would have been forever skeptical of a neat biochemical marker.
A chemical modification of DMPEA that has been explored in this question of pink spots, mental pathology, and diagnostic markers, is the corresponding acetamide. One of the metabolites of DMPEA was found to be the N-acetyl deriva-tive, N-acetyl-3,4-
dimethoxyphenethylamine. It was found to be demethylated in man, and to have pharmacological activity in animals. Maybe this was the active compound that could be involved in the schizophrenic process.
But human trials with it, as with the principal metabolite 3,4-dimethoxyphenylacetic acid, showed nothing at all in man.
Another chemical modification is the beta-hydroxy analogue of DMPEA.
It has been explored separately, and is the subject of its own recipe, in its own rights. See DME.
Pink was not the only colorful spot associated with schizophrenia.
Somewhere at about this same time, a research paper from Canada reported the observation of a mauve spot in the chromatographic analysis of urines of schizophrenic patients. This had nothing to do with DMPEA. I was working closely with a researcher at the psychiatric institute and we were fascinated by, again, a possible diagnostic marker. We assayed the urines of the next 10 patients being admitted as acute schizophrenics. No trace of mauve. We wrote to Canada, and verified the analytical procedure. We were told that the whatzis should have been added after, rather than before, the whosey, and that we should have heated for 30, not 10 minutes. Okay.
We assayed the urines of the next 10 patients being admitted using these new directions. No trace of mauve. Another call to Canada, and we were informed that we still werenUt doing it right. They were consistently batting a 100% positive correlation between mauve spots and schizophrenics, and 0% with healthy controls. In fact, they actually gave this positive test the name of a disease, Malvaria.
Then, that little burst of insight! Aha! What if, just what if, they had been seeing something given to their schizophrenics?
Chlorpromazine was the popular treatment of the day. We took a whopping dose of chlorpromazine, and over the next couple of days did manage (barely) to collect our urine samples. Both of us were positive Malvarians! And three days later, we were again negative.
We were most likely seeing a metabolite of chlorpromazine. One last call to Canada with the ultimate question Q had you given any medication to your schizophrenics before your urine analysis? Of course (came the answer) Q it would not be ethical to leave them untreated. Another color down the drain, and still no objective measure for mental illness.
By the way, I cannot say I like the chlorpromazine trip. There is no real communication either with others or with yourself, with that stuff. You are a zombie, but if you are both schizophrenic and a zombie, you cannot possibly be troublesome for anybody in the emergency room.
61 DOAM; 2,5-DIMETHOXY-4-(n)-AMYLAMPHETAMINE
SYNTHESIS: A solution of 110 g p-dimethoxybenzene and 102 g valeric acid in 168 g polyphosphoric acid was heated on the steam bath for 3
h, giving a deep red homogeneous solution. This was poured into 1 L
H2O with good stirring. The strongly acidic, cloudy suspension was extracted with 3x200 mL CH2Cl2, the extracts pooled, washed with 4x150
mL 5% NaOH, and finally once with dilute HCl. The solvent was removed under vacuum, and the residual amber oil cooled overnight at 0 !C.
Some 30 g of crystalline, unreacted dimethoxybenzene were removed by filtration, and the 85 g of residual oil distilled at the water pump.
Another 15 g of di-methoxybenzene came over as an early cut, but the fraction boil-ing at 184-192 !C (mostly 188-192 !C) weighed 53.0 g and was reasonably pure 2,5-dimethoxyamylophenone. The reaction of the acid chloride of valeric acid with p-dimethoxybenzene and anhydrous AlCl3 in CH2Cl2 (parallel to the preparation of the butyrophenone analog, see DOBU) gave an inferior yield (23.2 g from 92 g dimethoxybenzene), but did provide a sizeable sample (12.2 g) of 2-hydroxy-5-methoxyamylophenone from the basic washes of the crude reaction mixture. This pale yellow solid, after recrystallization from MeOH, had a mp of 62-62.5 !C. Anal. (C12H16O3) C,H.
To 360 g mossy zinc there was added a solution of 7.2 g mercuric chloride in 200 mL warm H2O, and this was swirled periodically for 2
h. The H2O was drained off, and the amalgamated zinc added to a 2 L
three-neck round-bottomed flask, treated with 200 mL concentrated HCl, and heated with an electric mantle. A solution of 53.0 g of 2,5-dimethoxyamylophenone in 107 mL EtOH containing 30 mL concentrated HCl was added drop-wise over the course of 4 h accomp
anied by 330 mL
of concentrated HCl added batchwise over this same period. The mixture was held at reflux overnight and, after cooling, diluted with sufficient H2O to allowed CH2Cl2 to be the lower phase. The phases were separated, and the aqueous phase was extracted with 2x200 mL
additional CH2Cl2. These organic phases were combined, washed first with 5% NaOH and then with H2O, and the solvent removed under vacuum.
Distillation at the water pump yielded two fractions. The first distilled from about 100-130 !C, weighed 8.8 g, had a faint smell of apples and fennel, and was free of a carbonyl group in the infra-red.
It proved to be only 50% pure by GC, however, and was discarded. The major fraction was a pale amber oil distilling between 152-170 !C and was substantially free of smell. It weighed 18.9 g, and was (by GC) 90% pure 2,5-dimethoxy-(n)-amylbenzene.
A mixture of 36.3 g POCl3 and 40.9 g N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 18.5 g of 2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath for 2 h. This mixture was poured into a large quantity of H2O and stirred overnight. The black oily product was extracted with 3x100 mL
CH2Cl2, and the extracts combined and stripped of solvent under vacuum. The black residue was distilled at 180-205 !C at 20 mm/Hg to give 12.5 g of a pale amber oil that slowly set up to a crystalline mass. An analytical sample was recrystallized from MeOH to provide 2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 !C. Anal.
(C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74.
A solution of 12.3 g 2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g anhydrous ammonium acetate and 12
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 3x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give a deep red oil that, on standing in the refrigerator, slowly set to a crystalline mass weighing 13.5 g. An analytical sample was recrystallized from MeOH to provide
1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow microcrystals with a mp of 44 !C sharp. Anal. (C16H23NO4) C,H,N.
To a gently refluxing suspension of 10 g LAH in 500 mL anhydrous Et2O
under a He atmosphere, there was added by 13.2 g 1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the condensing ether drip into a Soxhlet thimble containing the nitrostyrene which effectively added a warm saturated solution of it dropwise to the reaction mixture. Refluxing was maintained for 18 h, and the cooled reaction flask stirred for several additional days.
The excess hydride was destroyed by the cautious addition of 1 L 8%
H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and the aqueous layer was washed with an additional 2x100
mL Et2O. Removal of the solvent from the organic phase and washings provided 4.7 g of a thick red oil that was discarded. The aqueous phase was then extracted with 2x200 mL CH2Cl2 which actually removed the product as the sulfate salt. This organic phase was washed with 2x100 mL 5% K2CO3 (removing the H2SO4) and with the evaporation of the solvent there was obtained 6.2 g of an oily amber residue. This was dissolved in 200 mL Et2O and saturated with anhydrous HCl gas. Fine white crystals of 2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride (DOAM) separated, were removed by filtration, Et2O-washed and air dried, and weighed 5.2 g. The mp of 136-139 !C was increased to 145-146 !C by recrystallization from CH3CN. Anal. (C16H28ClNO2) C,H,N.
DOSAGE: greater than 10 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that in no way interfered with my day's activities. I was quite gay and voluble at lunch and bubbled on into the afternoon with puns and high spirits. There may have been a little motor incoordination as noted in handwriting, and there was a strange tenseness during driving.
There were no sequelae, there was no trouble sleeping, and with this potency way down from the lower homologues, I have no pressing desire to take this compound to a higher dose.
EXTENSIONS AND COMMENTARY: The actual procedure that was published for the isolation of this final amine was a different one, one that would certainly work, but which was based on the procedures tried and proven with the lower homologues. The process described above is just a bit bizarre (a sulfate salt extracting into methylene chloride) but it was the actual thing that was done. The work was started towards two additional compounds but these never got past the first Rketone and phenolS stage. p-Dimethoxybenzene was brought into reaction with n-caproic acid with polyphosphoric acid (aiming towards 2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when DOAM proved to be down in potency. And the reaction between p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ). A goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was obtained as fine yellow crystals, but this line of inquiry was also dropped.
The preparation of DOAM was, as a matter of fact, the last of the homol-ogous series of compounds actually completed, which stemmed from the original discovery of DOM. The RTen Classic LadiesS concept was mentioned under ARIADNE, and the adding of a methyl group in the place of a hydrogen atom at the 4-position-methyl led to the synthesis of Ms. HECATE and gave rise to DOET. The whole series of methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that the potency seemed to increase initially as the chain got longer, and then it abruptly dropped off. WouldnUt it be nice, I thought, if I could interest some pharmacologist in looking at this tight set of drugs with some animal model, to see if there is some neurotransmitter activity that would show a parallel action.
I learned of a curious young researcher in Washington who had an elegant procedure for measuring serotonin agonist action using the (otherwise) discarded sheep umbilical artery strips. These become available each year at lambing time, do not cost the life of anything, and require very little compound. He assayed my compounds and, lo and behold, the serotonin activity also went through a maximum in the middle of this series. We published a short paper to this effect, which served as a excellent vehicle to get the cogent human data into the scientific literature.
I have never understood the reasons that there might be connection between the twitching of a umbilical artery in a sheep and the appearance of an insight in the mind of man. And, I have never personally met this pharmacologist. Some day, I hope to do both.
62 DOB; 2,5-DIMETHOXY-4-BROMOAMPHETAMINE
SYNTHESIS: To a well-stirred solution of 1.95 g of the free base of 2,5-dimethoxyamphetamine (2,5-DMA) in 12 mL glacial acetic acid, there was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over the course of 5 min. The slightly exothermic reaction was allowed to stir for 3 h, and then added to about 200 mL H2O. The cloudy solution was washed with 2x100 Et2O, made basic with aqueous NaOH, and extracted with 3x100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave about 3 mL of a pale amber oil which was dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl gas. The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine hydrochloride, DOB, were removed by filtration, Et2O washed, and air dried. These weighed 1.7 g and had a mp of 195-196 !C.
Recrystallization from IPA brought this up to 207-208 !C. Proton NMR
spectroscopy of the hydrochloride salt in D2O gave confidence that the bromine atom had uniquely entered the 4-position, in that there were only two unsplit aromatic hydrogen atoms present, at 6.97 and at 7.20
ppm downfield from external TMS.
DOSAGE: 1.0 - 3.0 mg.
DURATION: 18 - 30 h.
QUALITATIVE COMMENTS: (with 0.4 mg) There was a distinct enhancement of visual perception, and some strengthening of colors. A clean, cold feeling of wind on the skin. I felt an enriched emotional affect, a comfortable and good feeling, and easy sleeping with colorful and important dreams.
(with 2.0 mg) There was a continuous tremor at the p
hysical level, and an incredible Moebius strip representation of reality at the intellectual level. I was able to enter into personal problems easily, and get out again when I chose to. During the next day, there were brief lapses of attention, or little fugue states, and it was not until the following evening that I was completely myself again.
(with 2.8 mg) About three hours into this I had a severe cramp, and had a near fainting response to the pain, and yet there was no pain!
I felt that I was very near a loss of consciousness, and this was most disturbing. There were flashes of depersonalization. I saw rings around the moon with prismatic colors, and there were long-lasting Rafter-imagesS following any viewings of points of light. I was still a good plus 1 at 14 hours, but did manage to sleep. It was the next day before I was again at baseline.
(with 3.0 mg) This was a complex, but a very good day. It involved making a large pot of chicken-vegetable soup, and listening to H.L., my favorite Saturday morning fundamentalist Christian radio preacher, bless Tim. The Democrats are not exactly all anti-American dupes of Moscow (or the Devil), but to H.L., they are practically, almost, next-door to it. The Rapture is supposed to happen tomorrow according to a certain book, newly published (just in time, looks like) and he is busy softening the possible disappointment of those who may find themselves unchanged Monday morning. Wunnerful. It's been one heck of a good experiment, and I canUt understand why we waited nine years to try this gorgeous stuff. Without going into the cosmic and delicious details, let's just say itUs a great material and a good level.
(with 0.5 mg of the RRS isomer) I am underway, and this is a smooth intoxication. I am completely functional, but still really a plus two. I would not choose to drive a car. Not very far. I felt a rather quick dropping to a plus-one at the fifth hour, but there is a residual stimulation still the following morning.
(with 1.0 mg of the RRS isomer) By the fourth hour I am absolutely a +++ and am searching the kitchen for food. But what I eat is only so-so. There is not the introspection or intensity of 2.0 milligrams of the racemate material, but this is a rewarding place nonethless.
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