EXTENSIONS AND COMMENTARY: It is clear that the three halo-amphetamine derivatives, DOI, DOB and DOC, are all pretty much of the same potency. And all of them very long lived. The difference between the various halogen atoms was brought up under the 2C-C discussion. DOC
is clearly a long-lasting, dyed-in-the-wool psychedelic.
In the making of this, by the procedures that have been followed in Canada, there are two chemical intermediates which might, some day, be looked at as potential psychedelics under their own colors. Reduction of the compound that is called DON in this Book II (2,5-dimethoxy-4-nitroamphetamine hydrochloride) with Pd/charcoal and hydrogen, gives the 4-amino derivative. This is 2,5-dimethoxy-4-aminoamphetamine dihydrochloride, DOA, which melts at 248-250 !C. And the reduction of an oxime intermediate gives rise to the acetamido analogue, 2,5-dimethoxy-4-acetamidoamphetamine hydrochloride, DOAA, with a mp of 249-250 !C. Neither compound has been tasted, but someday this omission will be corrected. DOA and DOAA have a sinister ring to them, however, and some changes of terminology might be needed. DOA, in the coroner's vocabulary, means Dead-On-Arrival. But then, AMA (the American Medical Association) just happens to also mean (in the jargon of emergency medicine) Against-Medical-Advice. Everything averages out, somehow. Remember that the amyl homolog (amyl at the 4-position) follows the 4-letter convention of all of the DOM homo-logues, and has the code name of DOAM. Thus, DOA, amino; DOAA, acetamido, and DOAM, amyl.
One must learn to keep one's sense of humor. The immortal humorist Wavy Gravy once said, RIf you canUt laugh at life, it just isnUt funny anymore.S The code name of this compound, 2,5-dimethoxy-4-chloroamphetamine is, after, all, DOC. This should certainly appeal to some physicians.
65 DOEF; 2,5-DIMETHOXY-4-(2-FLUOROETHYL)-
AMPHETAMINE
SYNTHESIS: A well-stirred solution of 0.45 g free base DOB in 2 mL
CH2Cl2 was treated with 0.37 g triethylamine, cooled to 0 !C, and there was then added a solution of 0.39 g 1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene in 2 mL CH2Cl2. The reaction mixture was allowed to return to room temperature, with stirring continued for 2 h. The solvent was removed under vacuum, the residue suspended in hexane, and the insoluble by-products removed by filtration through celite. Removal of the solvent under vacuum gave 0.60 g
1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane as a gold-colored impure semi-solid mass which was used without further purification.
To a solution of 0.60 g
1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane in 10 mL anhydrous Et2O under an inert atmosphere and cooled to -78 !C
there was added 1.8 mL of a 1.7 M solution of t-butyl lithium in hexane. The resulting yellow solution was stirred for 20 min, and then treated with 1.65 mL of a 1.4 M solution of ethylene oxide in Et2O, the stirring was continued for 40 min, then the reaction mixture allowed to come to room temperature over an additional 40 min. There was added 20 mL hexane, and the temperature increased to 50 !C for an additional 2 h. The reaction mixture was treated with 3 mL H2O and diluted with 60 mL Et2O. The organic phase was washed with saturated NH4Cl, dried over anhydrous MgSO4, and after filtering off the inorganic drying agent, the organic solvents were removed under vacuum. The gold-colored residual oil was dissolved in 10 mL MeOH and treated with a 10% KOH. This mixture was heated for 30 min on the steam bath, returned to room temperature, and the volatiles removed under vacuum. The residue was dissolved in 3% H2SO4, washed twice with CH2Cl2, brought to pH 12 with 25% NaOH, and extracted with 3x50
mL CH2Cl2. The pooled extracts were combined, dried with anhydrous Na2SO4, and the solvent removed under vacuum to give 0.24 g of 2,5-dimethoxy-4-(2-hydroxyethyl)amphetamine (DOEH) as a white solid with a mp of 102-104 !C.
To a suspension of 0.94 g DOEH in ice-cold anhydrous Et2O containing 1.4 g triethylamine, there was added 2.4 g trifluoroacetic anhydride dropwise over the course of 10 min. The reaction mixture was brought to reflux temperature, and held there with stirring for 1 h. After cooling, 60 mL of CH2Cl2 was added, and the organic phase washed with saturated NaHCO3. The solvent was removed under vacuum, providing a gold-colored solid as a residue. This was dissolved in 50 mL MeOH, diluted with 30 mL H2O and, following the addition of 0.76 g solid NaHCO3 the reaction mixture was stirred at room temperature for 3 h.
The excess MeOH was removed under vacuum, and the remaining solids were suspended in CH2Cl2 and washed with H2O. After drying the organic phase with anhydrous Na2SO4 and removal of the solvent under vacuum, there was obtained 1.34 g
1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane as white solid with a mp of 129-131 !C. Anal. (C15H20F3NO4) C,H.
A well-stirred solution of 0.09 g
1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane in 15 mL CH2Cl2 was cooled to -78 !C and treated with 0.05 g diethylaminosulfur trifluoride (DAST) added dropwise. The pale yellow reaction solution was stirred an additional 5 min and then brought up to room temperature and stirred for 1 h. There was then added (cautiously) 3 mL H2O followed by additional CH2Cl2. The phases were separated, the organic phase washed with H2O, dried with anhydrous Na2SO4 and, after filtering off the drying agent, stripped of solvent under vacuum. There was thus obtained 0.088 g of 1-[2,5-dimethoxy-4-(2-fluoroethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane as a white solid with a mp of 102-104 !C.
A solution of 0.12 g
1-[2,5-dimethoxy-4-(2-hydroxyethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane in a mixture of 5 mL CH2Cl2 and 5 mL IPA was treated with 0.2 mL 2 N
KOH, heated on the steam bath for 30 min, and then stripped of solvents under vacuum. The residue was suspended in CH2Cl2 and washed with 20% NaOH. The organic phase was dried with anhydrous Na2SO4
which was removed by filtration, and the combined filtrate and washings stripped of solvent under vacuum. The residual glass (0.08
g) was dissolved in IPA, neutralized with concentrated HCl and diluted with anhydrous Et2O to provide
2,5-dimethoxy-4-(2-fluoroethyl)amphetamine hydrochloride (DOEF) as a white crystalline solid with a mp of 205-208 !C. Anal. (C13H21ClFNO2) C,H.
DOSAGE: 2 - 3.5 mg.
DURATION: 12 - 16 h.
QUALITATIVE COMMENTS: (with 2.2 mg) Somewhere between the first and second hour, I grew into a world that was slightly unworldly. Why?
That is hard to say, as there was no appreciable visual component. I just knew that the place I was in was not completely familiar, and it was not necessarily friendly. But it was fascinating, and the music around me was magical. Time was moving slowly. I had to drive across the bay at about ten hours into this, and I was comfortable. That evening I slept well, but my dreams were pointless.
(with 3.0 mg) It took almost three hours to full activity. The first signs of effects were felt within a half hour, but from then on the progress was slow and easy, without any discernible jumps. There was absolutely no body discomfort at all. Completely comfortable. There was a general humorousness about my state of mind which is always a good sign. We went to the bedroom at the two and a half hour point, and proceeded to establish that the material is far from anti-erotic.
Beautiful response, without a mention of any feeling of risk at orgasm. I myself was not able to reach orgasm until about 5th to 6th hour, and then it was full and exceptionally delicious. So was the second one, a couple of hours later, if I remember correctly. All systems intact, body, mind and emotion. Gentle. Good for writing.
No dark corners apparent at all. For me, not highly visual. Would take again, higher.
(with 3.0 mg) There was no body threat at any time Q very comfortable. Good eyes closed, with complex imagery to music, but not too much with eyes-open. My attention span is relatively short, and easily diverted into new directions Q all quite reminiscent of DOI both as to dosage and effect. At 13 hours, I am still too alert to sleep, but a couple of hours later, OK. In the morning there is still a trace of somethi
ng going on. This was a valid +++.
EXTENSIONS AND COMMENTARY: I was asked by a student of mine a while ago, when I told him of this material, just why would anyone just happen to place a fluorine atom at the end of the 4-ethyl group of DOET? It wasnUt the sort of thing that someone would just happen to do. If there were a rationale, then that's fine. But by capricious impulse, no. But there is a rationale of sorts, which I just hinted at in the discussion under 2C-T-21.
This argument of reason goes as follows. Assume that I would like to put a fluorine atom into a drug that does not normally have one. Why would I want to? Because I want to have the molecule carry a radioactive fluorine atom into some inner recess of the brain. Why?
Because by using a positron-emitting fluorine I could possibly visualize the area of the brain that the drug went to. And if it went there in some abnormal way, the exact measure of that abnormality might give some clue as to potential brain misfunctioning.
But, if you put a fluorine atom on a drug, it becomes a totally new drug and, quite reasonably, a pharmacologically different drug.
However, a body of evidence is being accumulated that if a halogen, such as a bromine or an iodine atom, is replaced by a beta-fluoroethyl group, the electronic and polar properties of the drug can be pretty much the same. So, what psychedelics have a bromo or an iodo group?
Obviously, DOB and DOI. Thus, DOEF is a natural candidate for fluorine-18 positron emission tomography, and also a natural candidate for clinical trials. And, voila, it is an active material.
And IUll bet you dollars to doughnuts, that if one were to make the two-carbon analog 2,5-dimethoxy-4-(2-fluoroethyl)-phenethylamine, it would be every bit as much a treasure and ally as is 2C-B or 2C-I. In fact, I am sure enough about this prediction that I am willing to name the stuff 2C-EF. It will be easily made from 2C-B by the same reaction scheme that was used above for DOEF. And I will even guess that its activity level will be in the 20-30 milligram area.
66 DOET; HECATE; 2,5-DIMETHOXY-4-ETHYLAMPHETAMINE
SYNTHESIS: To a solution of 19.7 g 2,5-dimethoxy-4-ethylbenzaldehyde (see the recipe for 2C-E for its preparation) in 72 g glacial acetic acid there was added 6.5 g anhydrous ammonium acetate and 10.2 g nitroethane. After heating for 1.75 h on the steam bath, the reaction mixture was cooled in a wet ice bath, diluted with 10 mL H2O, and seeded with a small crystal of product. The yellow crystals were removed by filtration (7.6 g wet with acetic acid) and another 2.25 g was obtained from the mother liquors with additional H2O. The combined fractions were recrystallized from 25 mL boiling MeOH, to give 6.5 g fine yellow crystals of
1-(2,5-dimethoxy-4-ethyl)-2-nitropropene, with a mp of 67.5-68.5 !C.
Anal. (C13H17NO4) C,H,N.
A suspension of 6.5 g LAH in 500 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 6.5 g 1-(2,5-dimethoxy-4-ethylphenyl)-2-nitropropene. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 18 h, then cooled to room temperature.
The excess hydride was destroyed with 500 mL 8% H2SO4, added cautiously until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 150 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue, 7.9 g of a clear oil, was dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-ethylamphetamine hydrochloride (DOET) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 5.9 g of lustrous white crystal with a mp of 190-191 !C.
Recrystallization from CH3CN or EtOAc increased the mp to 194-195 !C.
Anal. (C13H22ClNO2) C,H,N.
DOSAGE: 2 - 6 mg.
DURATION: 14 - 20 h.
QUALITATIVE COMMENTS: (with 1.0 mg) This was a very gentle, relaxing level, but there were no psychedelic effects that were apparent.
Easy, and relaxed, and I am in no way intoxicated or turned on. But I was in the throes of my menstrual period, and the cramps (and the accompanying irritability) were completely knocked out. Perhaps this is why I felt so relaxed and at peace.
(with 2.5 mg) There is much, too much, movement with my eyes closed.
And an awful lot there with my eyes open. The movement on the concrete floor in the basement when I went downstairs for wood for the fireplace, was too much. I felt almost sea-sick. And I am having reality problems Q I cannot seem to find my centering point of reference. There has to be a place to pin myself down to, and it is not findable anywhere I look. And my legs are twitching, and feeling as if they are falling asleep, and I had a crawling sensation on my body, so the body is not at peace either. In the morning I was still ++, but there is a clear indication that I am repairing. Anyway, I survived the experience. This is definitely not my thing.
(with 4 mg) Just after an hour into the experiment, I was surprised by the awareness of some effects Q I had forgotten that I had taken something. At the second hour, it was real, but subtle. As a psychotomimetic or STP-like thing, there is very little there. But as a mood energizer, it is really a ++ or more. The clinical literature is right Q none of the hallucinogenic effects, but one brings into play whatever one wants to. Worked at cleaning up the office until 11
PM. I slept well. This has none of the LSD or STP seriousness.
(with 6 mg) The onset was slow, and subtle. But the effects are fully there in about three or so hours. Everything I smelled was vivid, as are all the colors and shapes; they are clean, beautiful, serenely self-contained. No visual movement. The eyes-closed fantasy images tend to take off on their own, however, and they are extremely rich. I donUt see any dark corners. I believe it might well be possible to be creative with this, and there is no suggestion of body depletion, of body load.
(with 7 mg) A hot day. Unbelievably lovely erotic-to-divine, deep loving, open, not much visual, eyes-closed form-image-symbol. Sleep attempts very shallow, slight TthinnessU, with an anticipation of darts. Intellect and feeling-emotion area intact and functioning at all times. Next morning still at a plus one. Incredible material.
Perhaps best at 6 to 7 milligrams, no higher due to body load.
EXTENSIONS AND COMMENTARY: The original code for this compound was DOE, which was completely logical based on DOM being the methyl member of this series (DO for the removal of the oxygen, desoxy, and M for putting a methyl in its place). And the putting of the ethyl thence should be DOE. This was fine until it was pointed out to me by a close colleague that DOE was a classic abbreviation for desoxyephedrine, a synonym for methamphetamine. The pressure to add the RTS of the RETS of the ethyl was heightened by looking ahead to other members of the series. DOA became DOAM, DOE became DOET, but DOM was already too firmly set in popular usage. And, anyway, DOME
really looked strange.
The original publications of the action of DOM clearly documented the compound as being a psychedelic and one with a sizeable measure of potential abuse. And, it is not a surprise that it was quickly shuffled into a legal classification that effectively precluded any further study of it. So, when this immediate homologue of DOM was studied and discussed in the literature, all reported dosages were those that were at the lowest levels, and no disturbing hints of abusability were mentioned. And this particular homologue has so far escaped the attention and restrictive action of the drug enforcement agencies, although the specific wording of the Controlled Substance Analogue Enforcement Act of 1986 might make this point moot, at least as far as human trials are concerned. At modest levels, DOET has the reputation of being a cognitive enhancer and is largely free of those sensory distortions that would catch the attention of the authorities who cannot tolerate drugs that distort the senses. The higher levels men
tioned here have never been put into the published literature. It must be noted that there is a considerable variation of individual responses to this material. The effective dose range stated is quite broad. Some people are quite sensitive. This is, after all, one of the Classic Ladies, namely HECATE.
The young experimental subject who had the dramatic relief from menstrual cramps at the one milligram dose tried the compound again the following month, and again had complete relief. But another volunteer, also plagued with severe cramping at that particular time of month, found no relief at all. A 50% success rate. No one else has, to my knowledge, explored this particular property.
67 DOI; 2,5-DIMETHOXY-4-IODOAMPHETAMINE
SYNTHESIS: A mixture of 14.8 g phthalic anhydride and 19.5 g of 2,5-dimethoxyamphetamine (2,5-DMA) as the free base was heated gradually to about 150 !C with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was allowed to cool to about 50 !C and then diluted with 100 mL of hot MeOH. The solution was stirred until homogenous, seeded with product, and then cooled in an ice bath to complete the crystallization. After removal of the product by filtration, washing sparingly with MeOH, and air drying, there was obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide as off-white crystals, with a mp of 105-106 !C. Anal. (C19H19NO4) C,H,N.
To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide in 15 mL warm acetic acid which was being vigorously stirred, there was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid.
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