In a word, many people truly believe that they cannot afford the time or energy required for a deep search into themselves. One has to make a living, one has to maintain a social life, one has a multitude of obligations that truly consume the oh-so-few hours in the day. I simply cannot afford to take a day off just to indulge myself in such-and-such (choose one: digging to the bottom of a complex concept, giving my energies to those whom I can help, to search out my inner strengths and weaknesses) so instead I shall simply do such-and-such (choose one: read the book review, go to church on Sunday morning, use a short-acting psychedelic). The world is too much with us. This may be a bit harsh, but there is some merit to it.
HOT-17 is by no means a particularly potent compound. The hundred milligram area actually has been the kiss of death to several materials, as it is often at these levels that some physical concerns become evident. And it certainly is not a short lived compound. But, as has been so often the case, the long lived materials have proven to be the most memorable, in that once the entertainment aspect of the experience is past you, there is time for dipping deeply into the rich areas of the thought process, and the working through of ideas and concepts that are easily available. And when this access is coupled to the capability of talking and writing, then a rewarding experience is often the result.
As with the parent compound, 2C-T-17 itself, the presence of an asym-metric carbon atom out there on the (s)-butyl side chain will allow the separation of HOT-17 into two components which will be different and distinct in their actions. The activity of the racemic mixture often is an amalgamation of both sets of properties, and the separate assay of each component can often result in a fascinating and unexpected fractionation of these properties.
From: [email protected]
Newsgroups: sci.med,sci.chem,alt.drugs Subject: PiHKAL: The Chemical Story. File 4 of 6
(I'm posting this for a friend.)
This is part 4 of 6 of the second half of PiHKAL: A Chemical Love Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos or misprints in this file; further, because of ASCII limitations, many of the typographical symbols in the original book could not be properly represented in these files.
If you are seriously interested in the chemistry contained in these files, you should order a copy of the book PiHKAL. The book may be purchased for $22.95 ($18.95 + $4.00 postage and handling) from Transform Press, Box 13675, Berkeley, CA 94701. California residents please add $1.38 State sales tax.
At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.... No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herin, without being familiar with that drug's action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.
90 IDNNA; 2,5-DIMETHOXY-N,N-DIMETHYL-4-IODOAMPHETAMINE
SYNTHESIS: To a stirred solution of 0.4 g 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in 12 mL MeOH
containing 4 mL of a 40% formaldehyde solution there was added 1 g sodium cyanoborohydride. The pH was kept at about 6 by the occasional addition of HCl. When the pH was stable (about 48 h) the reaction mixture was poured into 250 mL H2O and made strongly basic by the addition of aqueous NaOH. This was extracted with 3x75 mL CH2Cl2, the extracts pooled, and extracted with 2x75 mL dilute H2SO4, and the pooled acidic extracts again made basic and again extracted with CH2Cl2. The solvent was removed under vacuum to give 0.38 g of a colorless oil. This was dissolved in 2 mL IPA and treated with a solution of 0.13 g oxalic acid dihydrate in 1.5 mL warm IPA, and then anhydrous Et2O was added dropwise until a turbidity persisted. Slowly a granular white solid appeared, which was filtered off, Et2O washed, and air dried to give 0.38 g of
2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine oxalate (IDNNA) with a mp of 145-146 !C. Anal. (C15H22INO6) C,H. The hydrochloride salt of this base proved to be hygroscopic.
DOSAGE: greater than 2.6 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This base, if it were given a code name based upon its substituents arranged in their proper alphabetical order, would have to be called something like DNDIA, which is quite unpronounceable. But by a rearrangement of these terms, one can achieve IDNNA (Iodo-Dimethoxy-N,N-dimethyl-Amphetamine) which has a nice lilt to it.
One of the major goals of research in nuclear medicine is a drug that can be used to demonstrate the brain blood flow pattern. To do this job, a drug should demonstrate four properties. First, it must carry a radioactive isotope that is a positron emitter (best, a fluorine or an iodine atom, for use with the positron camera) that can be put onto the molecule quickly, synthetically, and which will stay on the molecule, metabolically. Second, as to brain entry, the drug should be rapidly and extensively taken up by brain tissue, without being selectively absorbed or concentrated at any specific sites. In other words, it should go where the blood goes. Thirdly, the absorption should be strong enough that it will stay in the brain, and not be washed out quickly. This allows time to both locate and count the radioactivity that was carried in there. And lastly, the drug must be without pharmacological action.
IDNNA looked like a promising candidate when tried with a radioactive iodine label, and there was quite a flurry of interest in using it both as an ex-perimental drug, and as a prototype material for the synthesis of structural variants. It went in quickly, extensively and quite diffusely, and it stayed in for a long time.
But was it pharmacologically active? Here one finds a tricky road to walk. The animal toxicity and behavioral properties can be determined in a straightforward manner. Inject increasing amounts into an experimental animal and observe him closely. IDNNA was quite inert.
But, it is a very close analogue to the extremely potent psychedelic DOI, and it is widely admitted that animal assays are of no use in trying to determine this specific pharmacological property. So, a quiet human assay was called for. Since it did indeed go into the brain of experimental animals, it could quite likely go into the brain of man. In fact, that would be a needed property if the drug were to ever become useful as a diagnostic tool.
It was assayed up to levels where DOI would have been active, and no activity was found. So one could state that it had none of the psychedelic properties of DOI at levels where DOI would be active (this, at 2.6 milligrams orally). But you donUt assay much higher, because sooner or later, something might indeed show up. So it can be honestly said, IDNNA is less active than DOI itself, in man. LetUs wave our hands a bit, and make our statement with aggressive confidence. IDNNA has shown no activity in the human CNS at any level that has been evaluated. This sounds pretty good. Just donUt go too far up there, and donUt look too carefully. This is not as unscrupulous as it might sound since, in practical terms, the extremely high specific activities of the radioactive 122I that would be used, would dictate that only an extremely small amount of the drug would be required. One would be dealing, not with milligram quantities, but with microgram quantities, or less.
Some fifteen close analogues of IDNNA were prepared, to see if any had a better balance of biological properties. A valuable intermediate was an iodinated ketone that could be used either to synthesize IDNNA itself or, if it were to be made radio-labelled, it would allow the preparation of any desired radioactive analogue in a single synthetic step. The iodination of p-dimethoxybenzene with iodine monochloride in acetic acid gave 2,5-diiodo-1,4-dimethoxybenzene as white crystals from acetonitrile, with a mp of 167-168 !C. Anal. (C8H8I2O2) C,H.
Treatment of thi
s with an equivalent of butyllithium in ether, followed with N-methyl formanilide, gave 2,5-dimethoxy-4-iodobenzaldehyde as pale yellow crystals from ethanol, with a mp of 136-137 !C. Anal. (C9H9IO3) C,H. This, in solution in nitroethane with a small amount of anhydrous ammonium acetate, gave the nitrostyrene 1-(2,5-dimethoxy-4-iodophenyl)-2-nitropropene as gold-colored crystals from methanol, mp 119-120 !C. Anal.
(C11H12INO4) C,H. This was smoothly reduced with ele-mental iron in acetic acid to give 2,5-dimethoxy-4-iodophenylacetone as white crystals from methylcyclopentane. These melted at 62-63 !C and were both spec-troscopically and analytically correct. Anal. (C11H13IO3) C,H.
This intermediate, when reductively aminated with dimethylamine, gives IDNNA identical in all respects to the product from the dimethylation of DOI above. But it has also been reacted with 131I NaI in acetic acid at 140 !C for 10 min, giving the radioactive compound by exchange, and this was reductively aminated with over a dozen amines to give radioactive products for animal assay. There was produced in this way, 2,5-dimethoxy-4-iodo-N-alkyl-amphetamine where the alkyl group was methyl, isopropyl, cyclopropylmethyl, hexyl, dodecyl, benzyl, cyanomethyl, and 3-(dimethylaminopropyl). Several dialkyl homologue were made, with the alkyl groups being dimethyl (IDNNA itself), diethyl, isopropyl-methyl, and benzyl-methyl. These specific homologues and analogues are tallied in the index, but a number of other things, such as hydrazine or hydroxylamine derivatives, were either too impure or made in amounts too small to be valid, and they are ignored.
The diethyl compound without the iodine is 2,5-dimethoxy-N,N-diethylamphetamine, which was prepared by the reductive alkylation of DMA with acetaldehyde and sodium cyanoborohydride. This product, DEDMA, was a clear white oil, bp 82-92 !C at 0.15 mm/Hg which did not form a crystalline hydrochloride.
An interesting measure of just how different these N,N-dialkylated homologues can be from the psychedelic primary amines, pharmacologically, can be seen in the published report that the beta-hydroxy derivative of DEDMA is an antitussive, with a potency the same as codeine.
None of these many iodinated IDNNA analogues showed themselves to be superior to IDNNA itself, in the rat model, and none of them have been tasted for their psychedelic potential in man.
91 IM; ISOMESCALINE; 2,3,4-TRIMETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 8.0 g 2,3,4-trimethoxybenzaldehyde in 125 mL
nitromethane containing 1.4 g anhydrous ammonium acetate was held at reflux for 1.5 h. The conversion of the aldehyde to the nitrostyrene was optimum at this time, with a minimum development of a slow-moving spot as seen by thin layer chromatography on silica gel plates using CHCl3 as a developing solvent; the Rf of the aldehyde was 0.31 and the Rf of the nitrostyrene was 0.61. The excess nitromethane was removed under vacuum, and the residue was dissolved in 20 mL hot MeOH. On cooling, the yellow crystals that formed were removed by filtration, washed with cold MeOH and air dried yielding 4.7 g yellow crystals of 2,3,4-trimethoxy-'-nitrostyrene, with a mp of 73-74 !C. From the mother liquors, a second crop of 1.2 g was obtained.
A solution of 4.0 g LAH in 80 mL THF under He was cooled to 0 !C and vigorously stirred. There was added, dropwise, 2.7 mL of 100% H2SO4, followed by a solution of 4.7 g 2,3,4-trimethoxy-'-nitrostyrene in 40
mL anhydrous THF. The mixture was stirred at 0 !C for 1 h, at room temperature for 1 h, and then brought briefly to a reflux on the steam bath. After cooling again, the excess hydride was destroyed with 4.7
mL H2O in THF, followed by the addition of 18.8 mL 15% NaOH which was sufficient to convert the solids to a white and granular form. These were removed by filtration, the filter cake washed with THF, the mother liquor and filtrates combined, and the solvent removed under vacuum. The residue was added to dilute H2SO4, and washed with 2x75
mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 2x50 mL CH2Cl2. The solvent was removed from these pooled extracts and the amber-colored residue distilled at 95-100 !C
at 0.3 mm/Hg to provide 2.8 g of 2,3,4-trimethoxyphenethylamine as a white oil. This was dissolved in 20 mL IPA, neutralized with about 1
mL concentrated HCl, and diluted with 60 mL anhydrous Et2O. After filtering, Et2O-washing, and air drying, there was obtained 3.2 g of 2,3,4-trimethoxyphenethylamine hydrochloride (IM) as a white crystalline product.
DOSAGE: greater than 400 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 300 mg) No effects whatsoever.
(with 400 mg) Maybe a slight tingle at the hour-and-a-half point.
Maybe not. Certainly nothing an hour later. Put this down as being without action.
EXTENSIONS AND COMMENTARY: Some fifty years ago this material was given the name Rreciprocal mescalineS in that it was believed to exacerbate the clinical symptoms in schizophrenic patients. In the original report, one finds: RThus we have discovered an extremely remarkable dependency of the intoxicating action upon the position of the three methoxy groups. Mescaline, the 3,4,5-trimethoxy-'-phenethylamine, produces in the normal subject a much stronger over-all intoxication than in the schizophrenic patient, whereas 2,3,4-trimethoxy-'-phenethylamine has quite the opposite effect. It has little action in healthy individuals, being almost without intoxicating properties, but it is very potent in the schizophrenic. The metabolic conversion products of the RreciprocalS
mescaline will be further studied as soon as the study of the metabolism of the proper mescaline is complete.
This is a pretty rich offering, and one that the present medical community has no qualms about discarding. At the bookkeeping level, the promised further studies have never appeared, so all may be forgotten as far as potential new discoveries might be concerned.
One recent related study has been reported, tying together isomescaline and schizophrenia. Through the use of radioactive labelling, the extent of demethylation (the metabolic removal of the methyl groups from the methoxyls) was determined in both schizophrenic patients and normal subjects. When there was a loading of the person with methionine (an amino acid that is the principal source of the body's methyl groups), the schizophrenics appeared to show a lesser amount of demethylation.
But might either of these two observations lead to a diagnostic test for schizophrenia? At the present time, the conventional thinking is that this probably cannot be. The illness has such social and genetic contributions, that no simple measure of a response to an almost-psychedelic, or minor shift of some urinary metabolite pattern could possibly be believed. No independent confirmation of these properties has been reported. But maybe these findings are valid. A major problem in following these leads does not involve any complex research protocols. What must be addressed are the present regulatory restrictions and the Federal law structure. And these are formidable obstacles.
92 IP; ISOPROSCALINE; 3,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE
SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under ESCALINE for its preparation) and 13.6 g isopropyl iodide in 50 mL dry acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux on the steam bath. After 6 h another 5 mL of isopropyl iodide was added, and refluxing continued for an additional 12 h. The mixture was filtered and the solids washed with acetone. The mother liquor and washes were stripped of solvent under vacuum, The residue was taken up in dilute HCl, and extracted with 3x100 mL CH2Cl2. The pooled extracts (they were quite deeply yellow colored) were washed with 2x75 mL 5% NaOH, and finally once with dilute HCl. Removal of the solvent under vacuum yielded 9.8 g of an amber oil, which on distillation at 125-135 !C at 0.3 mm/Hg provided 6.0 g of 3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile as a pale yellow oil. A pure reference sample is a white solid with a mp of 33-34 !C. Anal.
(C13H17NO3) C,H,N.
A solution of AH was prepared by the cautious addition of 0.84 mL of 100% H2SO4 to 32 mL of 1.0 M LAH in THF, which was being vigorously stirred under He at ice-bath temperature. A solution of 5.93 g of 3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile in 10 mL anhydrous THF
> was added dropwise. Stirring was continued for 30 min, then the reaction mixture was brought up to reflux on the steam bath for another 30 min. After cooling again to room temperature, 5 mL IPA was added to destroy the excess hydride, followed by about 10 mL of 15%
NaOH, sufficient to make the aluminum salts loose, white, and filterable. The reaction mixture was filtered, the filter cake washed with IPA, the mother liquor and washes combined, and the solvent removed under vacuum. The residue (7.0 g of an amber oil) was dissolved in dilute H2SO4 and washed with 3x75 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 3x75 mL CH2Cl2. The extracts were evaporated to a residue under vacuum, and this was distilled at 125-140 !C at 0.3 mm/Hg yielding 3.7
g of a colorless oil. This was dissolved in 15 mL IPA, neutralized with 50 drops of concentrated HCl which allowed the deposition of a white crystalline product. Dilution with anhydrous Et2O and filtration gave 3.7 g. of 3,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (IP) with a mp of 163-164 !C. Anal. (C13H22ClNO3) C,H,N. The catalytic hydrogenation process for reducing the nitrile that gives rise to escaline, also works with this material.
DOSAGE: 40 - 80 mg.
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 75 mg) Starts slowly. I develop some queasiness, turning into nausea. Feels good to lie down and let go, but the uneasiness remains. Just beginning to break through in 2
hours. But the occasional sense of relief, the breaking into the open, were transient as new sources of discomfort were always being dredged up. Then for some reason I chose to dance. Letting go to dancing, a marvelous ecstatic experience, flowing with and being the energy, body feeling completely free. Noticing how this letting go got one completely out of the feeling of unease, as though attention simply needs to be put elsewhere. Comedown was very slow, gentle, euphoric; a very signicant experience. Sleep that night was impossible, but felt good to simply release to the feelings. Keeping mind still, no thinking, just allowing feelings to go where they wished, became more and more ecstatic. Tremendous feeling of confidence in life and the life process. Complete sense of resolution.
Pihkal Page 100