162 TMA-6; 2,4,6-TRIMETHOXYAMPHETAMINE
SYNTHESIS: To a solution of 100 g phloroglucinol dihydrate in 320 mL
MeOH there was added 55 mL of concentrated H2SO4, and the clear solution held under reflux conditions overnight. After cooling, there was added 500 mL H2O, and the bulk of the MeOH was removed under vacuum. The residual oil was extracted with Et2O, and the removal of this left 60 g of a red oil as residue. This was dissolved in 300 g methyl sulfate (caution, this is extremely toxic through skin contact, and any exposure must be flushed thoroughly with dilute ammonium hydroxide). With good stirring, this was cautiously treated with 500
g of 40% aqueous KOH, and the exothermic reaction allowed to run its course. Extraction with 3x100 mL Et2O gave, after evaporation of the solvent from the pooled extracts, an oil that became largely crystalline. This was suspended in 100 mL hexane, and filtered through a coarse fritted funnel. With evaporation there was obtained 57 g of 1,3,5-trimethoxybenzene as a pale amber solid that melted at 44-50 !C. A sample purified by recrystallization from EtOH had the proper mp of 54-55 !C.
A mixture of 62.9 g N-methylformanilide and 71.3 g of POCl3 was allowed to stand for 0.5 h producing a light claret color. There was then added 30.9 g of 1,3,5- trimethoxybenzene and the mixture heated on the steam bath for 2 h. The reaction mixture then was poured into chipped ice, and allowed to stir for several h. The dark gummy mess was extracted with 2x100 mL Et2O (this was discarded) and then with 4x200 mL CH2Cl2. The latter extracts were pooled, and stripped of solvent under vacuum yielding 14 g of an amber solid. This was recrystallized from 80 mL boiling MeOH (with decolorizing charcoal employed and filtration of the boiling solution through paper) to give 10.0 g of 2,4,6-trimethoxybenzaldehyde as a white crystalline solid with a mp of 115-116 !C. The literature values are generally one-degree ranges, and they are reported as high as 121 !C. The malononitrile adduct was prepared from a solution of 0.5 g aldehyde and 0.5 g malononitrile in 10 mL warm MeOH treated with a drop of triethylamine. There was an immediate formation of a yellow crystalline mass which was removed by filtration, washed with EtOH, and air dried. The yield of 2,4,6-trimethoxybenzalmalononitrile was 0.5 g and the mp was 174-175 !C. Anal. (C13H12N2O3) N.
A solution of 5 g 2,4,6-trimethoxybenzaldehyde in 20 g nitroethane was treated with 1.0 g of anhydrous ammonium acetate and held on the steam bath for 24 h. The excess solvent/reagent was stripped from the deep-red colored solution under vacuum yielding a residue that spontaneously set to a crystalline mass. This was well triturated under 5 mL MeOH, filtered, and washed with 3 mL additional MeOH to give 5.4 g of 2-nitro-1-(2,4,6-trimethoxyphenyl)propene as yellow crystals. The mp of the crude material was 135-142 !C which could be raised to 147-148 !C by recrystallization from EtOH. The use of an alternate procedure for the synthesis of this nitrostyrene, using acetic acid as solvent and a stoichiometric amount of nitroethane (and ammonium acetate as catalyst), gave very poor yields. The use of butylamine as catalyst gave considerably better results.
A suspension of 50 g LAH in 1 L anhydrous THF was placed under an inert atmosphere, stirred magnetically, and brought to a gentle reflux. There was added a total of 56.9 g 2-nitro-1-(2,4,6-trimethoxyphenyl)propene as a saturated solution in THF. This was achieved by letting the condensed THF drip through a Soxhlet thimble containing the nitrostyrene with direct addition to the reaction mixture. The solubility was extremely low. The stirred mixture was maintained at reflux for 36 h, generating a smooth creamy gray color. After being brought to room temperature, the excess hydride was destroyed by the patient addition of 50 mL H2O, followed with 50 mL 15% NaOH (still some heat evolved) and then 150 mL
additional H2O. Stirring was continued until the insoluble salts were white and loose. These solids were removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the 73 g of pale amber residue dissolved in 200 mL IPA, neutralized with approximately 50 mL concentrated HCL, and diluted with 2 L anhydrous Et2O. A lower, oily phase separated slowly set up as a crystalline mass. This was removed by filtration, Et2O washed, and allowed to air dry to constant weight. The weight of 2,4,6-trimethoxyamphetamine hydrochloride was 41.3 g and the color was an off-white. There was a tendency to discolor upon air exposure. The mp was 204-205 !C which was increased to 207-208 !C upon recrystallization from IPA. The literature gives a mp of 214-215 !C for this salt after isolation and purification as the picrate salt (with a mp 212-213 !C from EtOH).
DOSAGE: 25 - 50 mg.
DURATION: 12 - 16 h.
QUALITATIVE COMMENTS: (with 25 mg) I was outside at the California-Washington State football game, which was completely nutty.
As was I. With the crowd activity, it was impossible to separate the drug's action from the environment. Later I simply sat in the car, and tried to define what the effects really were. Things were completely benign, there was ease with concepts, and writing was good and smooth. At twelve hours, comfortably down. Maybe a plus two.
(with 35 mg) My body was tingling all over, and there were times when walking was unsteady. Thinking was a little difficult, as I was quite intoxicated most of the day (all of the day, now that I think that over). To accomplish anything, such as toasting the toast in the toaster, was difficult. And things were so funny most of the time.
Setting the table for supper, six hours later, proved to be hilarious.
I like to think of the day as a mixture of the mad hatter's tea party, and a trip to the moon. We were all still intoxicated at bedtime, whatever time that was. Had difficult time sleeping. If I were to repeat, would go lighter in dosage, I feel.
(with 40 mg) This experiment was begun at noon of a cool rainy day.
Almost all of the day had to be spent indoors, without benefit of sunshine, This is worth mentioning because there was, for the first eight hours of the experiment, a decided feeling of inner chill which might not have occurred so strongly had it been a warm day. Most, if not all, of the other eight subjects also reported the same chill.
There was some visual sparkle which persisted throughout. At the two hour point a minor but persistent stomach queasiness came on, preceded by a diarrhea-like bowel movement. There was no impairment of speech, but there was some halting quality to all thought processes. It was easy to talk about personal matters, but there did not seem to be a significant insight increase. Appetite for food was lessened. Sleep was decidedly difficult after the effects of the material seemed otherwise gone.
(with 40 mg) As the experience grows in intensity for the first four hours, I feel a strange mixture of plateaus, exuberance, and strong negative feelings, all replacing each other. I found myself inside a stout, hemispherical shell, curled up in the solid part, thoroughly walled off but absolute master within the shell, calling all shots, making all decisions, in complete control. Moving beyond the half-shell meant becoming vulnerable, which I refused to do.
Consequently my difficulty in hearing what other people say, becoming involved in their perceptions and lives. I keep relationships shallow, pull away inside my shell rather than become involved. I like to be by myself. This was a great revelation; I had never seen it before. This material had an enormous drive. I feel extremely grateful for exposing a very deep personal problem.
(with 50 mg) My previous try at this level produced a record that said, 'alteration of consciousness, but no visual, no anything,' and oh my, surprise! It was very, very active, visual, colorful, etc., etc. Good talking, clear and steady control of body, despite intense energy flow. Extremely funny Q great humor, wonderful laughter.
EXTENSIONS AND COMMENTARY: Here is a simple and easily made compound that might well bid fair to be one of the most rewarding and pleasurable of the methoxylated amphetamines. It is fully as potent as its counterpart, TMA-2. This latter compound, with its 2,4,5-trisubstitution pattern, has served as a template from which an immense family of very active and fascinating drugs have arisen. The 2,5-dimethoxy aspect has been kept intact, a
nd modifications in the 4-position have given rise to treasures such as DOM, DOB, DOET, DOI, and the Aleph compounds. And, of course, the entire world of the 2C-X's has exploited this same orientation.
Here, there is the blatant, parallel call from TMA-6. It can serve, as the 2,4,6-counterpart, as a similar template compound. And the first indicators are that, in keeping the 2,6-dimethoxy aspect intact, a completely analogous series could be made, again with modifications of the 4-position. These have been named the psu-series, or psi-series, as an abbreviation for the prefix, pseudo, and can be differentiated from the 2,4,5-things with the use of the Greek letter RYS. Thus there is the Y-DOM (called Z-7 in this book, and certainly an active compound), and Y-DOB, Y-DOET, Y-DOI, and the Y-ALEPH
compounds. And, of course, the Y-2C-X counterparts. I would expect all of them to be active and, certainly, some of them interesting.
They will be considerably more difficult to synthesize. However, some of them, specifically things such as Y-2C-T-4, have already been prepared, and are being evaluated.
One of the guiding premises of this Book II was to make all recipes employ commercially available materials as starting materials. And in the case of TMA-6, the required benzaldehyde (2,4,6-trimethoxybenzaldehyde) is an easily obtained trade item from any of several supply houses. Why not start the recipe there? Why tell how to make it from 1,3,5-trimethoxybenzene (also presently available from commercial sources) and how to make the ether in turn, from phloroglucinol? This simply reflects a valid paranoia of our times. Today the aldehyde is available (at $2/g) and can be easily purchased. But tomorrow? What about in the year 2003? Who can tell what will, or will not, be easily available then? There might be a world-wide acknowledgment that the Rwar on drugsS is more destructive than any drug itself could ever be, and every law that had been written in the attempt to dictate human behavior will have been transformed into a force that truly educates and allows choice. This might really happen. But maybe, on the other hand, no fine chemicals may be permitted to be held in any hands, at any price, except for those of licensed chemists and in authorized laboratories. The black market price for the aldehyde might be $1000/g with another $1000 for protection.
But, it will be impossible to remove phloroglucinol from availability.
It is available as a natural component in the free form, in sources as diverse as the cones of the Sequoia sempervirens (the coast redwood tree) and species of Camillia (that provides the leaves of our morning tea). And combined with a molecule of glucose in the form of its glucoside, it is called phlorin, and it is present in the discarded rinds of almost all citrus fruits as well as the resins from many of the Eucalyptus species. And one step yet further back into nature, there is a dihydrochalcone glucoside called phloridzin which practically drips out of all parts of the apple and pear trees except for the apple or pear itself. It, on base hydrolysis, gives phlorin, which on acid hydrolysis gives phloroglucinol, which when dissolved in methanol and sulfuric acid gives Q. Nature is indeed most bountiful.
The phenethylamine homologue of TMA-6 is well known, but is virtually unexplored pharmacologically. The above benzaldehyde with nitromethane in glacial acetic acid containing ammonium acetate gave the appropriate beta-nitrostyrene as yellow crystals with a mp 177-177.5 !C. This, with LAH in ether, gave 2,4,6-trimethoxyphenethylamine (2,4,6-TMPEA, or 2C-TMA-6) as the picrate salt (mp 204-205 !C) or the hydrochloride salt (mp 234-235
!C). It has been shown not to be a substrate to the soluble amine oxidase from rabbit liver, a property it shares with mescaline, but whether it is or is not active in man is at present unknown.
163 3-TME; 3-THIOMETAESCALINE;
4,5-DIMETHOXY-3-ETHYLTHIOPHENETHYLAMINE) SYNTHESIS: A solution of 13.0 g of
3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine (see under MP for its preparation) in 125 mL anhydrous Et2O in a He atmosphere was cooled with an external dry ice acetone bath to -80 !C with good stirring. To this clear pale yellow solution there was added 32 mL
1.55 M butyllithium in hexane (about a 25% excess) which was stirred for 10 min producing a fine white precipitate. There was then added 7.0 g diethyl disulfide. The dry ice bath was removed and the reaction stirred as it came to room temperature. This was then added to 300 mL dilute HCl and the aqueous phase separated and heated on the steam bath for 45 min. A yellow oil was formed with a nearly colorless aqueous overhead. This was removed by decantation, and the remaining oil was diluted with a little MeOH and additional concentrated HCl. After further heating on the steam bath, this was added to the separated phase, all was cooled and extracted with 2x50
mL CH2Cl2. Removal of the solvent from these pooled extracts gave 11.8 g of a residue that was distilled. The product, 3-ethylthio-4,5-dimethoxybenzaldehyde boiling at 106-125 !C at 0.4
mm/Hg and was an almost colorless oil weighing 8.3 g. Anal.
(C11H14O3S) C,H.
To a solution of 8.2 g 3-ethylthio-4,5-dimethoxybenzaldehyde in 125 mL
nitromethane, there was added 1.0 g of anhydrous ammonium acetate and the mixture was heated on the steam bath for 1.5 h. The reaction mixture was stripped of nitromethane under vacuum, and the residual red oil was dissolved in 20 mL of boiling MeOH. This was decanted from a small amount of insolubles, and allowed to cool to room temperature. After considerable manipulation of a small sample with dry ice cooling, a seed of crystal was obtained, which successfully promoted crystallization of the entire MeOH solution. After standing for 1 h, the product 3-ethylthio-4,5-dimethoxy-'-nitrostyrene was removed by filtration and, after air drying, weighed 3.2 g with a mp of 96-98 !C. Upon recrystallization from MeOH, the mp was tightened to 98-99 !C. Anal. (C12H15NO4S) C,H.
AH was prepared in the usual manner from a suspension of 2.0 g LAH in 75 mL anhydrous THF, cooled to 0 !C and well stirred in an inert atmosphere of He, and treated with 1.33 mL of 100% H2SO4 added dropwise. There was added, dropwise and over the course of 10 min, a solution of 3.1 g 3-ethylthio-4,5-dimethoxy-'-nitrostyrene in 15 mL
anhydrous THF. At the end of the addition, the reaction mixture was returned to room temperature, and finally heated on the steam bath for 10 min. After cooling again, there was added enough IPA to decompose the excess hydride and sufficient 10% NaOH to convert the aluminum oxide to a white, easily filterable mass. This was removed by filtration, the filter cake washed with additional IPA, and the filtrate and washes combined and the solvent removed under vacuum.
This was dissolved in 100 mL of dilute H2SO4, which was washed with 2x50 mL CH2Cl2. The aqueous phase was made basic with NaOH, extracted with 2x50 mL CH2Cl2, and the extracts pooled and the solvent removed under vacuum to yield a residue of a colorless oil. This was distilled at 160-170 !C at 1.0 mm/Hg yielding 2.6 g of a colorless liquid. This was dissolved in 12 mL IPA, neutralized with 24 drops of concentrated HCl and diluted with 25 mL anhydrous Et2O. The clear solution was decanted from a little solid material, and the decantings diluted with a further 50 mL anhydrous ether. The still clear solution became cloudy after a few min, and then there was the slow formation of 3-ethylthio-4,5-dimethoxyphenethylamine hydrochloride (3-TME) as a fine white crystalline product. Removal by filtration, washing with Et2O, and air drying yielded 2.8 g of white gran-ular solids that melted at 171-172 !C. Anal. (C12H20ClNO2S) C,H.
DOSAGE: 60 - 100 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 60 mg) As important as the experience was, itself, I feel that it was in the two or three days that followed that it had the most profound impact on me. It was at the time of the death of my wife's mother, and I found that I could look directly towards death and its ramifications. Including my own death. I felt very close to the Higher Powers that seemed to make their presence felt all around. And there was still the deep internal strength that was the direct product of the 3-TME experience. I feel it very strongly, still, but I have no desire to repeat the experience right away. It is almost as if the effects are still in evidence, and one should take one's time in letting it manifest all its
ramifications.
But it is certainly an experience one should have once a year, if not oftener.
(with 100 mg) I was aware of the development quite early, and by the end of an hour and a half, I was in quite a remarkable state. I was extremely disinhibited, with easy verbal play and easily self-revealing, but not at too deep a level. There was great fun with a set of water colors but, when a used Kleenex became my canvas, the others failed to share my humor. I drove home at midnight with considerable care and was unable to sleep for another two hours. I would be very willing to repeat this experiment, at this level, to see if the good humor of it all was a consistent property.
(with 100 mg) I had a sudden revelation Q what I called the wet-paint theory of Christ. How does one find and identify the Messiah? It is most simple. All of life is nothing more than a freshly painted fence separating us from the rest of the world. And the fence has many, many signs on it that say: Beware. DonUt Touch. Wet Paint. And if you touch too soon, indeed you get a dirty finger because the paint really is still wet. But the very first man to touch it and find it dry? There is your natural leader, your Son of God, and all those who touch later than He are the followers of the leader who first touched and found the paint dry.
EXTENSIONS AND COMMENTARY: A short unraveling of the codes used here for the various materials is very much needed. There are 3's and 4Us and M's and IUs and incipient confusion. Mescaline is mescaline.
That much is simple. All homologs are the first letter of the homolog. Escaline is E, Proscaline is P, etc. If the group is at the three-position, then the term RmetaS is used and an M preceeds the name of the homolog, i.e., ME is Metaescaline. The number (3- or 4-
or 5-) gives the position of the sulfur, which is represented by the prefix RThioS so this compound, 3-TME, has the sulfur at the 3-position, and by chance, the ethyl group there as well.
Here is a brief presentation of the needed Rosetta Stone: Number of all three
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