PiHKAL: The Chemical Story 10
This is part 5 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.
#120 MEDA; 3-METHOXY-4,5-ETHYLENEDIOXYAMPHETAMINE
SYNTHESIS: To a solution of 50 g 3,4-dihydroxy-5-methoxybenzaldehyde in 100 mL distilled acetone there was added 70 g ethylene bromide and 58 g finely powdered anhydrous K2CO3. The mixture was held at reflux for 5 days. This was then poured into 1.5 L H2O and extracted with 4x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a residue which was distilled at 19 mm/Hg. Several of the fractions taken in the 203-210 °C range spontaneously crystallized, and they were pooled to give 18.3 g of 3-methoxy-4,5-ethylenedioxybenzaldehyde as white solids with a mp of 80-81 °C. A small sample with an equal weight of malononitrile in EtOH treated with a few drops of triethylamine gave 3-methoxy-4,5-ethylenedioxybenzalmalononitrile as pale yellow crystals from EtOH with a mp of 153-154 °C.
A solution of 1.50 g 3-methoxy-4,5-ethylenedioxybenzaldehyde in 6 mL acetic acid was treated with 1 mL nitroethane and 0.50 g anhydrous ammonium acetate, and held on the steam bath for 1.5 h. To the cooled mixture H2O was cautiously added until the first permanent turbidity was observed, and once crystal-lization had set in, more H2O was added at a rate that would allow the generation of additional crystals. When there was a residual turbidity from additional H2O, the addition was stopped, and the beaker held at ice temperature for several h. The product was removed by filtration and washed with a little 50% acetic acid, providing 0.93 g 1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene as dull yellow crystals with a mp of 116-119 °C. Recrystallization of an analytical sample from MeOH gave a mp of 119-121 °C.
A stirred suspension of 6.8 g LAH in 500 mL anhydrous Et2O under an inert atmosphere was brought up to a gentle reflux. A total of 9.4 g 1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene in warm Et2O was added over the course of 0.5 h. Refluxing was maintained for 6 h, and then the reaction mixture was cooled and the excess hydride destroyed by the cautious addition of 400 mL 1.5 N H2SO4. The two clear phases were separated, and the aqueous phase was brought to pH of 6 by the addition of a saturated Na2CO3 solution. This was filtered free of a small amount of insolubles, and the clear filtrate was heated to 80 °C. To this there was added a solution of 9.2 g picric acid (90% material) in 100 mL boiling EtOH, and the clear mixture allowed to cool in an ice bath. Scratching generated yellow crystals of the picrate salt. This salt was filtered free of the aqueous environment, treated with 50 mL of 5% NaOH, and stirred until the picric acid was totally in the form of the soluble sodium salt. This was then extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue weighed 6.0 g, and was dissolved in 100 mL anhydrous Et2O, and saturated with dry HCl gas. The white solids that formed were filtered free of the Et2O, and ground up under 50 mL of slightly moist acetone, providing 4.92 g of 3-methoxy-4,5-ethylenedioxyamphetamine hydrochloride monohydrate (MEDA) as white crystals.
DOSAGE: greater than 200 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: There are times when the Gods smile in unexpectedly nice ways. Having found the activity of MMDA, the "scientific" thing to do would be to compare it against the other "psychotomimetic" amphetamine that was known at that time (this was 1962), namely TMA. Comparing their structures, the only difference of any kind was that two of the adjacent methoxyl groups of TMA were replaced with a 5-membered ring, called the methylenedioxy ring.
Where does one go next? Some perverse inspiration suggested increasing the size of this ring to a 6-membered ring, the ethylenedioxy (or dioxene) homologue. Well, if you thought that getting myristicinaldehyde was a difficulty, it was nothing compared to getting this 6-membered counterpart. But I huffed and I puffed, and I did make enough to taste and to evaluate. And it was here that I got the divine message° No activity°° So, rather than being condemned forever a la Sisyphus to push ever larger rings up my psyche, I gave myself permission to pursue another path. The message was: "Don't change the groups. Leave them as they are, but relocate them instead." And that led directly to TMA-2 and its story.
A couple of diversions may be mentioned here. Before the blessed inactivity of MEDA was established, the 7-membered ring counterpart, 3-methoxy-4,5-trimethylenedioxyamphetamine (MTMA) was prepared by essentially the same procedure. The above 3-methoxy-4,5-dihydroxybenzaldehyde with trimethylene bromide gave 3-methoxy-4,5-trimethylenedioxybenzaldehyde, white solids, with a malononitrile derivative with a mp of 134-135 °C; the aldehyde with nitroethane gave the nitropropene with a mp of 86-87 °C; and this with LAH gave MTDA as the hydrochloride (mp 160-161 °C) again isolated first as the picrate. It had been tasted at up to an 8 milligram dosage (no activity, but none expected) before being abandoned. And, an initial effort was made to synthesize a five-member ring (methylenedioxy) with a methyl sticking out from it. This ethylidine homologue got as far as the aldehyde stage. The reaction between 3,4-dihydroxy-5-methoxybenzaldehyde and 1,1-dibromoethane in acetone containing anhydrous potassium carbonate gave a minuscule amount of a product that was a two-component mixture. This was resolved by dozens of separate injections into a preparatory gas chromatography system, allowing the isolation of the second of the two components in a quantity sufficient to demonstrate (by NMR spectroscopy) that it was the desired 3-methoxy-4,5-ethylidinedioxybenzaldehyde. Starting with the pre-prepared dipotassium salt or the lead salt of the catecholaldehyde gave nothing. With no activity being found with MEDA, all was abandoned.
There are some comments made under MDA for successful chemistry (using a different approach) alo#ng these lines when there is no methoxyl group present. These are the compounds EDA and IDA. But the pharmacology was still not that exciting.
#121 MEE; 4,5-DIETHOXY-2-METHOXYAMPHETAMINE
SYNTHESIS: To a solution of 166 g bourbonal in 1 L MeOH there was added a solution of 66 g KOH pellets in 300 mL H2O. There was then added 120 g ethyl bromide, and the mixture was held at reflux on the steam bath for 3 h. The reaction was quenched with three volumes of H2O, and made strongly basic by the addition of 25% NaOH. This was extracted with 3x300 mL CH2Cl2, and the pooled extracts stripped of solvent under vacuum. There remained 155 g of 3,4-diethoxybenzaldehyde as a fluid oil that had an infra-red spectrum identical (except for being slightly wet) to that of a commercial sample from the Eastman Kodak Company.
A solution of 194 g 3,4-diethoxybenzaldehyde in 600 g glacial acetic acid was arranged in a flask that could be magnetically stirred, yet cooled as needed with an external ice bath. A total of 210 g of 40% peracetic acid in acetic acid was added at a rate such that, with ice cooling, the exothermic reaction never raised the internal temperature above 26 °C. The reaction developed a deep red color during the 2 h needed for the addition. At the end of the reaction the mixture was quenched by the addition of three volumes of H2O, and the remaining acidity was neutralized by the addition of solid Na2CO3 (700 g was required). This aqueous phase was extracted several times with CH2Cl2, and the solvent was removed from the pooled extracts under vacuum. The residue was a mixture of the intermediate formate ester and the end product phenol. This was suspended in 800 mL 10% NaOH, and held on the steam bath for 1.5 h. After cooling, this was washed once with CH2Cl2 (discarded) and then acidified with HCl. There was the formation of an intensely hydrated complex of the product phenol, reminiscent of the problem encountered with 3-ethoxy-4-methoxyphenol. This was worked up in three parts. The entire acidified aqueous phase was extracted with Et2O (3x200 mL) which on evaporation gave 80 g of an oil. The hydrated glob was separately ground up under boiling CH2Cl2 which, on evaporation, gave an additional 30 g of oil, and the aqueous mother liquor from the glob was extracted with 2x200 mL CH2Cl2 which provided, after removal of the solvent, an additional 10 g. These crude phenol fractions were combined and distilled at 1.5 mm/Hg. Following a sizeable forerun, a fraction boiling at 158-160 °C was the anhydrous product, 3,4-diethoxyphenol. It was a clear, amber oil, and weighed 70.0 g. The slightest exposure to H2O, even moist air, give a solid hydrate, with mp of 63-64 °C. This phenol can be used for the synthesis of MEE (this recipe) or for the preparation of EEE (see the separate recipe). A solution of 2.0 g of this phenol in 5 mL CH2Cl2 was diluted with 15 mL hexane. This was treated with 2 g methyl isocyanate followed by a few drops of triethylamine. After about 5 min, white crystals formed of 3,4-diethoxyphenyl-N-methyl carbamate, with a mp of 90-91 °C.
A solution of 26.6 g 3,4-diethoxyphenol in 50 mL MeOH was mixed with another containing 9.6 g KOH pellets dissolved in 200 mL hot MeOH. There was then added 21.4 g methyl iodide, and the mixture was held at reflux for 2 h on the steam bath. This was then quenched in 3 volumes of water, made strongly basic with 25% NaOH, and extracted with 3x150 mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave 19.3 g of 1,2-diethoxy-4-methoxybenzene (3,4-diethoxyanisole) as a clear, pale amber oil that solidified when cooled. The mp was 20-21 °C.
A mixture of 32.0 g N-methyl formanilide and 36.2 g POCl3 was allowed to stand until it was a deep red color (about 0.5 h). To this there was added 18.3 g 1,2-diethoxy-4-methoxybenzene and the exothermic reaction was heated on the steam bath for 2.5 h. This was then poured over 600 mL chipped ice, and the dark oily material slowly began lightening in color and texture. A light oil was formed which, on continued stirring, became crystalline. After the conversion was complete, the solids were removed by filtration producing, after removal of as much H2O as possible by suction, 26.9 g of crude aldehyde. A small sample pressed on a porous plate had a mp of 87.5-88.5 °C. Recrystallization of the entire damp crop from 50 mL boiling MeOH gave, after cooling, filtering, and air drying, 17.7 g of 4,5-diethoxy-2-methoxybenzaldehyde as fluffy, off-white crystals with a mp of 88-88.5 °C. A solution of 1.0 g of this aldehyde and 0.5 g of malononitrile dissolved in warm absolute EtOH was treated with 3 drops triethylamine. There was the immediate formation of crystals which were filtered and air dried to constant weight. The product, 4,5-diethoxy-2-methoxybenzalmalononitrile, was a bright yellow crystalline material, which weighed 1.0 g and had a mp of 156-157 °C.
To a solution of 14.7 g 4,5-diethoxy-2-methoxybenzaldehyde in 46 g glacial acetic acid, there was added 8.0 g nitroethane and 5.0 g anhydrous ammonium acetate. The mixture was heated on the steam bath for 2 h, becoming progressively deeper red in color. The addition of a small amount of H2O to the hot, clear solution produced a slight turbidity, and all was allowed to stand overnight at room temperature. There was deposited a crop of orange crystals that was removed by filtration and air dried. There was obtained 7.0 g 1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene as brilliant orange crystals that had a mp of 89-90.5 °C. This was tightened up, but not improved, by trial recrystallization from acetic acid, mp 89-90 °C, and from hexane, mp 90-90.5 °C. Anal. (C14H19NO5) C,H.
To a gently refluxing suspension of 5.0 g LAH in 400 mL anhydrous Et2O under a He atmosphere, there was added 6.5 g 1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise. Refluxing was maintained for 5 h, and the reaction mixture was cooled with an external ice bath. The excess hydride was destroyed by the cautious addition of 400 mL of 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 100 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was extracted with 3x200 mL CH2Cl2. Removal of the solvent under vacuum produced an off-white oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. The crystals of 4,5-diethoxy-2-methoxyamphetamine hydrochloride (MEE) that formed were very fine and slow to filter, but finally were isolated as a white powder weighing 5.4 g and melting at 178.5-180 °C. Anal. (C14H24ClNO3) C,H,N.
DOSAGE: greater than 4.6 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: There were early trials made with MEE, before it became known what direction the ethoxy substitution results would take. A number of progressive trials, up to a dosage of 4.6 milligrams, were without any central effects at all.
There is an instinct in structure-activity studies to think of a change as a success or a failure, depending on whether there is an increase or a decrease in the desired activity. But if one were to look at the effects of putting an ethoxy group onto TMA-2 in place of a methoxy group as a way of decreasing the effectiveness, then the 4-position becomes the worst position (MEM is equipotent to TMA-2), and the 5-position is perhaps a little less bad (MME is almost as potent) and the 2-position is the best by far (EMM is out of it, potency-wise). In other words, in the comparison of the 2- and the 5-positions, the lengthening of the 5-position gives modest loss of activity, and the lengthening of the whatever in the 2-position is the most disruptive. With this as a basis for prediction, then MEE (which differs from MEM only by a lengthening of the 5-position substituent) might be only a little less active than MEM and, as MEM is about the same as TMA-2, it is distinctly possible that MEE may show activity in the area at dosages that are not much above the 25 to 50 milligram area. Of all the diethoxy homologues, it would be the most promising one to explore.
Which brings to mind a quotation of a hero of mine, Mark Twain. RI like science because it gives one such a wholesome return of conjecture from such a trifling investment of fact.
#122 MEM; 2,5-DIMETHOXY-4-ETHOXYAMPHETAMINE
SYNTHESIS: A solution of 83 g bourbonal (also called ethyl vanillin, or vanillal, or simply 3-ethoxy-4-hydroxybenzaldehyde) in 500 mL MeOH was treated with a solution of 31.5 g KOH pellets (85% material) dissolved in 250 mL H2O. There was then added 71 g methyl iodide, and the mixture was held under reflux conditions for 3 h. All was added to 3 volumes of H2O, and this was made basic with the addition of 25% NaOH. The aqueous phase was extracted with 5x200 mL CH2Cl2. The pooling of these extracts and removal of the solvent under vacuum gave a residue of 85.5 g of the product 3-ethoxy-4-methoxybenzaldehyde, with a mp of 52-53 °C. When this product was recrystallized from hexane, its mp was 49-50 °C. When the reaction was run with the same reactants in a reasonably anhydrous environment, with methanolic KOH, the major product was the acetal, 3-ethoxy-a,a,4-trimethoxytoluene. This was a white glistening product which crystallized readily from hexane, and had a mp of 44-45 °C. Acid hydrolysis converted it to the correct aldehyde above. The addition of sufficient H2O in the methylation completely circumvents this by-product. A solution of 1.0 g of this aldehyde and 0.7 g malononitrile in 20 mL warm absolute EtOH, when treated with a few drops of triethylamine, gave immediate yellow color followed, in a few min by the formation of crystals. Filtration, and washing with EtOH, gave bright yellow crystals of 3-ethoxy-4-methoxybenzalmalononitrile with a mp of 141-142 °C.
A well stirred solution of 125.4 g 3-ethoxy-4-methoxybenzaldehyde in 445 mL acetic acid was treated with 158 g 40% peracetic acid (in acetic acid) at a rate at which, with ice cooling, the internal temperature did not exceed 27 °C. The addition required about 45 min. The reaction mixture was then quenched in some 3 L H2O. There was the generation of some crystals which were removed by filtration. The mother liquor was saved. The solid material weighed, while still wet, 70 g and was crude formate ester. A small quantity was recrystallized from cyclohexane twice, to provide a reference sample of 3-ethoxy-4-methoxyphenyl formate with a mp of 63-64 °C. The bulk of this crude formate ester was dissolved in 200 mL concentrated HCl which gave a deep purple solution. This was quenched with water which precipitated a fluffy tan solid, which was hydrated phenolic product that weighed about 35 g, and melted in the 80-90 °C. range. The mother liquors of the above filtration were neutralized with Na2CO3, then extracted with 3x100 ml Et2O. Removal of the solvent gave a residue of about 80 g that was impure formate (containing some unoxidized aldehyde). To this there was added 500 mL 10% NaOH, and the dark mixture heated on the steam bath for several h. After cooling, the strongly basic solution was washed with CH2Cl2, and then treated with 200 mL Et2O, which knocked out a heavy semi-solid mass that was substantially insoluble in either phase. This was, again, the crude hydrated phenol. The Et2O phase, on evaporation, gave a third crop of solids. These could actually be recrystallized from MeOH/H2O, but the mp always remained broad. When subjected to distillation conditions, the H2O was finally driven out of the hydrate, and the product 3-ethoxy-4-methoxyphenol distilled as a clear oil at 180-190 °C at 0.8 mm/Hg. This product, 45.1 g, gave a fine NMR spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1, supporting the freedom of the OH group on the aromatic ring from adjacent oxygen. Efforts to obtain an NMR spectrum in D2O immediately formed an insoluble hydrate. This phenol can serve as the starting material for either MEM (see below) or EEM (see separate recipe).
To a solution of 12.3 g 3-ethoxy-4-methoxyphenol in 20 mL MeOH, there was added a solution of 4.8 g flaked KOH in 100 mL heated MeOH. To this clear solution there was then added 10.7 g methyl iodide, and the mixture held at reflux on the steam bath for 2 h. This was then quenched in 3 volumes H2O, made strongly basic with 10% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 9.4 g of an amber oil which spontaneously crystallized. The mp of 1,4-dimethoxy-2-ethoxybenzene was 42-43.5 °C, and was used, with no further purification, in the following step.
A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed to stand for 0.5 h, producing a deep claret color. To this there was added 9.2 g 1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on the steam bath for 2 h. It was then poured into chipped ice and, with mechanical stirring, the dark oily phase slowly became increasingly crystalline. This was finally removed by filtration, providing a brown solid mat which showed a mp of 103.5-106.5 °C. All was dissolved in 75 mL boiling MeOH which, on cooling, deposited fine crystals of 2,5-dimethoxy-4-ethoxybenzaldehyde that were colored a light tan and which, after air drying to constant weight, weighed 8.5 g and had a mp of 108-109.5 °C. Search was made by gas chromatography for evidence of the other two theoretically possible positional isomers, but none could be found. The NMR spectrum showed the two para-protons as clean singlets, with no noise suggesting other isomers. There was a single peak by GC (for the recrystallized product) but the mother liquors showed a contamination that proved to be N-methylformanilide. A 0.3 g sample, along with 0.3 g malononitrile, was dissolved in 10 mL warm absolute EtOH, and treated with a drop of triethylamine. There was the immediate formation of a yellow color followed, in 1 min, by the deposition of fine yellow needles. Filtering and air drying gave 0.25 g of 2,5-dimethoxy-4-ethoxybenzalmalononitrile, with a mp of 171-172 °C.
A solution of 7.3 g 2,5-dimethoxy-4-ethoxybenzaldehyde in 25 g glacial acetic acid was treated with 3.6 g nitroethane and 2.25 g anhydrous ammonium acetate, and heated on the steam bath. After two h, the clear solution was diluted with an equal volume of H2O, and cooled in an ice bucket. There was the formation of a heavy crop of orange crystals which were removed by filtration. The dry weight of 1-(2,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene was 4.8 g and the mp was 120-124 °C. Recrystallization of an analytical sample from MeOH gave a mp of 128-129 °C. Anal. (C13H17NO5) C,H.
To a gently refluxing suspension of 3.3 g LAH in 400 mL anhydrous Et2O under a He atmosphere, there was added 4.3 g 1-(2,5-dimethoxy-4-ethoxy)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble apparatus containing the nitrostyrene, thus effectively adding a warm saturated ether solution of it to the hydride mixture. The addition took 2 h. Refluxing was maintained for 5 h, and then the reaction mixture was cooled to 0 °C with an external ice bath. The excess hydride was destroyed by the cautious addition of 300 mL of 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 100 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts produced an almost white oil that was dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was deposited a white crystalline solid of 2,5-dimethoxy-4-ethoxyamphetamine hydrochloride (MEM) which weighed 3.1 g and had a mp of 171-172.5 °C. Anal. (C13H22ClNO3) C,H,N.
DOSAGE: 20 - 50 mg.
DURATION: 10 - 14 h.
QUALITATIVE COMMENTS: (with 20 mg) I experienced some physical discomfort, but doesn't that tell us about the work to be done, rather than the property of the material? The breakthrough I had was the following day (and this seems to be the way MEM operates, i.e., first the energy and expansion, next day insight) was of the highest value and importance for me. I was given a methodology for dealing with my shadow parts. No small gift. And I did it all alone and the results were immediate. I am so grateful.
(with 20 mg, at 1.5 h following 120 mg MDMA) RThe transition was very smooth, with no obvious loss of the MDMA experience. I felt less of a need to talk, but the intimate closeness with the others was maintained. The experience continues to grow more profound and euphoric and I prayed, in the latter part of the afternoon, that it wouldn't stop. It continued until midnight with marvelous feelings, good energy, and much hilarity. And it abated very little over the next several days leaving me with the feeling of lasting change with important insights still coming to mind one week later.
(with 25 mg, at 2 h following 120 mg MDMA) RI found that sounds in general were distracting. No, they were out-and-out annoying. I may have been in an introspective mood, but I really wanted to be alone. No body problems at all. Felt good. I developed some color changes and some pattern movement. Not much, but then I didn't explore it much. The wine party afterwards was certainly most pleasant. The soup was a great pleasure. And that hard bread was good. The material was clearly not anorexic, or at least I overcame whatever anorexia there might have been.
(with 30 mg) I was aware of this in thirty minutes and it slowly developed from there to an almost +++ in the following hour. There were visual phenomena, with some color enhancement and especially a considerable enhancement of brights and darks. The first signs of decline were at about six hours, but there was something still working there after another six hours had passed. A slow decline, certainly.
(with 50 mg) I came into the experience knowing that yesterday had been a very fatiguing and tense day. I felt this material within the first ten minutes which is the fastest that I have ever felt anything. The ascent was rapid and for the first hour I tended to an inward fantasying with a distinct sensual tinge. There was a persistent queasiness that never left me, and it contrasted oddly with a good feeling of outward articulation and lucidity which succeeded in coming to the fore after the introverted first hour. Sleep was difficult, but the next day was calm and clear.
(with 50 mg) Lots of energy, best directed into activity. Clear imaging, thinking. Intense yet serene. Good feeling of pleasantness and some euphoria. I felt the need to keep moving. Hard to stay still.
(with 70 mg, in two parts) RThe effects of the 40 milligrams were muted by another drug experiment yesterday morning, and I never got much over a plus 1. There is an erotic nature, tactile sensitivity perhaps not as delicate as with 2C-B, but it is there. At the 2 hour point, an additional 30 milligrams increased the body impact (a distinct tremor and sensitivity) but somehow not a lot more mental. I have been compromised by yesterday.
EXTENSIONS AND COMMENTARY: MEM was both a valuable and dramatic compound, as well as a drug that played a watershed role. The completion of all the possible trimethoxyamphetamines (the TMA's) showed that only two of them combined the values of dependability of positive psychedelic effects with a reasonably high potency. Both TMA-2 and TMA-6 are treasures, both active in similar dosages, and both offer methoxyl groups that are begging to be replaced by other things. The first focus was on TMA-2, partly because the needed synthetic chemistry was better known, and partly because I had discovered its activity earlier. But there were three entirely different and distinct methoxyl groups to work on, in TMA-2. There is one at the 2-position, one at the 4-position, and one at the 5-position. The most obvious thing to do, it seemed, was to make each of them one carbon longer. Replace a methoxy with an ethoxy. And a logical naming pattern could follow the use of M for methoxy, and E for ethoxy, in sequence right around the ring from the 2- to the 4- to the 5-positions. The first group to be compared, then, would be EMM, MEM, and MME. And of these three, it was only MEM that was right up there in drama and in potency. But, by the time that became apparent, I had already completed the diethoxy possibilities (EEM, EME, and MEE) as well as the triethoxy homologue, EEE. With the discovery that the 4-position was the magic leverage point, and that the homologues at positions 2- and 5- were clearly less interesting, all emphasis was directed at this target, and this has led to the many 4-substituted families that are now known to be highly potent and felt by many to be personally valuable.
Why put such emphasis on potency, I am frequently asked? Why should it matter how much of a compound you take, as long as the effective level is much lower than its toxic level? Well, in a sense, that is the very reason. There are no guides as to what the toxic levels of any of these many compounds might really be in man. There is simply no way of determining this. Only a few have been explored in animals in the pursuit of an LD-50 level. Most of them are similar to one-another, in that they are, in mice, of relatively low toxicity and, in rat, of relatively high toxicity. But this toxicity appears not to be related to potency in man. So, if one might extrapolate that they are of more or less the same risk to man (from the toxic point of view) then the lower the dosage, the greater the safety. Maybe. In the absence of anything factual, it makes a reasonable operating hypothesis.
Many of the reports of MEM effects have been with experiments in which an effective dose of MDMA had been taken shortly earlier. There has developed a concept, embraced by a number of researchers, that the ease and quietness usually seen with the development of the MDMA experience can mitigate some of the physically disturbing symptoms sometimes seen with other psychedelics. This may be partly due to a familiar entry into a altered place, and partly due to a lessening of dosage usually required for full effects. MEM seems to have had more trials using this combination than many of the other psychedelic drugs.
#123 MEPEA; 3-METHOXY-4-ETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 10.0 g 3-methoxy-4-ethoxybenzaldehyde in 150 mL nitromethane was treated with 1.7 g anhydrous ammonium acetate, and heated on the steam bath for 1 h. The excess nitromethane was removed under vacuum, yielding a loose, yellow crystalline mass that was filtered and modestly washed with cold MeOH. The 8.0 g of damp yellow crystals thus obtained were dissolved in 50 mL of vigorously boiling CH3CN, decanted from a small amount of insolubles (probably ammonium acetate residues) and cooled in an ice bath. The crystals so obtained were removed by filtration, washed with 2x5 mL cold CH3CN, and air dried to constant weight. The yield of 4-ethoxy-3-methoxy-'-nitrostyrene was 6.3 g of beautiful yellow crystals.
A solution of 2.3 g LAH in 70 mL anhydrous THF was cooled, under He to 0 °C with an external ice bath. With good stirring there was added 2.3 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 6.2 g 3-ethoxy-4-methoxy-'-nitrostyrene in anhydrous THF. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 °C. The excess hydride was destroyed by the cautious addition of IPA followed by sufficent 10% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered and the filter cake well washed with THF. The filtrate and washes were combined and stripped of solvent under vacuum. The residue was dissolved in dilute H2SO4. This was washed with 2x75 mL CH2Cl2, which removed the residual yellow color. The remaining aqueous phase was made basic with NaOH, and extracted with 3x75 mL CH2Cl2. These extracts were combined and the solvent removed under vacuum. The residue was distilled at 108-115 °C at 0.4 mm/Hg to give 4.2 g of a mobile, colorless liquid. This was dissolved in 12 mL IPA, neutralized with 60 drops concentrated HCl, and diluted with 100 mL anhydrous Et2O. There was deposited a fine white crystalline product which, after removal by filtration, ether washing, and air drying, yielded 3.8 g of 3-methoxy-4-ethoxyphenethylamine hydrochloride (MEPEA).
DOSAGE: 300 mg or greater.
DURATION: short.
QUALITATIVE COMMENTS: (with 120 mg) I am at perhaps a +1, a very slight effect of lightness, without any body awareness at all. And then in another hour, I was completely baseline again.
(with 300 mg) Whatever changes took place were complete at the end of an hour. The effects were very quiet, very pleasant, and very light. There was nothing psychedelic here, but rather a gentle lifting of spirits. No sensory enhancement or other expected changes.
EXTENSIONS AND COMMENTARY: This is one of the very few phenethylamines with only two substituents that shows even a hint of central activity. And there is an interesting story attached. I got a call out of absolutely nowhere, from a Stanislov Wistupkin, that he had discovered a number of new psychedelic drugs which he would like to share with me. Two of them were simple phenethylamines, one with an ethoxy group at the 4-position, and one with an allyloxy group there. Both, he said, were mood elevators active between 100 and 300 milligrams. One of them was this material, here called MEPEA, and the other one was 3-methoxy-4-allyloxyphenethylamine, or MAPEA. When I did meet him in person, he gave me a most remarkable publication which had been authored some ten years earlier, by a person named Leminger, now dead. It was all in Czech, but quite unmistakably, right there on the third page, were the structures of MEPEA and MAPEA, and the statement that they were active at between 100 and 300 milligrams. I have not yet made the allyloxy compound, but I feel that it too might be a gentle mood elevator similar to the ethoxy.
A most appealing extension of these materials would be the amphetamine derivatives, things with a 3-methoxy group, and something small and terse on the 4-position. The immediate analogies of MEPEA and MAPEA would be 3-methoxy-4-ethoxy- (and 3-methoxy-4-allyloxy)-amphetamine. And equally interesting would be the 4-hydroxy analogue. This would be an easily made compound from vanillin, one of our most enjoyable spices in the kitchen cabinet, and it would be directly related to the essential oils, eugenol and isoeugenol. This amphetamine compound has already been synthesized, but it is still unexplored in man.
Some years ago a report appeared in the forensic literature of Italy, of the seizure of a small semitransparent capsule containing 141 milligrams of a white powder that was stated to be a new hallucinogenic drug. This was shown to contain an analogue of DOM, 3-methoxy-4-methylamphetamine, or MMA. The Italian authorities made no mention of the net weight contained in each dosage unit, but it has been found that the active level of MMA in man is in the area of 40-60 milligrams. The compound can apparently be quite dysphoric, and long lived.
In the Czechoslovakian publication that presented MEPEA and MAPEA. there were descriptions of escaline (E), proscaline (P), and the allyloxy analogue (AL). These are all active in man, and have been entered elsewhere. This is the only published material dealing with psychedelic drugs I have ever been able to find, from the laboratory of Otakar Leminger. What sort of man was this chemist? He worked for years in industry, and only at the time of his retirement did he publish this little gem. He lived at Usti, directly north of Praha, on the Labe river (which is called by the better known name, the Elbe, as soon as it enters Germany). Might there be other treasures that he had discovered, and never published? Was young Wistupkin a student of his? Are there unrecognized notes of Otakar Leminger sitting in some farm house attic in Northern Czechoslovakia? I extend my heartfelt salute to an almost unknown explorer in the psychedelic drug area.
#124 META-DOB; 5-BROMO-2,4-DIMETHOXYAMPHETAMINE
SYNTHESIS: The reaction of 2,4-dimethoxyamphetamine (2,4-DMA) with elemental bromine proceeded directly to the formation of 5-bromo-2,4-dimethoxyamphetamine which was isolated as the hydrobromide salt with a melting point of 204.5-205.5 °C and in a 67% yield. A mp of 180-181 °C has also been published.
DOSAGE: 50 - 100 mg.
DURATION: 5 - 6 h.
EXTENSIONS AND COMMENTARY: There is very little synthetic information available, and some of it is contradictory. The initial human report in the medical literature says only that a dosage of about 100 milligrams produced effects that were similar to those produced by MDA. Both the quality of the experience and the potency of the compound have been modified in more recent publications by the originators of this compound. A 40 milligram dose, after an induction period of an hour, produced a vague uneasiness that was interpreted originally as a threshold psychedelic effect. At doses in the 60 to 90 milligram range, there were produced feelings of anxiety and paranoid fantasies, and distinct toxic signs such as flushing, palpitations, and occasional nausea, vomiting and diarrhea. Any psychedelic effects seem to have been blurred by the more obvious toxic actions of the drug. I have been told that their final conclusion was that the drug appears toxic in the 50 to 60 milligram range. I have not personally explored this positional isomer of DOB.
The positional isomer of DOB with the bromine in the ortho-position is 4,5-dimethoxy-2-bromoamphetamine and is called, not surprisingly, ORTHO-DOB. It has been made by the condensation of 2-bromo-4,5-dimethoxybenzaldehyde with nitroethane to give 1-(2-bromo-4,5-dimethoxyphenyl)-2-nitropropene with a mp of 105-106 °C. Reduction to the amphetamine had to be conducted at a low temperature and using only an equimolar amount of lithium aluminum hydride, to minimize reductive removal of the bromo group. The hydrochloride salt of 2-bromo-4,5-dimethoxyamphetamine (ORTHO-DOB) had a mp of 214-215.5 °C, and the hydrobromide salt a melting point of 196-197 °C or of 210 °C. Both have been reported. The yield from the direct bromination of 3,4-DMA was apparently very bad. I do not think that the compound has ever gone into man.
There are three other dimethoxyamphetamine isomers known, and each has been explored chemically as to its reactivity with elemental bromine. With 2,3-DMA, a mixture of the 5-Br-2,3-DMA and 6-Br-2,3-DMA was formed; with 2,6-DMA, 3-Br-2,6-DMA was formed; and with 3,5-DMA, a mixture of 2-Br-3,5-DMA and the 2,6-dibromo product was produced. The bromination of 2,5-DMA is, of course, the preferred procedure for the synthesis of 4-Br-2,5- DMA, or DOB, q.v. None of these positional isomers has evear been put into man, but 3-Br-2,6-DMA and the iodo-counterpart have been explored as potential radio-fluorine carriers into the brain. This is all discussed in the 3,4-DMA recipe.
#125 META-DOT; 2,4-DIMETHOXY-5-METHYLTHIOAMPHETAMINE
SYNTHESIS: To 27 g 1,3-dimethoxybenzene that was being well stirred, there was added, dropwise, 29 g concentrated H2SO4 over a period of 15 min. Stirring was continued for 1 hour, and then the mixture was poured slowly into 250 mL of saturated aqueous K2CO3. The precipitate that formed was removed by filtration, and dried at 125 °C to give 59.6 g crude potassium 2,4-dimethoxybenzenesulfonate. This was finely ground, and 30 g of it was treated with 35 g of POCl3 and the mixture heated on the steam bath for 2 h. This was cooled to room temperature, and then poured over 300 mL crushed ice. When all had thawed, this was extracted with 2x150 mL Et2O. The extracts were pooled, washed with saturated brine, and the solvent removed under vacuum to give a residue which solidified. There was thus obtained 14.2 g 2,4-dimethoxybenzenesulfonyl chloride as white solids with a mp of 69-72 °C. Heating of a small portion with concentrated ammonium hydroxide gave the corresponding sulfonamide which, on recrystallization from EtOH, produced white needles with a mp of 165.5-166.5 °C.
To a stirred and gently refluxing suspension of 11 g LAH in 750 mL anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl chloride in an Et2O solution. The refluxing was maintained for 48 h then, after cooling externally with ice water, the excess hydride was destroyed by the slow addition of 600 mL of 10% H2SO4. The phases were separated, and the aqueous phase extracted with 2x200 Et2O. The organics were pooled, washed once with 200 mL H2O, and the solvent removed under vacuum. The residue was dried azeotropically through the addition and subsequent removal of CH2Cl2. Distillation of the residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil, boiling at 89-92 °C at 0.5 mm/Hg.
To a solution of 7.8 g 2,4-dimethoxythiophenol in 40 mL absolute EtOH there was added a solution of 4 g 85% KOH in 65 mL EtOH. This was followed by the addition of 5 mL methyl iodide, and the mixture was held at reflux for 30 min. This was poured into 200 mL H2O, and extracted with 3x50 mL Et2O. The pooled extracts were washed once with aqueous sodium hydrosulfite, then the organic solvent was removed under vacuum. The residue was distilled to give 8.0 g of 2,4-dimethoxythioanisole as a colorless oil with a bp of 100-103 °C at 0.6 mm/Hg.
To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been warmed briefly on the steam bath there was added 7.8 g of 2,4-dimethoxythioanisole. The reaction was heated on the steam bath for an additional 20 min and then poured into 200 mL H2O. Stirring was continued until the insolubles had become completely loose and granular. These were removed by filtration, washed with H2O, sucked as dry as possible, and then recrystallized from boiling MeOH. The product, 2,4-dimethoxy-5-(methylthio)benzaldehyde, was an off-white solid weighing 8.6 g. It could be obtained in either of two polymorphic forms, depending on the concentration of aldehyde in MeOH at the time of crystal appearance. One melted at 109-110 °C and had a fingerprint IR spectrum including peaks at 691, 734, 819 and 994 cm-1. The other melted at 124.5-125.5 °C and had major fingerprint peaks at 694, 731, 839 and 897 cm-1. Anal. (C10H12O3S) C,H.
A solution of 8.2 g 2,4-dimethoxy-5-(methylthio)benzaldehyde in 30 mL nitroethane was treated with 1.8 g anhydrous ammonium acetate and heated on the steam bath for 4 h. Removal of the excess nitroethane under vacuum gave a colored residue which crystallized when diluted with MeOH. Recrystallization of the crude product from boiling EtOH gave, after filtration, washing and air drying to constant weight, 8.3 g 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene with a mp of 112-113 °C. Anal. (C12H15NO4S) C,H,N.
A suspension of 6.5 g LAH in 250 mL anhydrous THF was placed under a N2 atmosphere and stirred magnetically and brought to reflux. There was added, dropwise, 8.0 g of 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene in 50 mL THF. The reaction mixture was maintained at reflux for 18 h. After being brought to room temperature, the excess hydride was destroyed by the addition of 6.5 mL H2O in 30 mL THF. There was then added 6.5 mL of 3N NaOH, followed by an additional 20 mL H2O. The loose, white, inorganic salts were removed by filtration, and the filter cake washed with an additional 50 mL THF. The combined filtrate and washes were stripped of solvent under vacuum yielding a residue that was distilled. The free base boiled at 125-128 °C at 0.1 mm/Hg and was a white oil which solidified on standing. It weighed 5.1 g and had a mp of 47-48.5 °C. This was dissolved in 50 mL IPA, neutralized with concentrated HCl (until dampened universal pH paper showed a deep red color) and diluted with anhydrous Et2O to the point of turbidity. There was a spontaneous crystallization providing, after filtering, washing with Et2O, and air drying, 2,4-dimethoxy-5-methylthioamphetamine hydrochloride (META-DOT) with a mp of 140.5-142 °C. Anal. (C12H20ClNO2S) C,H,N.
DOSAGE: greater than 35 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 35 mg) There was a vague awareness of something all afternoon, something that might be called a thinness. Possibly some brief cardiovascular stimulation, but nothing completely believable. This is a threshold level at the very most.
EXTENSIONS AND COMMENTARY: Again, as with the studies with ORTHO-DOT, it is apparent that the activity of META-DOT is going to be way down from the most interesting of these isomers, PARA-DOT (ALEPH-1, or just ALEPH). In the rectal hyperthermia assay (which calculates the psychedelic potential of compounds by seeing how they influence the body temperature of experimental animals in comparison to known psychedelics) the three DOT's were compared with DOM. And the results fell into line in keeping with the activities (or loss of activities) found in man. PARA-DOT was about half as active as DOM, but both ORTHO-DOT and the compound described here, META-DOT, were down by factors of 50x and 30x respectively. These animal studies certainly seem to give results that are reasonable with a view to other known psychedelic drugs, in that mescaline was down from DOM by a factor of more than 1000x, and LSD was some 33x more potent than DOM.
I have a somewhat jaundiced view of this rabbit rectal hyperthermia business. One is presumably able to tell whether a compound is a stimulant or a psychedelic drug by the profile of the temperature rise, and how potent it will be by the extent of the temperature rise. But the concept of pushing thermocouples into the rear ends of restrained rabbits somehow does not appeal to me. I would rather determine both of these parameters from human studies.
#126 METHYL-DMA; DMMA; 2,5-DIMETHOXY-N-METHYLAMPHETAMINE
SYNTHESIS: To a stirred solution of 28.6 g methylamine hydrochloride in 120 mL MeOH there was added 7.8 g 2,5-dimethoxyphenylacetone followed by 2.6 g sodium cyanoborohydride. HCL was added as needed to maintain the pH at about 6. The reaction was complete in 24 h, but was allowed to stir for another 3 days. The reaction mixture was poured into 600 mL H2O, acidified with HCl (HCN evolution, caution) and washed with 3x100 mL CH2Cl2. Aqueous NaOH was added, making the solution strongly alkaline, and this was then extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 8.3 g of a clear, off-white oil that distilled at 95-105 °C. at 0.25 mm/Hg. The 6.5 g of colorless distillate was dissolved in 25 mL IPA, neutralized with concentrated HCl, and then diluted with anhydrous Et2O to the point of cloudiness. As crystals formed, additional Et2O was added in small increments, allowing clearing crystallization between each addition. In all, 200 mL Et2O was used. After filtering,Et2O washing, and air drying, there was obtained 6.2 g of 2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DMA) as fine white crystals with a mp of 117-118 °C. The mixed mp with 2,5-DMA (114-116 °C) was depressed to 96-105 °C. An alternate synthesis gave the same overall yield of an identical product, but started with 2,5-DMA. It required two synthetic steps. The free base amine was converted to the crystalline formamide with formic acid in benzene using a Dean Stark trap, and this intermediate was reduced to METHYL-MDA with LAH.
DOSAGE: above 250 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 250 mg) There is a slight paresthesia at about 45 minutes, an awareness on the surface of the skin as if I had been touched by a cold draft of air. But nothing more. At three hours, I am completely out, if I was ever in. In the evening I assayed 120 milligrams of MDMA, and it barely produced a threshold effect, so the two materials might be seeing one another.
EXTENSIONS AND COMMENTARY: This is a difficult compound to pin down in the anthology of drugs. For some reason it has intrigued several independent, quiet researchers, and I have accumulated a number of interesting reports over the years. One person told me that he had felt nothing at up to 60 milligrams. Another had found a threshold at 50 milligrams, and had complete and thorough experiences at both 150 and 200 milligrams. Yet another person described two incidents involving separate individuals, with intravenous administrations of 0.2 mg/Kg, which would be maybe 15 or 20 milligrams. Both claimed a real awareness in a matter of minutes, one with a tingling in the genitalia and the other with a strange presence in the spine. Both subjects reported increases in body temperature and in blood pressure. Apparently the effects were felt to persist for many hours.
There is an interesting, and potentially informative, convergence of the metabolite of one drug with the structure of another. Under 4-MA, mention was made of a bronchodilator that has been widely used in the treatment of asthma and other allergenic conditions. This compound, 2-methoxy-N-methylamphetamine is known by the generic name of methoxyphenamine, and a variety of trade names with Orthoxine (Upjohn) being the best known. The typical dosage of methoxyphenamine is perhaps 100 milligrams, and it may be used several times a day. It apparently produces no changes in blood pressure and only a slight cardiac stimulation. And one of the major metabolites of it in man is the analogue with a hydroxyl group at the 5-position of the molecule. This phenolic amine, 5-hydroxy-2-methoxy-N-methylamphetamine is just a methyl group away from METHYL-DMA; it could either be methylated to complete the synthesis, or METHYL-DMA could be demethylated to form this phenol. There is plentiful precedent for both of these reactions occuring in the body. It is always intriguing when drugs which show distinctly different actions can, in principle, intersect metabolically at a single structure. One wonders just what the pharmacology of that common intermediate might be.
Three additional N-methylated homologues of known psychedelics warrant mention, but do not really deserve separate recipes. This is because they have had only the most cursory assaying, which I have learned about by personal correspondence. All three were synthesized by the reduction of the formamide of the parent primary amine with LAH. METHYL-TMA (or N-methyl-3,4,5-trimethoxyamphetamine) had been run up in several trials to a maximum of 240 milligrams, with some mental disturbances mentioned only at this highest level. METHYL-TMA-2 (or N-methyl-2,4,5-trimethoxyamphetamine) had been tried at up to 120 milligrams without any effects. METHYL-TMA-6 (or N-methyl-2,4,6- trimethoxyamphetamine) had been tried at up to 30 milligrams and it, too, was apparently without effects. These are reports that I have heard from others, but I have had no personal experience with them. Those that I can describe from personal experience are entered separately as recipes of their own. And there are many, many other N-methyl homologues which have been prepared and characterized in the literature, and have yet to be tasted. So far, however, the only consistent thing seen is that, with N-methylation, the potency of the psychedelics is decreased, but the potency of the stimulants appears to be pretty much maintained.
#127 METHYL-DOB; 4-BROMO-2,5-DIMETHOXY-N-METHYLAMPHETAMINE
SYNTHESIS: To a solution of 6.0 g of the free base of 2,5-dimethoxy-N-methyl-amphetamine (see recipe under METHYL-DMA) in 30 mL glacial acetic acid there was added, dropwise and with good stirring, a solution of 5.5 g bromine in 15 mL acetic acid. The reaction became quite warm, and turned very dark. After stirring an additional 45 min, the mixture was poured into 200 mL H2O and treated with a little sodium hydrosulfite which lightened the color of the reaction. There was added 20 mL concentrated HCl, and the reaction mixture was washed with 2x100 mL CH2Cl2 which removed most of the color. The aqueous. phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. The removal of the solvent from the pooled extracts under vacuum gave 1.8 g of an oil which was dissolved in 10 mL IPA, neutralized with concentrated HCl, and diluted with 100 mL anhydrous Et2O. No crystals were obtained, but rather an oily and somewhat granular insoluble lower phase. The Et2O was decanted, and the residue washed by grinding up under 3x100 mL Et2O. The original decanted material was combined with the three washes, and allowed to stand for several h. The product 4-bromo-2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DOB) separated as fine white crystals which weighed, after filtering and air drying, 0.3 g and had a mp of 149-150 °C. The Et2O-insoluble residue finally set up to a pale pink mass which was finely ground under a few mL acetone. Filtration and air drying gave a second crop of product as 0.9 g of pale lavender solids, with a mp of 143-145 °C.
DOSAGE: greater than 8 mg.
DURATION: probably rather long.
QUALITATIVE COMMENTS: (with 8.0 mg) At an hour and twenty minutes, I was suddenly quite light headed. An hour later I must say that the effects are real, and generally good. I am spacey Q nothing tangible. And a couple of hours yet later I am still aware. My teeth are somewhat rubby, and as things have been pretty steady for the last three hours, this will prove to be long lasting. There are a lot of physical effects that may be kidding me into providing myself some of the mental. At the sixth hour, I find that this is almost entirely physical. My teeth are tight, there is a general physical tenseness, my reflexes seem exaggerated, and my eyes are quite dilated. All of these signs are lessened by the eighth hour, and do not interfere with sleep at the twelfth hour. There is no desire to proceed any further, at least at the present time. Mental (+) physical (++). Next day, slight impression of persistence of toxicity.
(with 10 mg) Nothing psychedelic, but awfully hard on the bod. The next day (24 hours later) I had a severe response to 5 milligrams of psilocybin.
EXTENSIONS AND COMMENTARY: The mention above, of the 10 milligrams of METHYL-DOB followed by 5 milligrams of psilocybin, leads to some interesting speculation. The usual pattern that is seen when two psychedelic drugs are taken too closely together is that the second experience is less effective than would have been expected. This is the property that is called tolerance, and it is frequently seen in pharmacology. The two exposures may be to a single drug, or they may be to two different drugs which usually have some properties in common. It is as if the spirit of the receptor site had become a little tired and needed a while to rest up and recuperate. When there is a demand for a repeat of full effectiveness, the user will customarily increase the dosage of the drug that is used. It is one of the built-in protections, in the area of psychedelics that, after one experience, you must wait for a period of time to lose the refractoriness that has set in.
The measure of the degree of tolerance that can be shared between different drugs, called cross-tolerance, can be used as an estimate of the similarities of their mechanisms of action. In other words, if A and B are somehow seen by the body as being similar, then a normally effective dose of A will make a next-day's normally effective dose of B weaker than expected. Or not active at all. And B will do the same job on A. If two drugs are different in their ways of doing things in the body, there is most often no cross-tolerance seen. This was described for MDMA and MDA, and is the basis of the argument that they act by distinctly separate mechanisms. A person who used what would be held as an active dose of MDMA for several days lost all response to the drug. He was tolerant to its effects. But an exposure to an effective dose of MDA at the time that tolerance to MDMA was complete, provided a normal response to the MDA. The drugs are not cross-tolerant and the body recognizes them as distinct individuals.
But for one drug to promote, or to exaggerate, the effect of another is called potentiation, and can be a clue to the dynamics going on in the brain or body. Here, admittedly in only a single report, METHYL-DOB had somehow sensitized the subject to a rather light dosage of psilocybin. But there have been other reports like this that I have heard of, from here and there. I have been told of an experiment with the dextro-isomer of DOM (this is the inactive optical isomer) at a level that was, not surprisingly, without any effects. The researcher had a severe reaction the following day with what was referred to as "poor" hashish. A similar form of potentiation has been commented upon under the recipe for TOMSO, where an inactive drug, and a most modest amount of alcohol, add together to create an unexpectedly intense intoxication. But note that in each of these cases, it is a phenethylamine interacting with a non-phenethylamine (psilocybin is an indole, hashish is a non-alkaloid terpene thing, and alcohol is, well, alcohol).
The bottom line with METHYL-DOB is, as with the other N-methylated psychedelics, that it is way down in potency, and probably not worth pursuing.
#128 METHYL-J; MBDB; EDEN; 2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE; N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE
SYNTHESIS: A solution of 0.12 g mercuric chloride in 180 mL H2O was added to 5 g aluminum foil that had been cut into 1 inch squares, and amalgamation allowed to proceed for 0.5 h. The gray cloudy aqueous phase was decanted, and the resulting aluminum washed with 2x200 mL H2O. After shaking as dry as possible, there was added, in sequence, a solution of 7.6 g methylamine hydrochloride in an equal weight H2O, 23 mL IPA, 18.3 mL 25% NaOH, 6.72 g 1-(3,4-methylenedioxyphenyl)-2-butanone (see under the recipe of J for its preparation), and finally 44 mL additional IPA. The mixture was occasional swirled, and cooled externally as needed to keep the temperature below 50 °C. After the reduction was completed (no metallic aluminum remaining, only gray sludge), it was filtered and the residues washed with MeOH. The combined filtrate and washes were stripped of organic volatiles under vacuum, the residue treated with 100 mL Et2O, and this was extracted with 2x50 mL 3 N HCl. After washing the pooled aqueous extracts with 3x100 mL CH2Cl2, they were made basic with an excess of 25% NaOH and extracted with 5x50 mL CH2Cl2. Drying of these extracts with anhydrous MgSO4 and removal of the solvent gave a residue that was distilled at 88 °C at 0.08 mm/Hg to give a colorless oil that was dissolved in IPA and neutralized with concentrated HCl. The solids that separated were removed by filtration, Et2O washed, and air dried to provide 6.07 g 2-methylamino-1-(3,4-methylenedioxyphenyl)butane hydrochloride (METHYL-J or MBDB) as white crystals with a mp of 156 °C. Anal. (C12H18ClNO2) C,H,N. Reductive amination of the butanone with methylamine hydrochloride in MeOH, employing sodium cyano-borohydride, gave an identical product but in a smaller yield.
DOSAGE: 180 - 210 mg.
DURATION: 4 - 6 h.
QUALITATIVE COMMENTS: (with 210 mg) Generally very, very friendly, very quiet effect. I can read easily, but looking at pictures in most books is relatively meaningless. Distinct de-stressing effect, to the point where it's too much trouble to set out to do anything at all, really. There is just no drive, and it isn't even bothersome to be missing it. Do I like it? Yes, very much. Feel that I've just begun to explore it, though. Would I consider this material in therapy? Well, sure, it's worth trying. Destressing would be excellent, and better than MDMA in some ways, but the empathy and intuition levels have yet to be explored in a therapy setting. I feel that they may be somehow lower.
(with 210 mg) Onset rapid. Alert 20 minutes, and to a +2.5 at 30 to 35 minutes. No physical symptoms, i.e., teeth clench, no stomach problems. Good visual enhancement; eyes open Q bright colors Q no visuals with eyes closed. No 'cone of silence' that I get with MDMA (and enjoy), otherwise I'm not sure I could tell which was which if I took them blind.
(with 210 mg and a 50 mg supplement) RTasted perfectly rotten. Suspect I was getting some type of alert in 5 minutes (I often get one quickly with MDMA) and at 30 minutes, a full blown high developed rather abruptly. It would be difficult to describe the high. I suspect it is the lack of language for the phenomenon. I would describe it somewhat like an alcohol high without the disabling side effects of confusion, slurring, staggering and etc. The high never got any more intense than at that 30 minute point and with a noticeable drop in another hour, I took a 50 mg supplement. I enjoyed the high. I relaxed with the material. However, it did not seem to have the same qualities as MDMA, in that it was not as stimulating, and it had very little visual activity. I talked with others, but found it easy to lie down and relax. There was some jaw-clenching towards the end, and I had considerable nystagmus at the peak which I could control. After the experience, I did not want to drink alcohol very much (sell it as a substitute for EtOH°).
(with 210 mg and a 70 mg supplement) RI begin to feel the rush at 20 minutes, increasing rapidly. Very much like MDMA, only more intense intoxication. Otherwise same symptoms: intense euphoria that I call a feeling of grace, soft skin, voices, youthful appearance, animated discussions, feelings of great closeness to others. I start to drop noticeably at less than an hour and a half into it, but I delayed a supplement until the hour and fifty minute point. It does not get me back to the original intoxication. However, it is very nice, very much like MDMA. Only difference is that there seems to be more quietness, less inclination to talk than with an MDMA supplement. My conclusion: Seems an excellent substitute for MDMA, Next time may try somewhat lower amount, supplement sooner.
EXTENSIONS AND COMMENTARY: An observer who was familiar with the outwardly apparent effects with groups experimenting with MDMA felt that, although most subjects commented favorably in their comparisons of METHYL-J with MDMA, there was lacking some of the spontaneity, the warmth, and the clear intimacy of the latter drug. The dosage range explored is remarkably tight, attesting to a consistency of response. The typical supplement used, if any, was 70 milligrams or less, just before the two hour point. This indicates a chronology similar to that of MDMA, and about two thirds the potency.
The arguments that weigh the use of the code name of MBDB against the use of METHYL-J are present in the recipe for BDB (or J). But what is the source of this H, I, J, K naming thing that I have called the Muni Metro?
First, a little bit of local color. In San Francisco, there is a public transportation called the S.F. Municipal Metropolitan System complex that has integrated an underground street-car system that emerges above ground and connects with a bus network. A number of the street-car lines fan across the city to the outer reaches which are called the Avenues. These lines are named by sequential letters. There is the J Church Street line, the K Ingelside line, the L Taraval line, the M Ocean line, and the N Judah. And in the pharmacological complex that involved the lengthening of the aliphatic chain, there were two coincidental benchmarks in the names that were proposed. Those without an alpha-substituent (no carbon atoms at the position alpha to the amine group, the phenethylamines) were originally called the H compounds. H stood for "homopiperonylamine." And the first of those with the alpha-ethyl group there (two carbon atoms at the position alpha to the amine group) was familiarly called "Jacobamine" in recognition of a famous chemist who had set the synthetic wheels in motion.
It is quite obvious, that with one carbon atom lying on that alpha-position, you are precisely half-way between no carbons and two carbons. And there was one letter of the alphabet that lies precisely half-way between an H and a J. So, an natural naming pattern developed. The I compounds were already pretty well known by names such as MDA and MDMA and MDE, so I, and METHYL-I, and ETHYL-I, didn't have any appeal. But for the new, the alpha-ethyl compounds, why not call them the J-compounds? If it has a methyl on the nitrogen it will be METHYL-J and if it has an ethyl group it will be ETHYL-J. And in the next longer group, the 3-carbon propyl group on the alpha-position becomes the K family, and the 4-carbon butyl group located there, the L family. Each with its METHYL and ETHYL prefixes, if the nitrogen atoms are substituted with a methyl or and ethyl group. V'la, comme on dit en Fran
ais. Le systme Muni Metro. Plus simple.
#129 METHYL-K; 2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)PENTANE; N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-PENTYLAMINE
SYNTHESIS: The Grignard reagent of butyl bromide was prepared in anhydrous Et2O by the dropwise addition of 68 g n-butyl bromide to a well-stirred suspension of 14 g magnesium turnings in 500 mL anhydrous Et2O. When the exothermic reaction had stopped, there was added a solution of 60 g piperonal in about 100 mL Et2O, over the course of 1 h. After the exothermic addition was complete, the reaction mixture was held at reflux for several h, then cooled and decomposed by the addition of dilute HCl. The phases were separated, and the aqueous phase extracted with 2x75 mL CH2Cl2. The organics were combined and gave, after the removal of the solvents under vacuum, 84 g of 1-hydroxy-1-(3,4-methylenedioxyphenyl)pentane as a yellow liquid. This was used in the following dehydration step without further purification.
A mixture of 52 g of the crude 1-hydroxy-1-(3,4-methylenedioxyphenyl)pentane and 2 g powdered KHSO4 was heated with a flame until there was no more apparent generation of H2O. The resulting dark, fluid oil was distilled at 100-110 °C at 0.3 mm/Hg to give 29.5 g of 1-(3,4-methylenedioxyphenyl)-1-pentene as a light yellow liquid. This was employed in the following oxidation step without further purification.
To 120 mL of 90% formic acid there was added, with good stirring, 15 mL H2O, followed by 23 mL of 35% H2O2 To this mixture, cooled with an external ice bath, there was added a solution of 24 g crude 1-(3,4-methylenedioxyphenyl)-1-pentene in 120 mL acetone at a rate slow enough to keep the internal temperature from exceeding 35 °C. At the end of the addition, the temperature was brought up to 45 °C by heating briefly on the steam bath, and then the reaction mixture was allowed to stand and stir at ambient temperature for several h. All volatiles were removed under vacuum, with a bath temperature maintained at 45 °C. The residue was dissolved in 30 mL MeOH, then there was added 200 mL 15% H2SO4 and the mixture held on the steam bath for 1.5 h. There was then added an additional 300 mL H2O, and this was extracted with 2x250 mL of a petroleum ether/EtOAc (5:1) mixture. The extracts were pooled, and the solvents removed under vacuum to give a residue that was distilled at 115-120 °C at 0.3 mm/Hg. This light yellow liquid weighed 13.5 g and was substantially pure 1-(3,4-methylenedioxyphenyl)-2-pentanone by TLC.
To 5.0 g of aluminum foil cut into 1 inch squares, there was added a solution of 150 mg HgCl2 in 200 mL H2O. The mixture was heated briefly until there were clear signs of active amalgamation, such as fine bubbling for the aluminum surfaces and the beginning of the formation of a gray, amorphous solid phase. The HgCl2 solution was decanted off and the aluminum was washed with 2x200 mL additional H2O. After shaking as dry as possible, there was added, in sequence and with good swirling agitation between each addition, 10 g methylamine hydrochloride in 10 mL H2O, 27 mL IPA, 22 mL of 25% NaOH, 5.0 g 1-(3,4-methylenedioxyphenyl)-2-pentanone, and finally an additional 50 mL IPA. The mixture was heated on the steam bath periodically to maintain the reaction rate at a vigorous boil. When all of the aluminum had been consumed, the cooled mixture was filtered and the solids washed with MeOH. The combined filtrate and washings were stripped of solvent under vacuum. The residue was dissolved in dilute H2SO4 and washed with 2x75 mL CH2Cl2. After making basic again with 25% NaOH, this was extracted with 2x100 mL CH2Cl2, and the pooled extracts were stripped of solvent under vacuum. The residue was distilled at 105-110 °C at 0.3 mm/Hg to give 2.7 g of a colorless liquid. This was dissolved in 15 mL IPA, neutralized with concentrated HCl, and diluted with 75 mL anhydrous Et2O which allowed a delayed appearance of a fine white crystal. This was removed by filtration, Et2O washed, and air dried to give 2.45 g 2-aminomethyl-1-(3,4-methylenedioxyphenyl)pentane hydrochloride (METHYL-K) as a white product with a mp of 155-156 °C. Anal. (C13H20ClNO2) C,H.
DOSAGE: greater than 100 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 100 mg) There were no effects. I was busy and totally wound up and didn't sleep until 3 AM, but this was probably unrelated to the Me-K.
EXTENSIONS AND COMMENTARY: The well appears to be running dry, with a pentane chain as a basic skeleton. METHYL-J, at this level, was already showing a number of hints and clues, largely physical such as coldness in the feet and a slight mastoidal pressure, that activity was right around the corner. But METHYL-K gave no such hints. The unmethylated homologue, 2-amino-1-(3,4-methylenedioxyphenyl)pentane (K), was also made, by the reductive amination of 1-(3,4-methylene-dioxyphenyl)-2-pentanone with ammonium acetate and sodium cyanoborohydride in methanol. It was a white crystalline solid, mp 202-203 °C, but is given here in the comments only, as its human assaying had never even been initiated. Anal. (C12H18ClNO2) C,H. The N-ethyl homologue, 2-ethylamino-1-(3,4-methylene-dioxyphenyl)pentane (ETHYL-K), is entered with its own recipe, on the other hand, since testing had been started with it.
And the longest chain that has been explored in this Muni Metro series is the six-carbon hexyl chain which is, quite logically, the L-series, sort of the end of the Taraval line (see under METHYL-J for an explanation). The central compound for all the L-compounds was the ketone 1-(3,4-methylenedioxyphenyl)-2-hexanone, which was prepared by the Grignard reagent of (n)-amyl bromide with piperonal to give 1-hydroxy-1-(3,4-methylenedioxyphenyl)hexane, dehydration of this with potassium bisulfate to the olefin, and oxidation of this with hydrogen peroxide and formic acid to the L-ketone which was an orange-colored liquid with a bp of 125-135 °C at 0.3 mm/Hg. This ketone was reductively aminated with ammonium acetate and sodium cyanoborohydride in methanol to produce 2-amino-1-(3,4-methylenedioxyphenyl)hexane hydrochloride (L) as a white crystalline product with a mp of 157-158 °C. Anal. (C13H20ClNO2) C,H. And this ketone was reductively aminated with methylamine hydrochloride and amalgamated aluminum in isopropanol to produce 2-methylamino-1-(3,4-methylenedioxyphenyl)hexane hydrochloride (METHYL-L) as a white crystalline product with a mp of 139-141 °C. Anal. (C14H22ClNO2) C,H. The reduction of this ketone in a similar manner with ethylamine hydrochloride produced 2-ethylamino-1-(3,4-methylenedioxyphenyl)hexane (ETHYL-L). None of this series has yet been explored either as psychedelic or entactogenic materials.
#130 METHYL-MA; PMMA; DOONE; 4-MMA; 4-METHOXY-N-METHYLAMPHETAMINE
SYNTHESIS: A solution of 20 g methylamine hydrochloride in 150 mL hot MeOH was treated with 10.0 g 4-methoxyphenylacetone and stirred magnetically. After returning to room temperature, there was added 5.0 g sodium cyanoborohydride, followed by cautious addition of HCl as required to maintain the pH at about 6. The reaction was complete after a few days, and the mixture was poured into 800 mL H2O. This was acidified with HCl (HCN evolution°) and washed with 3x75 mL CH2Cl2, which removed most of the yellow color. There was 25% NaOH added to make the reaction mixture strongly basic, and this was extracted with 3x75 mL CH2Cl2. The solvent was removed from the pooled extracts under vacuum, and the 10.3 g of residue distilled at 0.3 mm/Hg. The 9.7 g of colorless oil that distilled at 75-90 °C was dissolved in 50 mL IPA, neutralized with 4.5 mL concentrated HCl, and then diluted with 100 mL anhydrous Et2O. There were generated glistening crystals of 4-methoxy-N-methylamphetamine hydrochloride (METHYL-MA or DOONE) that weighed, after washing with Et2O and air drying to constant weight, 11.0 g and which had a mp of 177-178 °C. The same base can be made by the action of ethyl chloroformate on 4-MA in the presence of triethylamine to make the carbamate, or the action of formic acid to make the formamide. These can then be reduced with LAH to this same end product.
DOSAGE: greater than 100 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 110 mg) One hour into it, my pulse was up over 100, and I was compulsively yawning. There was some eye muscle disturbance, a little like the physical side of MDMA, but there was none of its central effects. But all the hints of the cardiovascular are there. By the fourth hour, I am pretty much back to baseline, but the yawning is still very much part of it. I might repeat this, at the same level, but with continuous close monitoring of the body.
EXTENSIONS AND COMMENTARY: Why would there be interest in this particular compound? The track record from the comparison of active compounds that are primary amines, and their N-methyl homologues, has shown that, in general, the stimulant component might be maintained, but the "psychedelic" contribution is generally much reduced. MDMA is, of course, an exception, but then, that particular compound is a one-of-a-kind thing which simply defies all the rules anyway, and I drop it from this kind of reasoning. And as 4-MA is a pretty pushy stimulant with little if any sensory sparkle, why bother with the N-methyl compound at all?
For a completely silly and romantic reason. When the MDMA story became front-page news back in mid-1985, the cartoonist-author of Doonesbury, Gary Trudeau, did a two-week feature on it, playing it humorous, and almost (but not quite) straight, in a hilarious sequence of twelve strips. On August 19, 1985 he had Duke, president of Baby Doc College, introduce the drug design team from USC in the form of two brilliant twins, Drs. Albie and Bunny Gorp. They vividly demonstrated to the enthusiastic conference that their new drug "Intensity" was simply MDMA with one of the two oxygens removed. "Voila," said one of them, with a molecular model in his hands, "Legal as sea salt." And what is MDMA with one oxygen atom removed? It is 4-methoxy-N-methylamphetamine or METHYL-MA which, according to the twins, should give the illusion of substance to one's alter ego. So, I called it Doonesamine, or simply "DOONE" for short. Maybe that was also a homonym for Frank Herbert's science fiction book, "Dune," wherein the magical drug "spice" provided a most remarkable alteration of the user's state of consciousness.
This comic strip presentation was the first nationally distributed allusion to the term "designer drugs," and perhaps it lent unexpected support for the passage, just a year later, of the Controlled Substances Analogue Enforcement Act of 1986. This intentionally vague piece of legislation makes the giving of, or the taking of, or even the possession with the intent to take, any drug that in any way alters your state of consciousness, a felony. A shameful and desperate effort by the governmental authorities to maintain the image of control in a lost situation.
Enough editorial. Back to historic technicalities. In truth, METHYL-MA is a well studied drug, at least in animals. In both mice and rats, it is an exceptionally potent agent in creating the state of catatonia. Animal studies, prompted by the clandestine synthesis of METHYL-MA, have shown that there is indeed locomotor stimulation and some central effects, but these effects are somehow different than those of a simple amphetamine-like agent. The experimenter's conclusions, based on its structural resemblance to 4-MA and its proclivity to produce catatonia in some animal species and the ever-present possibility that there might be unsuspected neurochemical changes to be seen with its use, are that human experimentation should be discouraged. I have come to the same conclusion, but in my case this is based on a much more succinct observation: I tried it and I didn't like it.
A brief comment on two of the N,N-dimethylhomologues of methoxyamphetamine. One was 4-methoxy-N,N-dimethylamphetamine, 4-MNNA. This material, made by the reductive amination of 4-methoxyphenylacetone with dimethylamine, was a colorless oil, which distilled at 70-85 °C at 0.3 mm/Hg. The corresponding 2-methoxy-N,N-dimethylamphetamine was similarly made. 2-MNNA was also a colorless oil and had the same bp. Both of them were fluorinated with 18F labelled acetyl hypofluorite (3% and 6% yields respectively) but neither of them was pursued any further in the search for a brain blood flow indicator.
#131 METHYL-MMDA-2; 2-METHOXY-N-METHYL-4,5-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: A suspension of 17.4 g electrolytic elemental iron in 100 g glacial acetic acid was heated on the steam-bath until there were the first signs of bubbling and reaction, about 60 °C. There was then added, in small portions, a suspension of 9.2 g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene (see under MMDA-2 for its preparation) in 40 g warm glacial acetic acid. The reaction was extremely exothermic. After the color had lightened as much as possible, there was added an additional quantity of iron sufficient to completely discharge the residual yellow color. Mechanical stirring was maintained as the reaction mixture was allowed to return to room temperature. All was poured into 800 mL H2O, and the insolubles were removed by filtration. These were washed alternately with H2O and with CH2Cl2, the combined filtrate and washes were separated, and the aqueous phase extracted with 3x100 mL CH2Cl2. All organics were combined, washed with 2x75 mL 5% NaOH (which removed most of the color) and the solvent removed under vacuum. The 8.7 g residue was distilled at 90-105 °C at 0.2 mm/Hg to give 6.7 g of 2-methoxy-4,5-methylenedioxyphenylacetone as a pale yellow oil.
To a magnetically stirred solution of 30 g methylamine hydrochloride in 150 mL warm MeOH, there was added 6.5 g 2-methoxy-4,5-methylenedioxyphenylacetone followed by 3.0 g sodium cyano-borohydride. Concentrated HCl was added as was required to keep the mixture at a pH of about 6. When the reaction was complete, it was added to 1 L H2O and made strongly basic with 25% NaOH. This was extracted with 3x100 mL CH2Cl2, and the pooled extracts were, in turn, extracted with 2x100 mL dilute H2SO4. This aqueous phase was washed with CH2Cl2, made basic with NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from these pooled extracts under vacuum gave 8.7 g of an amber oil. This was distilled at 110-125 °C at 0.25 mm/Hg to give 5.1 g of a colorless oil. This was dissolved in 30 mL IPA, neutralized with about 3 mL concentrated HCl, and diluted with 60 mL anhydrous Et2O. The clear solution slowly deposited white crystals which were removed by filtration and air dried to give 4.2 g 2-methoxy-N-methyl-4,5-methylenedioxyamphetamine hydrochloride (METHYL-MMDA-2) with a mp of 168-169 °C. Anal. (C12H18ClNO3) C,H.
DOSAGE: greater than 70 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 70 mg) Maybe a threshold Q pleasant but not possible to characterize it.
EXTENSIONS AND COMMENTARY: With the effective dosage of the unmethylated homologue being the range of 25 to 50 milligrams, this N-methyl compound is, as with the other N-methylated materials discussed here, again of reduced activity. The highest dose yet reported was 70 milligrams, and there is no way of estimating what miight be an active level nor, once there, what the quality of the effects might be.
This is the only MMDA analogue that has been explored as an N-methyl derivative. A more highly substituted analogue has also been made, the N-methyl derivative of DMMDA. Isoapiole (see its preparation under DMMDA) was oxidized with formic acid and hydrogen peroxide to the ketone (2,5-dimethoxy-3,4-methylenedioxyphenylacetone, a solid with a mp of 75-76 °C from methanol) which was reductively aminated with methylamine and amalgamated aluminum to give 2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine hydrobromide monohydrate (METHYL-DMMDA, or DMMDMA) as a white crystalline solid with a mp of 91-92 °C. The hydrochloride salt was a hygroscopic solid. Anal. (C13H22BrNO5) C,H. The above ketone has also been used in the synthesis of another methylated DMMDA, on the beta-carbon. This is described under DMMDA itself. DMMDMA has not yet been launched into an evaluation program, and I wouldn't be surprised if the needed dosage might be up there somewhere over 100 milligrams. I feel quite sure that the answers may be known in the near future. There is a surprisingly large number of inconspicuous chemical explorers out there all over the world, doing their synthetic thing in their private laboratories. They are truly the astronauts of inner space.
#132 MMDA; 3-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: (from protocatechualdehyde) A solution of 18 g commercial protocatechualdehyde (3,4-dihydroxybenzaldehyde) in 200 mL warm acetic acid was filtered free of any insolubles, to provide a very dark but clear solution. With good stirring there was then added 20 g elemental bromine. The reaction spontaneously heated to about 30 °C and solids appeared in about 5 min. Stirring was continued for 1 h, and then the light gray solids that had formed were removed by filtration and lightly washed with acetic acid. These were air dried on the steam bath until free of acetic acid smell. The product, 3-bromo-4,5-dihydroxybenzaldehde, weighed 11.7 g and had a mp of 222 °C.
To a solution of 11.7 g 3-bromo-4,5-dihydroxybenzaldehyde in 36 mL DMSO there was added 29 g methylene iodide followed by 20.8 g anhydrous K2CO3. This was heated on the steam bath for 3 h, added to 1 L H2O, made strongly basic with NaOH, then extracted with 3x100 mL CH2Cl2. These extracts were pooled, washed with H2O, and the solvent removed under vacuum. The dark brown semi-solid residue was distilled with the major fraction (6.0 g) coming over at 120-130 °C at 0.3 mm/Hg. This, upon recrystallization from 35 g boiling MeOH, gave 1.3 g of 3-bromo-4,5-methylenedioxybenzaldehyde as an off white crystalline solid with a mp of 123-124 °C.
A mixture of 2.2 g 3-bromo-4,5-methylenedioxybenzaldehyde and 3.6 mL cyclohexylamine in a distillation flask was heated to 100 °C to effect solution, and then with an open flame until the signs of H2O evolution were evident. This was then placed under a hard vacuum to remove the generated water and excess cyclohexylamine, and the product distilled at 120-125 °C at 0.2 mm/Hg. There was obtained 2.4 g of the Schiff base of the aldehyde and the amine, melting at 86-96 °C. Recrystallization of an analytical sample from 5 volumes of MeOH gave 3-bromo-4,5-methylenedioxybenzylidine-N-cyclohexylamine as a white solid with a mp of 97.5-98.5 °C. Anal. (C14H16BrNO2) H; C: calcd, 54.20; found, 53.78.
A solution of 2.2 g 3-bromo-4,5-methylenedioxybenzylidine-N-cyclohexylamine (the above Schiff base) in 50 mL anhydrous Et2O was placed in a He atmosphere, stirred magnetically, and cooled with a dry ice/acetone bath. A white fine crystalline phase appeared. There was then added 5.2 mL 1.55 M butyllithium in hexane (the fine solids dissolved) followed by 4.0 mL of tributyl borate. After returning to room temperature, the reaction was quenched with 20 mL of saturated aqueous ammonium sulfate. The Et2O/hexane layer was separated, washed with additional ammonium sulfate solution, and then stripped of volatiles under vacuum. The residue was dissolved in 100 mL 50% MeOH, treated with 2 mL of 30% hydrogen peroxide and, after 15 min swirling, quenched with a solution of 10 g ammonium sulfate in 50 mL H2O. This aqueous phase (pH about 8) was extracted with 2x50 mL CH2Cl2, the extract pooled and stripped of solvent under vacuum, and the residue dissolved in warm, dilute HCl. After all the residue had dissolved (a few min heating was sufficient), the solution was cooled to room temperature and extracted with 2x50 mL CH2Cl2. These organics were pooled and extracted in turn with 2x50 mL 5% NaOH. Acidification of the pooled aqueous fractions with HCl, followed by extraction with 2x50 mL CH2Cl2 gave, after evaporation of the solvent, a residue that was distilled at 140-150 °C at 0.25 mm/Hg to give 3-hydroxy-4,5-methylenedioxybenzaldehyde. This was recrystallized from toluene (40 mL/g) to give 0.46 g of an off-white product with a mp of 134-134.5 °C. Anal. (C8H6O4) C,H.
A solution of 0.44 g 3-hydroxy-4,5-methylenedioxybenzaldehyde in 10 mL dry acetone was treated with 0.5 g methyl iodide and 0.5 g powdered anhydrous K2CO3, and was held at reflux for 6 h. All volatiles were stripped under vacuum, the residue dissolved in water, made strongly basic with NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent gave myristicinaldehyde (mp 133-134 °C) which, on recrystallization from hexane, gave a final yield of 0.42 g with a mp of 134-135 °C. Care must be taken with two sequential products that have identical mps. A mixed mp with the unmethylated phenol above is strong depressed, whereas that with an authentic sample is not.
A solution of 9.8 g myristicinaldehyde in 35 mL glacial acetic acid was treated with 5.3 mL nitroethane and 3.2 g anhydrous ammonium acetate, and heated on the steam bath for 1.5 h. It was removed, treated with H2O with good stirring to just short of turbidity, seeded with product nitrostyrene, and allowed to come slowly to room temperature. The bright yellow solids that formed were removed by filtration, washed with a small amount of aqueous acetic acid, and sucked as free of solvent as possible. This material, pressed on a porous plate, had a mp of 107-110 °C. Recrystallization from 60 mL boiling EtOH gave, after filtering and air drying, 5.1 g of 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene as light yellow solids with a mp of 109-110 °C.
A suspension of 7.5 g LAH in 500 mL anhydrous Et2O was magnetically stirred, and heated in an inert atmosphere to a gentle reflux. The condensing Et2O leached out a total of 9.8 g 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene from a Soxhlet thimble in a shunted reflux condenser. This, in effect, added the nitrostyrene to the reaction medium as a warm saturated Et2O solution. When the addition was completed, the refluxing was maintained for an additional 5 h, then the reaction mixture was cooled and the excess hydride destroyed by the addition of 400 mL 1.5 N H2SO4 (the first 20 mL a drop at a time and with very good stirring). The phases were separated, and sufficient saturated aqueous Na2CO3 was added to the aqueous phase to bring the pH up to about 6.0. This was heated to 80 °C and filtered through a coarse sintered glass funnel to remove some insoluble fines. The clear filtrate was brought up almost to a boil, and treated with a solution of 10.2 g of 90% picric acid in 110 mL boiling EtOH. Crystals of the picrate formed immediately at the edges, and as the reaction flask was cooled in an ice tub, the entire reaction set to a yellow mass of crystals. These were removed by filtration, washed sparingly with 80% EtOH, and air dried to give 14.0 g of the picrate salt of MMDA, with a mp of 182-184 °C. Recrystallization of a small sample from EtOH dropped this to 179-181 °C. This salt was treated with 30 mL 5% NaOH, and the red solution decanted from some insolubles. Additional H2O and NaOH effectively dissolved everything, and the resulting basic aqueous phase was extracted with 3x50 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue dissolved in 200 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was a heavy precipitation of white crystals, which were removed by filtration, Et2O washed, and air dried to give 6.37 g 3-methoxy-4,5-methylenedioxyamphetamine hydrochloride (MMDA) with a mp of 190-191 °C. Anal. (C11H16ClNO3) Cl.
(from Oil of Nutmeg) The careful distillation of Oil of Nutmeg (or the Oil of Mace) allowed the isolation of a number of compounds in varying degrees of purity. The fraction that boiled in the 110-115 °C range at about 1.0 mm/Hg was myristicin (3-methoxy-4,5-methylenedioxyallylbenzene). It constituted some 7% of the original oil of commerce and, in its original isolated form, was obtained with a purity of 87%. The major contaminant was elemicin (3,4,5-trimethoxyallylbenzene). A solution of 100 g myristicin in 100 g absolute EtOH was treated with 200 g solid KOH and heated on a steam bath overnight. Removal of the volatiles under vacuum, flooding the residue with H2O, and extraction with 3x100 mL CH2Cl2 gave, after removal of the solvent from the combined extracts, a residue of crude isomyristicin (a mixture of the cis- and trans-isomers). This product was distilled, and the fraction boiling at 125-130 °C at 1 mm/Hg gave 63 g of isomyristicin as a pale yellow oil that spontaneously crystallized. The mp was 41.5-42.5 °C. Part of the losses associated with the purification of these solids was due to formation of the cis-isomer of isomyristicin, which was an oil.
A solution of 50 g isomyristicin in 300 mL dry acetone containing 24 g pyridine was vigorously stirred and cooled to 0 °C with an ice bath. To this there was added 54 g tetranitromethane which had been pre-cooled to 0 °C. Stirring was continued for exactly 2 min, and then the reaction was quenched by the addition of a cold solution of 16.8 g KOH in 300 mL H2O. Stirring was continued until the temperature had again been lowered to near 0 °C. The product was removed by filtration. Extraction of the filtrate with CH2Cl2 and removal of the solvent provided additional nitrostryrene, for a combined yield of 50.7 g with a mp of 103 °C due to the presence of a small amount of free myristicinaldehyde. A recrystallization from MeOH produced 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of 109-110 °C. This material was completely adequate for the above-described reduction to MMDA. The conversion of this nitropropene to myristicinaldehyde is an alternative to the lengthy synthesis given above), and can be used in the preparation of LOPHOPHINE.
A mixture of 50 g 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene and 26 g racemic a-methylbenzylamine was heated on the steam bath. The mixture gradually formed a clear solution with the steady evolution of nitroethane. When the reaction became quiet, there was added a mixture of 20 mL concentrated HCl in 100 mL H2O. The reaction mixture dissolved completely, and as the temperature continued to rise there was the abrupt solidification as the formed myristicinaldehyde crystallized out. This product was removed by filtration and, when combined with a second crop obtained by the hexane extraction of the filtrate, gave 36.9 g of myristicinaldehyde. The mp of 128-129 °C was raised to 133-134 °C by recrystallization from hexane.
DOSAGE: 100 - 250 mg.
DURATION: moderate.
QUALITATIVE COMMENTS: (with 100 mg) I felt completely relaxed at one hour. Almost as if I was floating. There were no obvious effects on taste, and the relaxation and composed feeling is much like a small dose, maybe 20 mikes, of LSD. There was some dilation, and in the evening I was a little restless and slightly tired. I slept well, and awoke refreshed and happy.
(with 100 mg) It seemed to take 45 minutes to work and then it came on very suddenly, as if my eyeballs were being pulled out and my whole head expanding. Soon a cold feeling set in with shivering Q this was not unpleasant. My state in about two hours seemed to be one of empathy and passivity, compassion of an impersonal sort. The music sounded artificial and canned and tinny, in contrast to the voices, which sounded rich and full and finely articulated and melodious.
(with 150 mg) We are on the beach at the river mouth drying seaweed, on split redwood. There is a slight nausea, slight cramps, and then my visual field starts to light up. Still vertigo but only with my eyes open, and heaviness and time stretches out; numbness in the chest as when an opiate is taken. There are geometric patterns, but the excess light on my closed eyelids interferes with this. A dance of the glittering diamond studded sea waves, increasing motion and beauty. More landscapes appear inside. This is a good introductory drug to the drugs of this class, to become familiar with the drug state in as gentle a fashion as possible. This substance seems to have a much gentler action than others of this class; perhaps more like cannabis or psilocybin. There is very little paranoia. I note hallucinations of two types: those which are strictly retinal and more minute and small and influenced by light and focused on the light ahead on the retina or lids; and the other, those deep in the visual tract and occiput which are larger and more global and dream-like and, when solid, are quite dramatic and unforgettable as in meditation.
(with 210 mg) MMDA tastes awful. The bitter alkaloid taste is followed by a distinctively chemical laboratory flavor as if from old rubber tubing. Nothing seems to happen for about 45 minutes when rather suddenly an anvil seems to lower itself over your head; you feel disoriented, and tend to withdraw from social contact a little. The drug gives less feeling of being ill than mescaline. The effect definitely reaches a climax with a pleasant afterglow following. Apparently there are no profound motor coordination problems. MMDA yields that 'Sunday afternoon' feeling of desiring to lie down and enjoy life; a luxurious feeling of 'layback.' No enhancement of colors in visual scene (except for some greenish tinges in faces) but upon closing eyes hallucinations appear to be quite real in 3-D, like watching a movie. First these dreams appear in black and white, but later colors start appearing. Chartreuse and magenta first appear, then blue and finally red. First I had visions of large numbers on gaming tables, then people. MMDA appears to bring dreams to the conscious level; is a link between the subconscious and the conscious.
(with 225 mg) I had a strange awareness of my hands in about 20 minutes Q not a feeling in them as just that I was attracted to them somehow. Then I began to get fearful, an acute experience of aloneness. I lay face down (a depressed position for me). Next I was talking to the kids at school (an image) or to other teachers. This was very vivid. The scenes at school were more vivid that the real scenes around me here. Those people were much more real. I am actually very sleepy right now during the experiment. Of any experience I have had, this was most like a series of dreams easily remembered. When it was over, I felt as if I had had a long period of sleeping Q I had gone to bed and had a series of dream-like states very vivid and colorful and real.
EXTENSIONS AND COMMENTARY: The phrase that had been used by several of the subjects in the early trials with MMDA, again and again, was "brain movies." Apparently the richest of the effects were to be had with the eyes closed. This is the compound that I had first completed in 1962, and had named it MMDA, and had begun the exploring of it when I heard that Dr. Gordon A. Alles, a professor of pharmacology at U. C. L. A. who had his own private laboratory in Los Angeles, had also synthesized it in 1962, had also named it MMDA, and had also begun exploring it. We made a date to meet and share ideas, and then he died, at the age of 62, in 1963.
This is a material that might be a contributing factor to the pharmacology of nutmeg. The major essential oil from that spice is myristicin, and it is the easiest source of MMDA. It has been reported that the passage of this oil through the liver of a rabbit will generate MMDA in that animal. The only difference between the two molecules, structurally, are the elements of ammonia. Myristicin plus ammonia gives MMDA. Another natural source of myristicin is Oil of Parsley, which is also an excellent source of apiole, mentioned under DMMDA. A rumor that had currency in the 1960's, that parsley could get you high, probably had its origins in the reports of myristicin being present, coupled with myristicin being the principal source of MMDA. The relationship to myristicin (an essential oil) led to the classifying of MMDA as a Essential Amphetamine. These relationships are expanded upon, under TMA.
At the time that the FDA issued its proclamation of dangerous drugs (in the mid-1960's), MMDA was being talked about, and in fact it had just become available commercially in England through the Koch Light Industries. But to my knowledge it had never appeared on the street, so its having being swept into the listings of evil drugs was simply a coincidence of bad timing. The close resemblance of initials between MMDA, and the currently notorious MDMA, has led to no small amount of confusion in the popular press. They remain totally separate and completely different drugs.
#133 MMDA-2; 2-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: A solution of 11.5 g pellet KOH (85%) in 75 mL EtOH was treated with 25 g sesamol followed by 27 g methyl iodide. This was brought to reflux on the steam bath. Salt formation was apparent in 20 min, and refluxing was main-tained for a total of 4 h. The solvent was removed under vacuum, and residue poured into 400 mL H2O. This was acidified with HCl and extracted with 3x150 mL CH2Cl2. The pooled extracts were washed with 3x100 mL 5% NaOH, which removed most of the color. The solvent was removed under vacuum to provide 24.0 g of 3,4-methylenedioxyanisole as a pale amber oil.
A mixture of 56.4 g POCl3 and 49.1 g N-methylformanilide was allowed to stand for 40 min and then it was poured into a beaker containing 64 g 3,4-methylenedioxyanisole. There was an immediate exothermic reaction with darkening and the generation of bubbles. This was heated on the steam bath for 1 h, then poured into 1 L H2O with extremely vigorous stirring. The dark brown phase was quite opaque, and then there was a sudden lightening of color with the generation of a fine pale yellow solid. Stirring was continued for 2 h, then these crystals were removed by filtration. This crude product was recrystallized from 400 mL boiling MeOH yielding, after filtering, washing, and air drying to constant weight, 44.1 g 2-methoxy-4,5-methylenedioxybenzaldehyde with a mp of 110-111 °C. Only one positional isomer was visible in the final product by GC, but extraction of the original mother liquors with CH2Cl2 produced, after evaporation of the solvent under vacuum, 2 g of a red oil that showed two earlier peaks on OV-17. These were consistent with about 1% of each of the two alternate positional isomers that could result from the Vilsmeier formylation reaction.
A solution of 43 g 2-methoxy-4,5-methylenedioxybenzaldehyde in 185 g nitroethane was treated with 9.3 g anhydrous ammonium acetate and heated on the steam bath for 4.5 h. The excess nitroethane was removed under vacuum to give a residue that spontaneously crystallized. These solids were washed out mechanically with the aid of 200 mL cold MeOH, and the brilliant orange crystals recovered by filtering and air drying to constant weight. There was obtained 35.7 g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of 166-167 °C. This was not improved by recrystallization from IPA. Evaporation of solvent from the methanolic washes gave yellow solids (4.6 g melting at 184-186 °C) which, on recrystallization from THF/hexane, melted at 188-190 °C. This showed a molecular weight of 416 by chemical ionization mass spectroscopy (isobutane at 0.5 torr) and is the C20H20N2O8 adduct of one molecule each of nitrostyrene, aldehyde, and ammonia that frequently appears as a very insoluble impurity in aldehyde-nitroethane condensations that are catalyzed by ammonium acetate.
To a refluxing suspension of 36 g LAH in 1 L anhydrous THF under an inert atmosphere, there was added 44.3 g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene in hot THF. The solubility was very low, so that it was necessary to use a heat lamp on the dropping funnel to maintain a clear solution for addition. The addition required 2 h and the reflux was maintained for 36 h. The reaction mixture was then cooled in an ice bath and there was added, in sequence and commensurate with heat evolution, 36 mL H2O, 36 mL 15% NaOH, and finally 108 mL H2O. The granular solids were removed by filtration and washed with THF. The combined filtrate and washes were stripped of solvent under vacuum yielding 58.8 g of a pale amber oil. This was dissolved in 100 mL IPA, neutralized with con-centrated HCl (20 mL was needed) and diluted with 500 mL anhydrous Et2O. More IPA was required to keep an oil phase from appearing. After the crystalline product was completely formed, it was removed by filtration, washed with IPA/Et2O, and finally with Et2O. Air drying gave 31.1 g of 2-methoxy-4,5-methylenedioxyamphetamine hydrochloride (MMDA-2) with a mp of 186-187 °C.
DOSAGE: 25 - 50 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 25 mg) Had some not-too-pleasant jangly effects Q this is not the smoothest of drugs. Duration: onset at 1 1/2 hours (dose after lunch), acute 3 to 4 hours, seconal at 11 hours to stop residual effects so I could sleep. Occasionally from 5 to 10 hours acute abdominal distress, resembling gas pains but unable to defecate. Abdominal muscles tight and hard. This occurred for about 15 minutes every hour or so. Rather unpleasant.
(with 30 mg) There was the first subtle note at 45 minutes, and the slow development makes the changes easy to assimilate, but difficult to quantitate. My awareness is truly enhanced. Nothing is distorted, so there can be no misrepresentation as a result. This would be a good material to introduce someone to the slow-on slow-off type of experience. It would be impossible for any person, at this level, on this drug, to have a bad experience. This is very much like a slow MDA, perhaps 80 milligrams of it, and fully as controllable. The N-methyl of this is a must.
(with 40 mg) The chemical is primarily a visual enhancer with only an extremely modest amount of visual distortion. The retinal activity was of a minor and non-threatening nature. The chemical seemed to facilitate empathic communication and the emotions felt strong and clean. Conversation flowed easily, without inhibitions or defensiveness. Anorexia accompanied experience. There was no impotence. There was some restless movement which dissipated with exercise (walking and playing frisbee). Next day woke feeling energetic, no muscular stiffness, alert. I would repeat this experience.
(with 50 mg) I was coming on within 40-60 minutes, easy and slow, but the body was +3 before the mind. The mental was strange for the first 2-3 hours Q I called it 'High Sierras' Q realistic, dispassionate, not kind. Some dark areas are persistent. Watched last half of Circus of Dr. Lao and the whole feeling changed from pornographic to erotic. Delightful. Some fantasy. On coming down, sleep was difficult. The body feels unexpectedly depleted. Rubber legs and handwriting jerky.
EXTENSIONS AND COMMENTARY: A comparison of this material to MDA was often made by subjects who were familiar with both. But it is hard to separate that which is intellectualized from that which is felt. An awareness of the chemical structure immediately shows, of course, the close resemblance. There is the complete MDA molecule, with the addition of a methoxy group. And for the non-chemist, the name itself (MMDA-2) represents the second possible methoxy-MDA. Certainly one property that is shared with MDA is the broad variety of opinions as to the quality of its action. Some like it much, and some like it not at all. The N-methyl homologue was indeed made, for direct evaluation in comparison to N-methyl MDA (which is MDMA).
The phenethylamine analog of MMDA-2 has been prepared by the condensation of the above benzaldehyde with nitromethane (in acetic acid with ammonium acetate catalyst, giving an equal weight of the nitrostyrene as deep orange crystals with a mp of 166-167 °C from ethyl acetate) followed by lithium aluminum hydride reduction (in ether). The product, 2-methoxy-4,5-methylenedioxyphenethylamine hydrochloride (2C-2) melted at 218-219 °C. There were no effects observed at up to 2.6 milligrams, but no higher trials were made. The 4-carbon homologue was made similarly (from the aldehyde and nitropropane but using tert-butylammonium acetate as a reagent in 100% excess and isopropanol as solvent, giving orange crystals melting at 98-99 °C from methanol) followed by reduction (with lithium aluminum hydride in ether) to give 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-aminobutane hydrochloride (4C-2) with a mp of 172-174 °C. This material has never even been tasted.
The Tweetio homologue of MMDA-2 has been tasted, however. This is 2-ethoxy-4,5-methylenedioxyamphetamine, or EMDA-2. The allyl ether of sesamol (3,4-methylenedioxy-allyloxybenzene) was rearranged to the 2-allyl phenol which was, in turn, converted to the ethyl ether. Reaction with tetranitromethane gave the nitrostyrene intermediate which had a mp of 120-121 °C. The final hydrochloride salt of EMDA-2 had a mp of 188-188.5 °C. At 135 milligrams, there have been reported eyes-closed visual phenomena, with intense colors. The overall duration is similar to MMDA-2 (some 10 hours) and there are reported sleep disturbances. At 185 milligrams, the feelings were intensified, there were "marvelous eyes-closed visuals (the colors were incredible), good concentration, but distinct body-tingles and rushes." The time span was about 12 hours from start to finish, but it proved to be impossible to sleep afterwards. This homologue is thus about a third the potency of MMDA-2.
#134 MMDA-3a; 2-METHOXY-3,4-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: To a solution of 100 g of 2,3-dihydroxyanisole in 1 L dry acetone there was added 110 g of powdered anhydrous K2CO3 followed by 210 g of methylene iodide. This was brought up to a reflux on the steam bath. There was a sudden appearance of a solid phase, and then a gentle reflux was maintained for three days, during which time much of the heavy solid that initially formed had redissolved. The reaction mixture was filtered to remove the insoluble salts, and these were washed with hot acetone. The combined mother liquor and washes were stripped of solvent under vacuum, leaving a solid residue. This was leached with several portions of boiling hexane. These were pooled, and removal of the solvent under vacuum provided 53.6 g of 2,3-methylenedioxyanisole as white crystals with a sharp spicy smell.
A mixture of 120 g N-methylformanilide and 137 g POCl3 was allowed to incubate at ambient temperature for 0.5 h, then there was added 53 g of crude 2,3-methylenedioxyanisole. The dark reaction mixture was heated on the steam bath for 2 h and then poured into a beaker filled with shaved ice. This was stirred until hydrolysis was complete, and the black, almost crystalline gunk that separated was removed by filtration. The 53.6 g of crude product was analyzed by GC using an ethylene glycol succinate column at 190 °C. Three peaks were apparent and had baseline separation. The major peak at 7.8 min constituted 82% of the product and was 2-methoxy-3,4-methylenedioxybenzaldehyde. A minor peak at 12.0 min represented 16% of the product and was the positional isomer 4-methoxy-2,3-methylenedioxybenzaldehyde. A trace component (2%) lay intermediate (at 9.5 min) and was myristicinaldehyde. The mps of the two major benzaldehydes were sufficiently different that they could serve as means of identification. The major product was obtained directly from the black gunk by repeated extraction with boiling cyclohexane which, upon removal of the solvent, gave 33.1 g of a yellow-colored product. This, upon one additional recrystallization from boiling cyclohexane, gave 24.4 g of 2-methoxy-3,4-methylenedioxybenzaldehyde as pale yellow crystals with a mp of 103-105 °C. The mother liquors were pooled and, after removal of all volatiles under vacuum, yielded an amber-colored solid that upon recrystallization provided a yellowish crystals. These, after yet another crystallization from cyclohexane, gave 4.1 g of 4-methoxy-2,3-methylenedioxybenzaldehyde with a mp of 85-86 °C. This latter isomer was used in the synthesis of MMDA-3b.
To a solution of 3.5 g 2-methoxy-3,4-methylenedioxybenzaldehyde in 14 g acetic acid there was added 1.4 g anhydrous ammonium acetate and 2.3 mL of nitroethane. The mixture was brought to reflux and held there for 35 min. It was then quenched by the addition of 40 mL H2O, knocking out an orange, gummy solid. This was removed by filtration, and recrystallized from 50 mL boiling MeOH. After cooling for a few h in an ice bath, the bright yellow crystals were removed by filtration, washed with MeOH and air dried to constant weight, yielding 2.15 g 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene. The mp was 106-107 °C. Recrystallization from EtOH raised this mp to 109.5-110.5 °C.
A suspension of 2.2 g LAH in 300 mL anhydrous Et2O under an inert atmosphere was brought to a gentle reflux. The reflux condensate was passed through a modified Soxhlet thimble containing 1.95 g 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene effectively adding it, over the course of 0.5 h, to the reaction mixture as a saturated Et2O solution. The mixture was maintained at reflux for 16 h. After cooling to 0 °C with an ice bath, the excess hydride was destroyed by the addition of 1.5 N H2SO4. The phases were separated, and the aqueous phase washed with 2x100 mL Et2O. To the aqueous phase there was added 50 g potassium sodium tartrate followed by sufficient 25% NaOH to raise the pH >9. This was then extracted with 3x100 mL CH2Cl2, and the solvent from the pooled extracts removed under vavuum. The residual white oil was dissolved in 250 mL anhydrous Et2O, and saturated with anhydrous HCl gas. There was produced a crop of white microcrystals of 2-methoxy-3,4-methylenedioxyamphetamine hydrochloride (MMDA-3a) which was removed by filtration, washed with Et2O, and air dried to a constant weight of 1.2 g. The mp was 154-155 °C.
DOSAGE: 20 - 80 mg.
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 20 mg) I became aware at about an hour, and an hour later I found myself suddenly caught up in the marvelous world of insects. Right alongside a pile of bricks I saw a measuring worm, and with great tenderness and patience I picked him up, observed his fore and aft 'feet' and finally replaced him and watched him acclimate himself. There was also a spider on the bricks, and I was compelled to watch him in action. I was grateful that I was not being observed. Time was moving slowly, and I felt I should intentionally move slowly, so as not to exhaust myself.
(with 40 mg) This developed between one and two hours into it, and there were considerable body tremors. Talking directed the energy outwards, and I became aware of a visually sparkling world about me. I started dropping way too soon; it would have been interesting to have gone higher. By early evening I was left only with an awareness of some residual physical hypersensitivity, and there was light diarrhea. I am not at all sure just what to compare this drug to. It is gentle.
(with 60 mg) There were visuals of a soft sort Q things moved with eyes open, and with eyes closed the music was great. There seemed to be some lasting stimulation, but it didn't get in the way of sleeping. The next morning, however, I was still on. A good compound.
EXTENSIONS AND COMMENTARY: The term MMDA-3a has the feel of being complicated, but there is a reason for the code. As had been mentioned, MMDA was the initials for methoxy (the M) methylenedioxy (the MD) amphetamine (the A). And with a molecule of amphetamine there are six ways of sticking these two groupings on the aromatic ring. The numbers 1-6 had already been assigned to the six ways of sticking three methoxyl groups onto an amphetamine molecule (with the trimethoxyamphetamines, the TMA's) and I decided to hew to the same convention with the methylenedioxy counterparts. However, there are two #3's (the methoxy and the methylenedioxy can go onto the three oxygen atoms in a row in two different ways, whereas the three methoxys can go on in just one way) and there can be no #6 (since a methylenedioxy must, perforce, have two oxygens that are adjacent, and there are none to be so found in the 2,4,6-orientation of TMA-6). So, with two possible MMDA-3's it becomes reasonable, in fact essential, to name one of them "a" and the other "b". The "a" orientation occurs in nature as the essential oil croweacin, or 1-allyl-2-methoxy-3,4-methylenedioxybenzene. It thus can allow MMDA-3a to be classified as an Essential Amphetamine, since it can arise, in principle, by amination in the liver in vivo. But in the laboratory, croweacin is certainly not a practical starting material in this synthesis.
I have been told of a number of clinical trials that have explored MMDA-3a at considerably higher levels, but I have no explicit quotations to give, and the details are quite sketchy. Three trials at 80 milligrams, and one at 100 milligrams, all made comparisons, in both quantity and quality of the experience, to 100 micrograms of LSD. However, two events occurred that may or may not be related to these trials; one subject had a spontaneous peak experience five days after the experiment, and another made a symbolic suicide attempt.
And, as with MMDA-2, both the 2-carbon "phenethylamine" analogue and the 4-carbon RARIADNES analogue of MMDA-3a have been made. The phenethylamine analog was prepared by the condensation of 7.6 g of the above benzaldehyde with nitromethane (in acetic acid with ammonium acetate catalyst, giving 5.4 g of the nitrostyrene with a mp of 115.5-116.5 °C from methanol) followed by lithium aluminum hydride reduction (in ether). The product, 2-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (2C-3a) melted at 143-145 °C. A series of subjective evaluations were made, and there are reports of marginal effects in the 40 to 120 milligram range. At 40 milligrams, perhaps the hint of a psychic energizer; at 65 milligrams, there was a pleasant mood elevation; at 80 milligrams, there was a brief paresthetic twinge noted at about the hour and a half point, and at 120 milligrams, about the same at one hour, and then nothing. The fact that there can be such a modest change of effect over a three-fold range of dosage suggests that this compound might have some merit as an anti-depressant. It would be interesting to know if it blocks serotonin reuptake°
The 4-carbon analog was made similarly (from the aldehyde and nitropropane but using tert-butylammonium acetate as a reagent in 100% excess and isopropanol as solvent, giving bright yellow crystals melting at 105.5-106.5 °C from 25 volumes of boiling methanol) followed by reduction (with lithium aluminum hydride in ether) to give 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-aminobutane hydrochloride (4C-3a) with a mp of 183-185 °C with prior sintering at 173 °C. This material has been tasted at up to 3.5 milligrams with nothing noted. There have been no trials at any higher dose.
#135 MMDA-3b; 4-METHOXY-2,3-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: A solution of 7.0 g of 98% pure (by GC) 4-methoxy-2,3-methylenedioxybenzaldehyde (see under MMDA-3a for its preparation) in 30 mL glacial acetic acid was treated with 5 mL nitroethane and 3 g anhydrous ammonium acetate, and heated on the steam bath for 3.5 h. H2Owas added to the hot solution to the point of turbidity, then it was allowed to cool to room temperature with occasional stirring. A modest crop of yellow crystals formed which were removed by filtration, washed with aqueous acetic acid and air dried to constant weight. There was obtauned 4.6 g of 1-(4-methoxy-2,3-methylenedioxphenyl)-2-nitropropene, with a mp of 95-102 °C. Recrystallization from EtOH tightened this to 97-101.5 °C. The infra-red spectrum is completely different from that of its positional isomer 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene.
A suspension of 7.0 g LAH in 1 L anhydrous Et2O under an inert atmosphere was brought to a gentle reflux. The reflux condensate was passed through a Soxhlet thimble containing 6.15 g 1-(4-methoxy-2,3-methylenedioxyphenyl)-2-nitropropene which was effectively adding the nitropropene as a saturated solution. The mixture was maintained at reflux for 16 h. After cooling to 0 °C with an ice bath, the excess hydride was destroyed by the addition of 800 mL of 1.5 N H2SO4. The phases were separated, and the aqueous phase washed with 2x100 mL Et2O. To this phase there was added 175 g potassium sodium tartrate followed by sufficient 25% NaOH to raise the pH >9. This was then extracted with 3x100 mL CH2Cl2, and the solvent from the pooled extracts removed under vacuum. The residual off-white oil weighed 5.4 g and was dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was produced a crop of slightly sticky white solids that finally became granular and loose. These were removed by filtration, washed with Et2O, and air dried to give 5.56 g of 4-methoxy-2,3-methylenedioxyamphetamine hydrochloride (MMDA-3b) with a mp of 196-199 °C. A small sample from propanol had a mp of 199-200 °C, and a sample from nitromethane/MeOH (5:1) had a mp of 201-202 °C.
DOSAGE: greater than 80 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 60 mg) Definitely active. Qualitatively like MDA; quantitatively perhaps less.
(with 80 mg) No more effective than 60 mg.
EXTENSIONS AND COMMENTARY: And that's all there is known as to the activity of MMDA-3b in man. Very, very little. Nothing has ever been tried in excess of 80 milligrams that I know of, and the above trials were made over 20 years ago. There can be little argument that the 3b is less effective than the 3a, but no one can say by how much. The literature statement is that it is threefold less, but that was based on the relative responses at just-above-threshold levels. The effects here are hand-wavingly similar to those reported for MMDA-3a at 20 milligrams, but these are difficult to compare accurately as they were reported by different people. There have been absolutely no animal studies reported with MMDA-3b in the scientific literature. And neither the 2-carbon nor the 4-carbon analogues of MMDA-3b has even been prepared.
The remaining MMDA-analogue that has been prepared, is the 2,3,6-isomer. The flow diagram started with sesamol (3,4-methylenedioxyphenol) which was methylated with methyl iodide, converted to the aldehyde using butyllithium and N-methylformanilide (putting the new group directly between the two oxygen atoms, giving 2,3-methylenedioxy-6-methoxybenzaldehyde), reaction with nitroethane to the nitrostyrene, and its reduction with lithium aluminum hydride in ether. The product, 6-methoxy-2,3-methylenedioxyamphetamine hydrochloride (MMDA-5) is practically unexplored in man. I have heard one report that 30 milligrams was modestly active, but not a particularly pleasant experience. Another person told me that he had tried 15 milligrams, but he neglected to mention if there had been any effects. I have not tried it myself. But, I have succumbed to the pressure of the experimental pharmacologists to give a number for the "Y-axis" of their animal behavior studies. So I said to myself, if this is active at 30 milligrams, and mescaline is active at 300 milligrams, why not say that it is 10x the activity of mescaline? So I did. But I have absolutely no confidence in that number.
And if the information on MMDA-5 is sparse, look at the positional isomer, MMDA-4, which I have discussed under its analogue TMA-4. Here nothing is known at all, since the compound itself is unknown. No one has yet found a way of making it.
#136 MME; 2,4-DIMETHOXY-5-ETHOXYAMPHETAMINE
SYNTHESIS: A solution was made of 166 g ethylvanillin (4-ethoxy-3-methoxybenzaldehyde) in 600 mL glacial acetic acid and arranged so that it can be stirred continuously, magnetically, and cooled as needed with an external ice bath. There was then added a total of 218 g of 40% peracetic acid in acetic acid, at a rate that permitted the temperature to stay at 25 °C with the continuous application of the ice bath. The temperature should not drop below 23 °C (the reaction stops) but it absolutely cannot be allowed to exceed 29 °C (the reaction can no longer be controlled). The addition takes about 1.5 h. At the end of the reaction, there was added 3 volumes of H2O, and all acids were neutralized with solid K2CO3. The 3 or so L of black, gooey mess was extracted with 2x400 mL boiling Et2O which, on pooling and evaporation, provided 60 g of a black oil which was a mixture containing mainly the intermediate formate and the product phenol. This was treated with 300 mL 10% NaOH, and heated on the steam bath for 1 h. After cooling, this was washed with 2x150 mL CH2Cl2 (discarded), acidified with HCl, and extracted with 3x200 mL Et2O. The pooled extracts were washed with 2x200 mL saturated NaHCO3, and then the Et2O was removed under vacuum. The residual black oil, 41.3 g, was distilled at 1.0 mm/Hg to give a fraction boiling at 140-145 °C as a pale amber oil that set up as crystals. The weight of the isolated 4-ethoxy-3-methoxyphenol was 29.1 g. An analytical sample had a mp of 45.5-46 °C. This product can be used either for the synthesis of MME (see below) or for the synthesis of EME (see separate recipe). A solution of 0.5 g of this phenol, and 0.5 g methyl isocyanate in 10 mL hexane containing 1 mL CH2Cl2 was treated with three drops of triethylamine. In about 1 h, there was the spontaneous formation of white crystals of 4-ethoxy-3-methoxyphenyl N-methyl carbamate, with a mp of 104-105 °C.
A solution of 14 g of the distilled, solid 4-ethoxy-3-methoxyphenol in 20 mL MeOH was treated with a solution of 5.3 g KOH in 100 mL hot MeOH. There was then added 11.9 g methyl iodide, and the mixture was held at reflux temperature for 2 h. The reaction was quenched with 3 volumes H2O, made strongly basic by the addition of 1 volume of 5% NaOH, and extracted with 2x150 mL Et2O. Pooling the extracts and removal of the solvent under vacuum gave 9.7 g of 2,4-dimethoxy-1-ethoxybenzene as a clear, off-white oil that showed a single peak by GC. An acceptable alternate synthesis of this ether is the ethylation of 2,4-dimethoxyphenol, which is described in the recipe for TMA-4. The index of refraction was nD25 = 1.5210.
A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed to stand at room temperature until a strong red color had been generated (about 0.5 h). There was then added 9.2 g 2,4-dimethoxy-1-ethoxybenzene and the mixture was heated on the steam bath for 2 h. The black, viscous product was poured onto 800 mL cracked ice, and mechanically stirred. The deep color gradually faded to a yellow solution, and then yellow crystals began to form. After standing overnight, these were removed by filtration and sucked as dry as possible, yielding 16 g of a wet, crude product. This was dissolved in 100 mL boiling MeOH which, on cooling, deposited fluffy, white crystals of 2,4-dimethoxy-5-ethoxybenzaldehyde. The dry weight was 8.8 g and the mp was 107-108 °C. The mother liquor showed no isomeric aldehydes by GC, but there were small suggestions of isomers seen in the CH2Cl2 extracts of the original water filtration. A sample of 0.7 g of the aldehyde obtained as a second crop from the methanolic mother liquors was dissolved, along with 0.5 g malononitrile, in 20 mL hot EtOH. The addition of 3 drops of triethylamine generated the almost immediate formation of brilliant yellow crystals, 1.4 g after filtration and EtOH washing, with a mp of 134-135.5 °C. Recrystallization from toluene gave an analytical sample of 2,4-dimethoxy-5-ethoxybenzalmalononintrile with a mp of 135-136 °C.
A solution of 6.7 g 2,4-dimethoxy-5-ethoxybenzaldehyde in 23 g glacial acetic acid was treated with 3.3 g nitroethane and 2.05 g anhydrous ammonium acetate. The mixture was heated on the steam bath for 2.5 h. The addition of a little water to the cooled solution produced a gel which was a mixture of starting aldehyde and product nitrostyrene. The solvent was decanted from it, and it was triturated under MeOH, to provide a yellow solid with a mp of 76-84 °C. Recrystallization from 30 mL boiling MeOH gave, after filtering and air drying, 4.3 g of a yellow solid with a mp of 90-92 °C. There was still appreciable aldehyde present, and this was finally removed by yet another recrystallization from toluene. The product, 1-(2,4-dimethoxy-5-ethoxyphenyl)-2-nitropropene, was obtained as bright yellow crystals with a mp of 96-97 °C. The analytical sample was dried in vacuum for 24 h to completely dispel the tenacious residual traces of toluene. Anal. (C13H17NO5) C,H.
To a gently refluxing suspension of 1.6 g LAH in 120 mL anhydrous Et2O under a He atmosphere, there was added 2.1 g 1-(2,4-dimethoxy-5-ethoxyphenyl)-2-nitropropene by allowing the condensing ether to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added, dropwise, a warm saturated solution of the nitrostyrene to the reaction mixture. Refluxing was continued for 6 h, and after cooling the reaction flask to 0 °C the excess hydride was destroyed by the cautious addition of 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 40 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x200 mL CH2Cl2. Evaporation of the solvent under vacuum produced 1.6 g of an amber oil that was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was an immediate white blush, then there was the generation of an oily solid that upon further administration of HCl became a fine, loose white powder. This was removed by filtration, Et2O washed, and air dried to give 1.6 g 2,4-dimethoxy-5-ethoxyamphetamine hydrochloride (MME) with a mp of 171-172 °C. Anal. (C13H22ClNO3) C,H,N.
DOSAGE: 40 mg and above.
DURATION : probably 6 - 10 h.
QUALITATIVE COMMENTS: (with 40 mg) At the one hour point there was a real threshold, and at the second hour, while I was walking down 24th Street, there was an honest 1+. By the third hour it was at, or just under a ++, with the earmarks of a possibly interesting collection of effects, were it just a bit more intense. I had unexpected diarrhea at hour #5, and by #6 I was mending, and by #8 I was largely down. The day was very encouraging, and this must be re-tried at 50 or 60 milligrams.
EXTENSIONS AND COMMENTARY: This is one of the very few compounds with which I actually risked (and took) the lives of experimental animals. I was still impressed by the scientific myth that pharmacological research wasn't really acceptable without animal support data. And I had access to an experimental mouse colony at the University. I injected one mouse with a dose of 300 mg/Kg., i.p. That sounds pretty scientific. But what it really means is that I picked up a mouse by the scruff of the back with my left hand, then turned my hand over so that the mouse was belly-up. I put the ring finger over a hind leg to keep things relatively immobile. Usually at this point there is a little urine evident where there had been none before. And I took a syringe equipped with a very fine needle and containing about 8 milligrams of MME in a fraction of a mL of a water solution and pushed that needle into the mouse at about where the navel would be if one could see the mouse's navel, and then I pulled the needle back just a little so that there should be nothing at the business end but the loose folds of the peritoneum. Then I pushed the syringe plunger home, effectively squirting the water solution into the area that surrounds the intestines. I dropped the mouse back into his cage, and watched. In this case, the mouse went into a twitching series of convulsions (known as clonic in the trade) and in five minutes he was dead.
Fired with the lust for killing, I grabbed another mouse, and nailed him with 175 mg/Kg. Dead in 6 minutes. Another one at 107 mg/Kg. Dead in 5 minutes. Another at 75 mg/Kg. Well, he looked pretty sick there for a while, and had some shakes, and then he seemed to be pretty much OK. One final orgy of murder. I injected 5 mice at 100 mg/Kg i.p., and watched four of them die within 20 minutes. I took in my hands the sole survivor, and I went outside the laboratory and let him loose on the hillside. He scampered away and I never saw him again.
And what did I learn, at the cost of seven precious lives which I can never replace? Not a damned thing. Maybe there is an LD-50 somewhere around 60 or 80 mg/Kg. This is for mice, not for men. I was intending to take an initial trial dose of 300 micrograms of this completely untested compound, and it would have made no difference to me if the LD-50 had been 600 mg/Kg or 6 mg/Kg. I still took my trial dose, and had absolutely no effects, and I never killed another mouse again. No, that is simply out-and-out dishonest. I had an invasion of field mice last winter coming up through a hole in the floor behind the garbage holder under the kitchen sink, and I blocked the hole, but I also set some mouse traps. And I caught a couple. But never again for the simple and stupid reasons of being able to say that "This compound has an LD-50 in the mouse of 70 mg/Kg." Who cares? Why kill?
But there are two very valuable things that have come out of this simple study with MME. One is, of course, that it is an active compound and as such warrants additional attention. And the other, and even more important, is that as one of the three possible ethoxy homologues of TMA-2, it is less active than MEM. The third possible ethoxy compound is EMM and, as will be found elsewhere in this book, it is even less active. Thus it is MEM, only, that maintains the potency of TMA-2, and this was the initial observation that really focused my attention on the importance of the 4-position.
#137 MP; METAPROSCALINE; 3,4-DIMETHOXY-5-(n)-PROPOXYPHENETHYLAMINE
SYNTHESIS: There was mixed 96 g of 5-bromovanillin and 90 mL 25% NaOH. The solution was almost complete, when there was a sudden deposition of a heavy precipitate. This was diluted with 200 mL water. There was then added 300 mL methylene chloride, 85 g methyl iodide, and 3 g decyltriethylammonium chloride. The heterogenous mixture was vigorously stirred for 2 days. The organic phase was separated, and the aqueous phase extracted once with 100 mL CH2Cl2. The organic phase and extract were pooled, washed with water and the solvent removed under vacuum The residue weighed 46.3 g and spontaneously crystallized. It was recrystallized from 40 mL of MeOH to yield 34 g of 3-bromo-4,5-dimethoxybenzaldehyde as white crystals with a mp of 60.5-61 °C. An additional 4 g product was obtained from the mother liquor. Acidification of the aqueous phase above produced, after recrystalization from IPA/acetone, 13.2 g of recovered 5-bromo-vanillin, with a mp of 166-169 °C.
A mixture of 38.7 g 3-bromo-4,5-dimethoxybenzaldehyde and 17.2 g cyclohexylamine was heated with an open flame at about 120 °C until it appeared to be free of H2O. The residue was put under a vacuum (0.2 mm/Hg) and distilled at 146-160 °C yielding 44.6 g 3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine as a clear oil which did not crystallize. The imine stretch in the infra-red was at 1640 cm-1. Anal. (C15H20BrNO2) C,H.
A solution of 31.6 g 3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine in 300 mL anhydrous Et2O was placed in an atmosphere of He, stirred magnetically, and cooled with an dry ice/acetone bath. Then 71 mL of a 1.55 M solution of butyllithium in hexane was added over a 2 min period. The reaction mixture turned cloudy and a light precipitate formed which seemed heaviest at the half-way point. Stirring remained easy and was continued for 10 min. There was then added 35 mL of butyl borate at one time. The precipitate dissolved, and the stirred solution allowed to return to room temperature. There was then added 200 mL of an aqueous solution containing 20 g ammonium sulfate. The Et2O layer was separated, washed with saturated ammonium sulfate solution, and the organic solvents removed under vacuum. The residue was dissolved in 250 mL of 70% MeOH and 14 mL of 30% hydrogen peroxide added in small portions. This reaction was very exothermic, and stirring was continued for 1 h. The reaction mixture was then added to 500 mL H2O, which knocked out white solids. A small sample of this intermediate, N-cyclohexyl-3,4-dimethoxy-5-hydroxybenzylidineimine was recrystallized from MeOH to a white crystal with a mp of 148-149 °C and which showed the C=N bond as a doublet at 1635 and 1645 cm-1 in the infra-red. These wet solids were suspended in 200 mL 5% HCl and heated on the steam bath for 1 h. Stirring was continued until the reaction was again at room temperature and then it was extracted with 2x100 mL CH2Cl2. These extracts were pooled and in turn extracted with 2x75 mL dilute NaOH. The aqueous extracts were reacidified with HCl, and reextracted with 2x100 mL CH2Cl2. These extracts were pooled, and the solvent removed under vacuum to yield a brown viscous oil as a residue. This was distilled at 105-120 °C at 0.2 mm/Hg to yield 8.8 g of 3,4-dimethoxy-5-hydroxybenzaldehyde as a distillate that set to white crystals. Recrystallization from toluene/hexane gave a sample with the mp 64-65 °C. The literature mps are several, ranging from at about 60 °C to about 70 °C.
A solution of 4.7 g of 3,4-dimethoxy-5-hydroxybenzaldehyde in 75 mL acetone was treated with 6.0 g powdered KI, 16 mL (21 g) propyl bromide, and 7.0 g finely powdered anhydrous K2CO3, and this mixture was held at reflux on a steam bath for 15 h. The reaction mixture was added to 1 L H2O, made strongly basic, and extracted with 3x100 mL CH2Cl2. The extracts were pooled, washed with 5% NaOH, and the solvent removed under vacuum yielding 8.8 g of a yellow oil, undoubtedly containing propyl iodide. This residue was distilled at 133-145 °C at 0.15 mm/Hg to yield 4.5 g of 3,4-dimethoxy-5-(n)-propoxybenzaldehyde as a white oil which did not crystallize. There was an appreciable pot residue. This product was clearly impure, having a minor, slower moving component not the starting phenol, as seen by TLC (on silica gel, with CH2Cl2 as a developing solvent). Fusion of a small amount of impure aldehyde with p-anisidine produced a crystalline anil which, on hydrolysis with dilute acid, produced an aldehyde sample free of this impurity. But as this sample also remained as an oil, the above crude product was used in the following preparation.
To a solution of 3.8 g 3,4-dimethoxy-5-(n)-propoxybenzaldehyde in 50 mL nitromethane, there was added 0.5 g anhydrous ammonium acetate. This was held at reflux for 50 min. The excess nitromethane was removed under vacuum and 2 volumes of boiling MeOH were added to the residue. The hot solution was decanted from some residual insolubles, and on cooling spontaneously crystallized. These solids were removed by filtration, washed sparingly with MeOH and air dried yielding 3.3 g yellow crystals of 3,4-dimethoxy-'-nitro-5-(n)-propoxynitrostyrene as yellow crystals melting at 79-81 °C. Recrystallization from MeOH or cyclohexane neither improved the mp nor freed the product from a residual opalescenceseen in the melt. Anal. (C13H17NO5) C,H.
A solution of 1.5 g LAH in 30 mL anhydrous THF under He was cooled to 0 °C and vigorously stirred. There was added, dropwise, 1.0 mL of 100% H2SO4, followed by the dropwise addition of a solution of 2.3 g 3,4-dimethoxy-'-nitro-5-(n)-propoxynitrostyrene in 10 mL anhydrous THF, over the course of 5 min. The mixture was stirred at 0 °C for a while, and then brought to a reflux on the steam bath. After cooling again, the excess hydride was destroyed with IPA added dropwise, followed by the addition of about 10 mL of 10% NaOH which was sufficient to covert the solids to a white, granular form. These were removed by filtration, the filter cake washed with IPA, the mother liquor and filtrates were combined, and the solvents were removed under vacuum to yield an amber oil. This residue was added to 75 mL dilute H2SO4 which produced a gummy insoluble phase which was physically removed with a spatula. The aqueous phase was washed with 3x50 mL CH2Cl2. It was then made basic with 25% NaOH, and extracted with 2x75 mL CH2Cl2. The solvent was removed from these pooled extracts and the residue distilled at 106-116 °C at 0.2 mm/Hg to provide 1.3 g of the product as a colorless liquid. This was dissolved in 4 mL IPA, neutralized with about 20 drops of concentrated HCl, and diluted with 4 volumes of anhydrous Et2O added slowly with continuous stirring. A white crystalline salt crystallized out spontaneously and was isolated by filtration, washed first with IPA, then with Et2O, and air dried giving 1.3 g 3,4-dimethoxy-5-(n)-propoxyphenethylamine hydrochloride (MP) with a mp of 170-171 °C. Anal. (C13H22ClNO3) C,H.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 160 mg) There might have been some disturbance at the three to four hour point, but it was extremely light if at all.
(with 240 mg) No effects whatsoever.
EXTENSIONS AND EXTRAPOLATIONS: The loss of activity on lengthening the carbon chain on the meta-oxygen from two to three (from metaescaline to metaproscaline) discouraged any further exploration at this specific point of the molecule. The isopropyl analog (3,4-dimethoxy-5-(i)-propoxyphenethylamine, metaisoproscaline, MIP) was started and carried along as far as the aldehyde, and abandoned with the discovery that metaproscaline was without activity. There were other fish to fry.
#138 MPM; 2,5-DIMETHOXY-4-(n)-PROPOXYAMPHETAMINE
SYNTHESIS: To a solution of 68 g 2,5-dimethoxybenzaldehyde in 250 mL glacial acetic acid that had been warmed to 25 °C and well stirred, there was added, dropwise, 86 g of a 40% peracetic acid solution (in acetic acid). The reaction was exothermic, and the rate of addition was dictated by the need to maintain the internal temperature within a few degrees of 28 °C. External cooling was used as needed. The addition took 1 h, and when the reaction had clearly been completed (there was no further temperature rise) the entire reaction mixture was added to 3 volumes of H2O. The excess acid was neutralized with solid K2CO3. The dark solution was extracted with 3x100 mL Et2O, the extracts pooled, and stripped of solvent under vacuum to give 59 g of crude 2,4-dimethoxyphenyl formate. This was suspended in 200 mL 10% NaOH, and the mixture heated on the steam bath for 1 h. On cooling, the reaction mixture was washed with 2x200 mL methylene chloride, acidified with HCl, and extracted with 3x200 mL CH2Cl2. The extracts were pooled and the solvent removed under vacuum. There remained as residue, 47.4 g 2,5-dimethoxyphenol which was deep amber in color, but clear and fluid. It was homogenous by GC and completely correct by NMR. It was used without further purification.
To a solution of 3.08 g 2,5-dimethoxyphenol in 20 g MeOH, there was added a solution of 1.26 g flaked KOH in 20 g hot MeOH. There was then added 2.46 g n-propyl bromide, and the mixture held at reflux for 2 h on the steam bath. This was quenched in 5 volumes H2O, made strongly basic with 10% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts left 2.0 g of 1,4-dimethoxy-2-(n)-propoxybenzene as a clear, amber oil. The IR spectrum was appropriate, no phenol was present, and this residue was used in the following reaction without further purification or characterization.
A mixture of 3.5 g N-methylformanilide and 4.0 g POCl3 was held at room temperature for 0.5 h producing a deep red color. To this there was added 2.0 g 1,4-dimethoxy-2-(n)-propoxybenzene, and the mixture was held on the steam bath for 1.75 h. It was then poured over 400 mL shaved ice, and vigorous stirring was maintained until the dark complex had completely broken up. This aqueous mixture was allowed to stand overnight, and the crude aldehyde solids that had formed were removed by filtration, water washed, and sucked as dry as possible. This 2.0 g damp material was crystallized from 20 mL boiling MeOH giving, after filtering and drying to constant weight, 1.4 g 2,5-dimethoxy-4-(n)-propoxybenzaldehyde as reddish-tan solids, with a mp of 97-98 °C. To the methanolic mother liquors of this crystallization there was added a gram of malononitrile and a few drops of triethylamine. The eventual addition of a little H2O encouraged the separation of crystals which were removed, and had a mp of 150-152 °C. Recrystallization from toluene gave gold-colored crystals of the benzalmalononitrile with a mp of 153.5-155 °C, but the melt remained slightly cloudy.
To a solution of 1.4 g 2,5-dimethoxy-4-(n)-propoxybenzaldehyde and 0.65 g nitroethane in 4.4 g glacial acetic acid there was added 0.4 g anhydrous ammonium acetate, and the mixture was heated on the steam bath for 5 h. The addition of a modest amount of H2O and scratching with a glass rod produced crystal seed. The reaction was diluted with about 5 mL H2O, seeded, and allowed to stand at room temperature overnight. There was generated a crystalline product which was removed by filtration and air dried. There was thus obtained 0.6 g 1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene as yellow-orange crystals, with a mp of 83-84 °C. The addition of H2O to the mother liquors provided an additional 0.3 g of an orange solid which proved to be largely unreacted starting aldehyde.
To a stirred, warm suspension of 0.5 g LAH in 20 mL anhydrous Et2O under a He atmosphere, there was added 0.6 g 1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene dissolved in a little anhydrous Et2O. The mixture was heated and stirred for a few h, and the excess hydride decomposed with 30 mL 1.5 N H2SO4. The two layers were separated, and 15 g potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x50 mL CH2Cl2. Removal of the solvent under vacuum gave 0.7 g of an amber oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. No crystals formed, and so the ether was removed under vacuum, leaving a residue that set up to crystals that were then no longer soluble in ether. They were, however, very soluble in chloroform. These were ground under dry Et2O, removed by filtration, and air dried giving 0.35 g 2,5-dimethoxy-4-(n)-propoxyamphetamine hydrochloride (MPM) with a mp of 123 - 125 °C.
DOSAGE: 30 mg or more.
DURATION: probably short.
QUALITATIVE COMMENTS: (with 15 mg) This is just barely threshold. A marginal intoxication at best. This level is producing less response that the 11 mg. trial of MEM, so the propoxy is off in potency. At four and a half hours I am out of whatever little there was.
(with 30 mg) By the mid-second hour, I am at a valid plus one. I cannot identify the nature Q with eyes closed it would be lost, as it would also be if I were watching a play or movie. It would have been interesting to see where it could have gone. Seventh hour, completely clear.
EXTENSIONS AND COMMENTARY: The 4-propoxy homologue of TMA-2 and MEM is clearly less active, and this has discouraged me from putting too much more effort in this direction. Three additional materials of this pattern were prepared and either shown to be even less active, or simply were not assayed at all. These are the 4-isopropoxy isomer (MIPM), the (n)-butoxy homologue (MBM), and the (n)-amyl homologue (MAM). They scarcely warrant separate recipes as they were all made in a manner similar to this one describing MPM.
For the preparation of MIPM, the above phenol, 2,5-dimethoxyphenol was isopropylated with isopropyl bromide in methanolic KOH giving 2,5-dimethoxy-1-(i)-propoxybenzene as an oil. This formed the benzaldehyde with the standard Vilsmeier conditions, which melted at 77-78 °C from hexane and which gave a yellow malononitrile derivative melting at 171.5-173 °C. The nitrostyrene, from nitroethane in acetic acid was orange colored and melted at 100-101 °C from either methanol or hexane. This was reduced with lithium aluminum hydride in ether to give 2,5-dimethoxy-4-(i)-propoxyamphetamine hydrochloride (MIPM). The properties of the isolated salt were strange (soluble in acetone but not in water) and the microanalysis was low in the carbon value. The molecular structure had a pleasant appeal to it, with a complete reflection symmetry shown by the atoms of the amphetamine side chain and the isopropoxy side chain. But the nature of the actual product in hand had no appeal at all, and no assay was ever started.
For the preparation of MBM, the starting phenol was alkylated to 2-(n)-butoxy-1,4-dimethoxybenzene in methanolic KOH with n-butyl bromide. The benzaldehyde melted at 79.5-81 °C from methanol, and formed a malononitrile derivative that had a melting point of 134.5-135 C. The nitrostyrene from the aldehyde and nitroethane in acetic acid crystallized from methanol with a mp of 71-72 °C. Lithium aluminum hydride reduction in ether gave the ether-insoluble chloroform-soluble product 4-(n)-butoxy-2,5-dimethoxyamphetamine hydrochloride (MBM) with a melting point of 128-130 °C. This product met all tests for structural integrity, and assays were started. At levels of up to 12.0 milligrams, there were no effects noted.
As to the preparation of MAM, the exact same sequence was used, except for the employment of n-amyl bromide. The benzaldehyde crystallized from methanol with a mp of 79-80 °C, and formed a malononitrile derivative which was bright yellow and melted at 103-104 °C. The nitrostyrene, when pure, melted at 57-58.5 °C but proved very difficult to separate from the aldehyde. The final product, 4-(n)-amyl-2,5-dimethoxyamphetamine hydrochloride (MAM) was obtained by lithium aluminum hydride reduction in ether and melted at 125-127 °C. It was assayed at up to 16 milligrams, at which level there was noted a heaviness in the chest and head at the 2-hour point, but no cardiovascular disturbance and no mydriasis. This was called an inactive level, and no higher one has yet been tried.
