#136 MME 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 2×400 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 2×150 mL CH2Cl2 (discarded), acidified with HCl, and extracted with 3×200 mL Et2O. The pooled extracts were washed with 2×200 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 (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 2×150 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 . 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 3×200 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 LD50 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 LD50 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 LD50 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 , it is less active than . The third possible ethoxy compound is 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.
6 November 2017 · Creative Commons BY-NC-SA ·

About PiHKAL · info

This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.

Cautionary note

“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 herein, 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.”
Alexander T. Shulgin

Copyright notice

The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.

Ordering information

PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.
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