Pihkal

by Alexander Shulgin

  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 RY-axisS 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 wasnUt 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 RThis compound has an LD-50 in the mouse of 70 mg/Kg.S 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