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 deg 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 deg C. At the end of the addition, the temperature was brought up to 45 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 RDOONES 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg C) which, on recrystallization from hexane, gave a final yield of 0.42 g with a mp of 134-135 deg 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 deg 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 deg 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 deg 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 deg C. Recrystallization of a small sample from EtOH dropped this to 179-181 deg 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 deg 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 deg 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 deg 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 deg 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 deg C with an ice bath. To this there was added 54 g tetranitromethane which had been pre-cooled to 0 deg 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 deg 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 deg 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 deg 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 deg C was raised to 133-134 deg 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 deg 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 deg 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 deg C) which, on recrystallization from THF/hexane, melted at 188-190 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg C. The final hydrochloride salt of EMDA-2 had a mp of 188-188.5 deg 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 deg 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 deg 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 deg 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 deg C. Recrystallization from EtOH raised this mp to 109.5-110.5 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg C with prior sintering at 173 deg 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 deg C. Recrystallization from EtOH tightened this to 97-101.5 deg 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 deg 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 deg C. A small sample from propanol had a mp of 199-200 deg C, and a sample from nitromethane/MeOH (5:1) had a mp of 201-202 deg 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 deg C with the continuous application of the ice bath. The temperature should not drop below 23 deg C (the reaction stops) but it absolutely cannot be allowed to exceed 29 deg 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 deg 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 deg 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 deg 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 deg 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 deg C. Recrystallization from toluene gave an analytical sample of 2,4-dimethoxy-5-ethoxybenzalmalononintrile with a mp of 135-136 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg C. The literature mps are several, ranging from at about 60 deg C to about 70 deg 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 deg 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-beta-nitro-5-(n)-propoxynitrostyrene as yellow crystals melting at 79-81 deg 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 deg 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-beta-nitro-5-(n)-propoxynitrostyrene in 10 mL anhydrous THF, over the course of 5 min. The mixture was stirred at 0 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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 deg C. Recrystallization from toluene gave gold-colored crystals of the benzalmalononitrile with a mp of 153.5-155 deg 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 deg 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 deg 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 deg C from hexane and which gave a yellow malononitrile derivative melting at 171.5-173 deg C. The nitrostyrene, from nitroethane in acetic acid was orange colored and melted at 100-101 deg 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 deg 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 deg 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 deg 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 deg C, and formed a malononitrile derivative which was bright yellow and melted at 103-104 deg C. The nitrostyrene, when pure, melted at 57-58.5 deg 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 deg 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.      

 

#139 ORTHO-DOT; 4,5-DIMETHOXY-2-METHYLTHIOAMPHETAMINE

 

SYNTHESIS: To 26.4 g veratrol that was being magnetically stirred without any solvent, there was added 50 g chlorosulfonic acid a bit at a time over the course of 20 min. The reaction was exothermic, and evolved considerable HCl. The deeply colored mixture that resulted was poured over 400 mL crushed ice and when all had thawed, it was extracted with 2x150 mL CH2Cl2. Removal of the solvent under vacuum gave a residue that set up as a crystalline mass. The weight of the crude 3,4-dimethoxybenzenesulfonyl chloride was 37.1 g and it had a mp of 63-66 deg C. Recrystallization raised this to 72-73 deg C. Reaction with ammonium hydroxide gave the sulfonamide as colorless needles from EtOH, with a mp of 132-133 deg C.

 

The finely pulverized 3,4-dimethoxybenzenesulfonyl chloride (33 g) was added to 900 mL of crushed ice in a 2 L round-bottomed flask equipped with a heating mantle and reflux condenser. There was then added 55 mL concentrated H2SO4 and, with vigorous mechanical stirring, there was added 50 g of zinc dust in small portions. This mixture was heated until a vigorous reaction ensued and refluxing was continued for 1.5 h. After cooling to room temperature and decantation from unreacted metallic zinc, the aqueous phase was extracted with 3x150 mL Et2O. The pooled extracts were washed once with saturated brine and the solvent was removed under vacuum. The residue was distilled to give 20.8 g of 3,4-dimethoxythiophenol boiling at 86-88 deg C at 0.4 mm/Hg.

 

A solution of 10 g 3,4-dimethoxythiophenol in 50 mL absolute EtOH was protected from the air by an atmosphere of N2. There was added a solution of 5 g 85% KOH in 80 mL EtOH. This was followed by the addition of 6 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 10.3 g of 3,4-dimethoxythioanisole with a bp of 94-95 deg C at 0.4 mm/Hg. The product was a colorless oil that crystallized on standing. Its mp was 31-32 deg C.

 

To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been warmed briefly on the steam bath there was added 8.2 g of 3,4-dimethoxythioanisole, the exothermic 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 100 mL boiling EtOH. The product, 4,5-dimethoxy-2-(methylthio)benzaldehyde, was an off-white solid, weighing 8.05 g and having a mp of 112-113 deg C. Anal. (C10H12O3S) C,H.

 

A solution of 2.0 g 4,5-dimethoxy-2-(methylthio)benzaldehyde in 8 mL nitroethane was treated with 0.45 g anhydrous ammonium acetate and heated on the steam bath for 4.5 h. Removal of the excess solvent under vacuum gave a red residue which was dissolved in 5 mL boiling MeOH. There was the spontaneous formation of a crystalline product which was recrystallized from 25 mL boiling MeOH to give, after cooling, filtering and air drying, 1.85 g of 1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene as bright orange crystals with a mp of 104-105 deg C. Anal. (C12H15NO4S) C,H,N.

 

A suspension of 1.3 g LAH in 50 mL anhydrous THF was placed under an inert atmosphere and stirred magnetically. When this had been brought to reflux conditions, there was added, dropwise, 1.65 g of 1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF. The reaction mixture was maintained at reflux for 18 h. After being brought back to room temperature, the excess hydride was destroyed by the addition of 1.3 mL H2O in 10 mL THF. There was then added 1.3 mL of 3N NaOH followed by an additional 3.9 mL H2O. The loose, inorganic salts were removed by filtration, and the filter cake washed with additional 20 mL THF. The combined filtrate and washes were stripped of solvent under vacuum yielding a light yellow oil as a residue. This was dissolved in 20 mL IPA, neutralized with 0.9 mL concentrated HCl, and diluted with 200 mL anhydrous Et2O. There was thus formed 1.20 g of 4,5-dimethoxy-2-methylthioamphetamine hydrochloride (ORTHO-DOT) as a pale yellow crystalline product. This melted at 218-219.5 deg C, and recrystallization from EtOH yielded a white product and increased the mp to 222-223 deg C with decomposition Anal. (C12H20ClNO2S) C,H,N.

 

DOSAGE: greater than 25 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 25 mg) Vague awareness, with the feeling of an impending something. Light food sat uncomfortably. By the late afternoon there was absolutely nothing. Threshold at best.

 

EXTENSIONS AND COMMENTARY: This material, ORTHO-DOT, can be looked at as the sulfur homologue of TMA-2 with the sulfur atom located in place of the oxygen at the 2-position of the molecule. At what level this compound might show activity is completely unknown, but wherever that might be, it is at a dosage greater than that for the PARA-DOT isomer, ALEPH-1 (or ALEPH), which was fully active at 10 milligrams (ALEPH can be looked at as TMA-2 with the sulfur atom located in place of the oxygen at the 4-position of the molecule). A lot of variations are easily makable based on this structure, but why bother? ALEPH is the much more appealing candidate for structural manipulation.      

 

 

 

#140 P; PROSCALINE; 3,5-DIMETHOXY-4-(n)-PROPOXYPHENETHYLAMINE

 

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for its synthesis), 100 mg decyltriethylammonium iodide, and 10 g n-propyl bromide in 50 mL anhydrous acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux for 10 h. An additional 5 g of n-propyl bromide was added to the mixture, and the refluxing continued for another 48 h. The mixture was filtered, the solids washed with acetone, and the combined filtrate and washes stripped of solvent under vacuum. The residue was suspended in acidified H2O, and extracted 3x175 mL CH2Cl2. The pooled extracts were washed with 2x50 mL 5% NaOH, once with dilute HCl (which lightened the color of the extract) and then stripped of solvent under vacuum giving 9.0 g of a deep yellow oil. This was distilled at 132-142 deg C at 0.3 mm/Hg to yield 4.8 g of 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile as a clear yellow oil. Anal. (C13H17NO3) C H N.

 

A solution of 4.7 g 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile in 20 mL THF was treated with 2.4 g powdered sodium borohydride. To this well-stirred suspension there was added, dropwise, 1.5 mL trifluoroacetic acid. There was a vigorous gas evolution from the exothermic reaction. Stirring was continued for 1 h, then all was poured into 300 mL H2O. This was acidified cautiously with dilute H2SO4, and washed with 2x75 mL CH2Cl2. The aqueous phase was made basic with dilute NaOH, extracted with 2x75 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was distilled at 115-125 deg C at 0.3 mm/Hg to give 1.5 mL of a colorless oil which upon dissolving in 5 mL IPA, neutralizing with 27 drops concentrated HCl, and dilution with 25 mL anhydrous Et2O yielded 1.5 g 3,5-dimethoxy-4-(n)-propoxyphenethylamine hydrochloride (P) as spectacular white crystals. The catalytic hydrogenation process for reducing the nitrile (see under E) also succeeded with this material. The mp was 170-172 deg C. Anal. (C13H22ClNO3) C,H,N.

 

DOSAGE: 30 - 60 mg.

 

DURATION: 8 - 12 h.

 

QUALITATIVE COMMENTS: (with 30 mg) Proscaline dulled my sense of pain and made the other senses really sharp. Everything felt really soft, and clean and clear. I could feel every hair my hand was touching. I felt so relaxed and at ease. I know that under the appropriate circumstances, this material would lead to uninhibited eroticism.

 

(with 35 mg) The whole experiment was very quiet. There was no nystagmus, no anorexia, and insignificant visuals with the eyes closed. I was restless with a bit of tremor for the first couple of hours, and then became drowsy. Would I do this again? Probably not. It doesn't seem to offer anything except speculation about the nature of the high. The high was pleasant, but quite uneventful.

 

(with 40 mg) For me there was a deep feeling of peace and contentment. The euphoria grows in intensity for several hours and remains for the rest of the day making this one of the most enjoyable experiences I have ever had. It was marvel-ous talking and joking with the others. However, I was a little disappointed that there was no enhanced clarity and no deep realizations. There was not a problem to be found. There were no motivations to discuss anything serious. If I had any objection, it would be with the name, not the pharmacology.

 

(with 60 mg) The development of the intoxication was complete in a couple of hours. I feel that there is more physical effect than mental, in that there is considerable irritability. This should probably be the maximum dose. Despite feeling quite drunk, my thinking seems straight. The effects were already waning by the fifth hour, but sleep was not possible until after the twelth hour. There was no hangover the next day.

 

EXTENSIONS AND COMMENTARY: There is a very early report describing the human use of proscaline tucked away in the Czechoslovakian literature that describes experiments at up to 80 milligrams. At these dosages, there were reported some difficulty with dreams, and the residual effects were still apparent even after 12 hours.

 

The amphetamine homologue of proscaline, 3,5-dimethoxy-4-(n)-propoxy-amphetamine is an unexplored compound. Its synthesis could not be achieved in parallel to the description given for P. Rather, the propylation of syringaldehyde to give 3,5-dimethoxy-4-(n)-propoxybenzaldehyde, followed by coupling with nitroethane and the reduction of the formed nitrostyrene with lithium aluminum hydride would be the logical process. Following the reasoning given under E, the initials for this base would be 3C-P, and I would guess it would be active, and a psychedelic, in the 20 to 40 milligram range.     

 

 

 

#141 PE; PHENESCALINE; 3,5-DIMETHOXY-4-PHENETHYLOXYPHENETHYLAMINE

 

SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for its preparation) in 50 mL of acetone containing 100 mg decyltriethylammonium iodide, there was added 14.8 g beta-phenethylbromide and 6.9 g of finely powdered anhydrous K2CO3. The greenish mixture was refluxed for 3 days, with two additional 4 g batches of anhydrous K2CO3 being added at 24 h intervals. After addition to aqueous base, the product was extracted with CH2Cl2, the pooled extracts were washed with dilute base (the organic phase remained a deep purple color) and then finally with dilute HCl (the organic phase became a pale yellow). The solvent was removed giving 15.6 g crude 3,5-dimethoxy-4-phenethyloxyphenylacetonitrile which distilled at 165-185 deg C at 0.3 mm/Hg to yield 3,5-dimethoxy-4-phenethyloxyphenylacetonitrile as a reddish viscous oil weighing 8.1 g. Anal. (C18H19NO3) C,H.

 

A solution of 7.9 g of distilled 3,5-dimethoxy-4-phenethyloxyphenylacetonitrile in 15 mL dry THF was added to a 0 deg C solution of AH prepared from a vigorously stirred solution of 4.6 g LAH in 160 ml THF which had been treated, at 0 deg C with 3.6 mL 100% H2SO4 under an atmosphere of He. The gelatinaceous reaction mixture was brought to a brief reflux on the steam bath, then cooled again. It was treated with 5 mL IPA which destroyed the unreacted hydride, followed by sufficient 15% NaOH to give loose, white filterable solids. These were removed by filtration and washed with THF. The filtrate and the washes were combined and, after removal of the solvent under vacuum, there remained 7.8 g of the product as a crude base which crystallized spontaneously. Distillation of this product at 170-180 deg C at 0.35 mm/Hg gave 5.1 g white solids, with a mp of 85-86 deg C from hexane. This base was dissolved in 20 mL warm IPA and treated with 1.6 mL concentrated HCl. To the resulting clear solution, there was added 75 mL anhydrous Et2O which gave, after a few moments of stirring, a spontaneous crystallization of 3,5-di-methoxy-4-phenethyloxyphenethylamine hydrochloride (PE) as beautiful white crystals. The weight was 5.4 g after air drying, and the mp was 151-152 deg C. Anal. (C18H24ClNO3) C,H.

 

DOSAGE: greater than 150 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 150 mg) At most, there was a bare threshold over the course of the afternoon. A vague unreal feeling, as if I had not had quite enough sleep last night. By late afternoon, even this had disappeared and I was left with an uncertainty that anything at all had occurred.

 

EXTENSIONS AND COMMENTARY: There is not much there, so there is not much to make commentary on. This response is called a "threshhold" effect, and cannot be used to predict with any confidence just what level (if any) would produce psychological effects.

 

A similar chain on the 4-position, but with one less carbon atom, deserves special comment. Rather than a phenethyloxy group, this would be benzyloxy group (which in this day and age of Chemical Abstracts purity should probably be called a phenylmethoxy group). If one were to follow the naming philosophy of Rproscaline equals P and buscaline equals BS convention, one would call it 4-benzescaline, and give it the code name BZ. The nomenclature purist would probably call the compound PM (for phenylmescaline or, more likely phenylmethoxydimethoxyphenethylamine), since the term BZ is awkward and misleading. It is a code name that has been given to a potent CNS agent known as quinuclidin-3-yl benzilate, which is a chemical and biological warfare (CBW) incapacitating agent currently being stored by the military to the extent of 20,000 pounds. And, BZ has also recently become the jargon name given to benzodiazepine receptors. They have been called the BZ-receptors.

 

However, let's be awkward and misleading, and call this benzyloxy-base BZ. For one thing, the three-carbon analogue 3C-BZ has already been described in its own recipe using this code. And the 4-fluoroanalogue of it, 3C-FBZ, is also mentioned there. And BZ has already been described synthetically, having been made in exactly the procedure given for escaline, except that the reduction of the nitrile was not done by catalytic hydrogenation but rather by sodium borohydride in the presence of cobalt chloride.  It has been shown to be a effective serotonin agonist, and may warrant human experimentation. The serotonin activity suggests that it might be active at the same levels found for proscaline.

 

All of this says very little about PE. But then, there is very little to say about PE except that it may be active at very high levels, and I am not sure just how to get there safely.      

 

 

 

#142 PEA; PHENETHYLAMINE

 

SYNTHESIS: This compound has been made industrially by a number of routes, the motant being the reduction of benzyl cyanide and the decarboxylation of phenylanaline. It is offered in the catalogs of all the major chemical supply houses for a few pennies per gram. It is a very strong base with a fishy smell, and rapidly forms a solid carbonate salt upon exposure to the air. It is a natural biochemical in both plants and animals.

 

DOSAGE: greater than 1600 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 200, 400, 800 and 1600 mg) No effects.

 

(with 500 mg) No effects.

 

(with 800 and 1600 mg) No effects.

 

(with 25 and 50 mg i.v.) RNo effects.

 

EXTENSIONS AND COMMENTARY: Here is the chemical that is central to this entire book. This is the structural point of departure for every compound that is discussed here. It is the RPS in PIHKAL. It is without activity in man! Certainly not for the lack of trying, as some of the dosage trials that are tucked away in the literature (as abstracted in the "Qualitative Comments" given above) are pretty heavy duty. Actually, I truly doubt that all of the experimenters used exactly that phrase, "No effects," but it is patently obvious that no effects were found. It happened to be the phrase I had used in my own notes.

 

This, the simplest of all phenethylamines, has always been the darling of the psychopharmacologists in that it is structurally clean, it is naturally present in various human fluids and tissues, and because of its close chemical relationship to amphetamine and to the neurotransmitters. These facts continuously encourage theories that involve PEA in mental illness. Its levels in urine may be decreased in people diagnosed as being depressed. Its levels may be increased in people diagnosed as being paranoid schizophrenics. Maybe it is also increased in people under extreme stress. The human trials were initially an attempt to provoke some psychological change, and indeed some clinicians have reported intense headaches generated in depressives following PEA administration. But then, others have seen nothing. The studies evolved into searches for metabolic difference that might be of some diagnostic value. And even here, the jury is still out.

 

Phenethylamine is found throughout nature, in both plants and animals. It is the end product of phenylalanine in the putrefaction of tissue. One of its most popularized occurrences has been as a major component of chocolate, and it has hit the Sunday Supplements as the love-sickness chemical. Those falling out of love are compulsive chocolate eaters, trying to replenish and repair the body's loss of this compound Q or so the myth goes. But this amine is voraciously metabolized to the apparently inactive compound phenylacetic acid, and to some tyramine as well. Both of these products are also normal components in the body. And, as a wry side-comment, phenylacetic acid is a major precursor in the illicit synthesis of amphetamine and methamphetamine.

 

Phenethylamine is intrinsically a stimulant, although it doesn't last long enough to express this property. In other words, it is rapidly and completely destroyed in the human body. It is only when a number of substituent groups are placed here or there on the molecule that this metabolic fate is avoided and pharmacological activity becomes apparent.

 

           To a large measure, this book has emphasized the "phenyl" end of the phenethylamine molecule, and the "what," the "where," and the "how many" of the substituent groups involved. There is a broad variety of chemical groups that can be attached to the benzene ring, at one or more of the five available positions, and in an unending number of combinations. And, in any given molecule, the greater the number of substituents on the benzene ring, the greater the likelihood that there will be psychedelic action rather that stimulant action.

 

           But what can be said about the "ethylamine" end of the phenethylamine molecule? This is the veritable backbone that holds everything together, and simple changes here can produce new prototypes that can serve as starting points for the substituent game on the benzene ring. Thus, just as there is a "family" of compounds based on the foundation of phenethylamine itself, there is an equally varied and rich "families" of other compounds that might be based on some phenethylamine with a small modification to its backbone.

 

           So, for the moment, leave the aromatic ring alone, and let us explore simple changes in the ethylamine chain itself. And the simplest structural unit of change is a single carbon atom, called the methyl group. Where can it be placed?

 

The adding of a methyl group adjacent to the amine produces phenylisopropylamine, or amphetamine. This has been exploited already as one of the richest families of psychedelic drugs; and over half of the recipes in Book II are specifically for amphetamine analogues with various substituents on the aromatic ring. The further methylation of amphetamine with yet another methyl group, this time on the nitrogen atom, yields methamphetamine. Here the track record with various substituents on the aromatic ring is not nearly as good. Many have been explored and, with one exception, the quality and potency of human activity is down. But the one exception, the N-methyl analogue of MDA, proved to be the most remarkable MDMA.

 

The placement of the methyl group between the two carbons (so to speak) produces a cyclopropyl system. The simplest example is 2-phenylcyclopropylamine, a drug with the generic name of tranylcypromine and the trade name Parnate. It is a mono-amine oxidase inhibitor and has been marketed as an antidepressant, but the compound is also a mild stimulant causing insomnia, restlessness and photophobia. Substitutions on the benzene ring of this system have not been too promising. The DOM analogue, 2,5-dimethoxy-4-methyltranylcypromine is active in man, and is discussed in its own recipe under DMCPA. The inactive mescaline analogue TMT is also mentioned there.

 

The dropping of one carbon from the phenethylamine chain gives a benzyl amine, basically an inactive nucleus. Two families deserve mention, however. The phencylidine area, phenylcyclohexylpiperidine or PCP, is represented by a number of benzyl amines. Ketamine is also a benzyl amine. These are all analgesics and anesthetics with central properties far removed from the stimulant area, and are not really part of this book. There is a benzyl amine that is a pure stimulant, which has been closely compared to amphetamine in its action This is benzylpiperazine, a base that is active in the 20 to 100 milligram range, but which has an acceptability similar to amphetamine. If this is a valid stimulant, I think that much magic might be found in and around compounds such as (1) the MDMA analogue, N-(3,4-methylenedioxybenzyl)piperazine (or its N-methyl-counterpart N-(3,4-methylenedioxybenzyl)-N'-methylpiperazine) or (2) the DOM analogue, 2,5-dimethoxy-4-methylbenzylpiperazine. The benzyl amine that results by the relocation of the amine group of MDA from the beta-carbon atom to the alpha-carbon atom is known, and is active. It, and its N-methyl homologue, are described and discussed in the commentary under MDA. Dropping another carbon atom gives a yet shorter chain (no carbons at all!) and this is to be found in the phenylpiperazine analogue 3-trifluoromethylphenylpiperazine. I have been told that this base is an active hallucinogen as the dihydrobromide salt at 50 milligrams sublingually, or at 15 milligrams intravenously in man. The corresponding 3-chloro analogue at 20 to 40 milligrams orally in man or at 8 milligrams intravenously, led to panic attacks in some 10% of the experimental subjects, but not to any observed psychedelic or stimulant responses.

 

What happens if you extend the chain to a third carbon? The parent system is called the phenyl-(n)-propylamine, and the parent chain structure, either as the primary amine or as its alpha-methyl counterpart, represents compounds that are inactive as stimulants. The DOM-analogues have been made and are, at least in the rabbit rectal hyperthermia assay, uninteresting. A commercially available fine chemical known as piperonylacetone has been offered as either of two materials. One, correctly called 3,4-methylenedioxyphenylacetone or 3,4-methylenedioxybenzyl methyl ketone, gives rise upon reductive amination to MDA (using ammonia) or MDMA (using methylamine). This is an aromatic compound with a three-carbon side-chain and the amine-nitrogen on the beta-carbon. The other so-called piperonylacetone is really 3,4-methylenedioxybenzylacetone, an aromatic compound with a four-carbon side-chain. It produces, on reductive amination with ammonia or methylamine, the corresponding alpha-methyl-(n)-propylamines, with a four-carbon side-chain and the amine-nitrogen on the gamma-carbon. They are completely unexplored in man and so it is not known whether they are or are not psychedelic. As possible mis-synthesized products, they may appear quite unintentionally and must be evaluated as totally new materials. The gamma-amine analogue of MDA, a methylenedioxy substituted three carbon side-chain with the amine-nitrogen on the gamma carbon, has indeed been made and evaluated, and is discussed under MDA. The extension of the chain of mescaline to three atoms, by the inclusion of an oxygen atom, has produced two compounds that have also been assayed. They are mentioned in the recipe for mescaline.

 

The chain that reaches out to the amine group can be tied back in again to the ring, with a second chain. There are 2-aminobenzoindanes which are phenethylamines with a one-carbon link tying the alpha-position of the chain back to the aromatic ring. And there are 2-aminotetralines which are phenethylamines which have a two-carbon link tying the alpha-position of the chain back to the aromatic ring. Both unsubstituted ring systems are known and both are fair stimulants. Both systems have been modified with the DOM substituent patterns (called DOM-AI and DOM-AT respectively), but neither of these has been tried in man. And the analogues with the MDA substitution pattern are discussed elsewhere in this book.

 

And there is one more obvious remaining methylation pattern. What about phenethylamine or amphetamine compounds with two methyl groups on the nitrogen? The parent amphetamine example, N,N-dimethylamphetamine, has received much notoriety lately in that it has become a scheduled drug in the United States. Ephedrine is a major precursor in the illicit synthesis of methamphetamine, and with the increased law-enforcement attention being paid to this process, there has been increasing promotion of the unrestricted homologue, N-methylephedrine, to the methamphetamine chemist. This starting material gives rise to N,N-dimethylamphetamine which is a material of dubious stimulant properties. A number of N,N-dimethylamphetamine derivatives, with "psychedelic" ring substituents, have been explored as iodinated brain-flow indicators, and they are explicitly named within the appropriate recipes. But none of them have shown any psychedelic action.

 

This is as good a place as any to discuss two or three simple compounds, phenethylamines, with only one substituent on the benzene ring. The 2-carbon analog of 4-MA, is 4-methoxyphenethylamine, or MPEA. This is a kissing cousin to DMPEA, of such fame in the search for a urine factor that could be related to schizophrenia. And the end results of the search for this compound in the urine of mentally ill patients are as controversial as they were for DMPEA. There has been no confirmed relationship to the diagnosis. And efforts to see if it is centrally active were failures Q at dosages of up to 400 milligrams in man, there was no activity. The 4-chloro-analogue is 4-chlorophenethylamine (4-Cl-PEA) and it has actually been pushed up to even higher levels (to 500 milligrams dosage, orally) and it is also without activity. A passing bit of charming trivia. A positional isomer of MPEA is 3-methoxyphenethylamine (3-MPEA) and, although there are no reported human trials with this, it has been graced with an Edgewood Arsenal code number, vis., EA-1302.      

 

 

 

#143 PROPYNYL; 3,5-DIMETHOXY-4-(2-PROPYNYLOXY)PHENETHYLAMINE

 

SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for its preparation) in 50 mL acetone containing 100 mg decyltriethylammonium iodide, there was added 12 g of an 80% solution of propargyl bromide in toluene and 6.9 g of finely powdered anhydrous K2CO3. This mixture was held at reflux on the steam bath for 12 h, after which the solvent was removed under vacuum. The residues were added to 0.5 L H2O, acidified, and extracted with 3x75 mL CH2Cl2. The extracts were pooled, washed with 5% NaOH, and then with dilute HCl which discharged the deep color. Removal of the organic solvent under vacuum yielded 6.6 g of crude product. This was distilled at 138-148 deg C at 0.25 mm/Hg, yielding 4.3 g 3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile which spontaneously crystallized. A small sample from MeOH had a mp of 94-95 deg C. Anal. (C13H13NO3) C,H.

 

A suspension of 2.8 g LAH in 70 mL anhydrous THF was cooled to 0 deg C with good stirring under He, and treated with 2.0 g 100% H2SO4. To this, a solution of 4.2 g 3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile in 30 mL anhydrous THF was added very slowly. After the addition had been completed, the reaction mixture was held at reflux on the steam bath for 0.5 h, cooled to room temperature, treated with IPA to decompose the excess hydride, and finally with 15% NaOH to convert the solids to a white filterable mass. The solids were separated by filtration, the filter cake was washed with THF, and the filtrate and washes were pooled. After removal of the solvent, the residue was added to 100 mL dilute H2SO4, and washed with 3x75 mL CH2Cl2. The aqueous phase was made basic with dilute NaOH, and the product extracted with 2x75 mL CH2Cl2. After removal of the solvent under vacuum, the residue was distilled at 125-155 deg C at 0.3 mm/Hg to provide 2.4 g of a light amber viscous liquid. This was dissolved in 10 mL IPA, acidified with concentrated HCl until a droplet produced a red color on dampened, external universal pH paper, and then diluted with 40 mL anhydrous Et2O with good stirring. After a short delay, 3,5-dimethoxy-4-(2-propynyloxy)phenethylamine hydrochloride (PROPYNYL) spontaneously crystallized. The product was removed by filtration, washed first with an IPA/Et2O mixture, and finally with Et2O. The yield was 3.0 g of white needles.

 

DOSAGE: 80 mg or more.

 

DURATION: 8 - 12 h.

 

QUALITATIVE COMMENTS: (with 55 mg) I have cold feet Q literally Q I don't mean that in the spiritual or adventurous sense. But also I am somewhat physically fuzzy. I feel that if I were in public my behavior would be such that someone would notice me. Everything was OK without any question at the ninth hour. I could walk abroad again.

 

(with 80 mg) There is a body load. The flow of people around me all day has demanded my attention, and when I had purposefully retreated to be by myself, there was no particular reward as to visuals or anything with eyes closed, either. Sleep was easy at midnight (the twelth hour of the experiment) but the morning was sluggish, and on recalling the day, I am not sure of the events that had taken place. Higher might be all right, but watch the status of the body. There certainly wasn't that much mental stuff.

 

EXTENSIONS AND COMMENTARY: No experiments have been performed that describe the action of this drug at full level. This compound does not seem to have the magic that would encourage exploration at higher levels.  

 

 

 

#144 SB; SYMBESCALINE; 3,5-DIETHOXY-4-METHOXYPHENETHYLAMINE

 

SYNTHESIS: A solution of 15 g 1,3-diethoxybenzene and 15 mL of N,N,N',N'-tetramethylethylenediamine in 200 mL anhydrous Et2O was placed in a He atmosphere, magnetically stirred, and cooled to 0 deg C with an ice bath. Over the course of 10 min there was added 63 mL of a 1.6 M solution of butyllithium in hexane, which produced a fine white precipitate. After an additional 15 min stirring, 20 mL of tributyl borate was added which dissolved the precipitate. The stirring was continued for an additional 15 min. The reaction was quenched by the addition of 50 mL of a concentrated aqueous solution of ammonium sulfate. The resulting "cottage cheese" mass was transferred to a beaker, treated with an additional 300 mL of the ammonium sulfate solution, and allowed to stir until the solids had dispersed to a fine texture. The organic phase was separated and the aqueous phase extracted with 2x100 mL Et2O. The organic phases were combined, evaporated under vacuum, and the off-white residue dissolved in 100 mL MeOH. This cloudy solution was cooled (ice bath) and, with stirring, 20 mL of 35% hydrogen peroxide was added portionwise, . The reaction was allowed to continue stirring for 15 min, and then with the addition of 600 mL H2O, crystalline solids were formed. These were removed, washed with H2O, and upon drying yielded 15.4 g of 2,6-diethoxyphenol with a mp of 79.5-81.5 deg C. Efforts to diethylate pyrogallol produced mixtures of 2,6-diethoxyphenol and the isomer, 2,3-diethoxyphenol, and these proved difficult to separate. The pure 2,3-isomer was synthesized from ortho-diethoxybenzene by the process used above, and the product was an oil. Both phenols yielded crystalline 3,5-dinitrobenzoates. This derivative of 2,6-diethoxyphenol, upon recrystallization from CH3CN had a mp of 161-162 deg C. The derivative from 2,3-diethoxyphenol, also upon recrystallization from CH3CN, melted at 167-168 deg C. The mixed mp was appropriately depressed (mp 137-140 deg C.).

 

A solution of 7.6 g 2,6-diethoxyphenol in 40 mL MeOH was treated with 4.9 g of a 40% aqueous solution of dimethylamine followed by 3.6 g of a 40% aqueous solution of formaldehyde. The mixture was heated 1 h on the steam bath, and all volatiles were removed under vacuum. The residual dark oil was dissolved in 36 mL IPA and 10.3 g of methyl iodide was added. There was spontaneous heating, and the deposition of fine white solids. After standing for 10 min, these were removed by filtration, and the filter cake washed with more IPA. The crude product was freed from solvent (air dried weight, 1.7 g) and dissolved in 7 mL hot H2O. To this hot solution there was added 1.7 g sodium cyanide which slowly discharged the color and again deposited flocculant white solids. After cooling, these were removed by filtration, washed with H2O, and after thorough drying the isolated 3,5-diethoxy-4-hydroxyphenylacetonitrile weighed 0.5 g and had a mp of 107.5-108.5 deg C. Anal. (C12H15NO3) C,H.

 

To a solution of 2.1 g 3,5-diethoxy-4-hydroxyphenylacetonitrile in 20 mL anhydrous acetone, there was added 30 mg triethyldecylammonium iodide, 4.6 g methyl iodide, and finally 2.3 g powdered anhydrous K2CO3. This mixture was held at reflux for 5 h. The reaction mixture was quenched with 200 mL acidified H2O and extracted with 3x75 mL CH2Cl2. The extracts were pooled, washed with 2x75 mL 5% NaOH, and finally once with dilute HCl. The solvent was removed under vacuum, and the residue distilled at 110-115 deg C at 0.3 mm/Hg to provide 3,5-diethoxy-4-methoxyphenylacetonitrile as a solid. This weighed 1.3 g and had a mp of 58-59 deg C. Anal. (C13H17NO3) C,H.

 

To 30 mL of a 1 M solution LAH in THF that had been cooled to 0 deg C with vigorous stirring, under a He atmosphere, there was added dropwise 0.78 mL of 100% H2SO4. When the addition was complete, there was added dropwise a solution of 1.3 g of 3,5-diethoxy-4-methoxyphenylacetonitrile in 10 mL anhydrous THF. The reaction mixture was brought to room temperature and stirred an additional 10 min, then refluxed on a steam bath for 1.5 h. After cooling to room temperature the excess hydride was destroyed by the addition of about 2 mL IPA, followed by sufficient 15% NaOH to make the reaction basic to external pH paper and to render the aluminum oxides white and filterable. These were removed by filtration, the filter cake was washed with IPA, then the filtrate and washes were combined. The solvents were removed under vacuum and the residue dissolved in dilute H2SO4. This was washed with 2x75 mL CH2Cl2, the aqueous phase made basic with 5% NaOH, and extracted with 3x75 mL CH2Cl2. The extracts were pooled, the solvent removed under vacuum, and the residue distilled at 120-140 deg C at 0.3 mm/Hg to yield 0.9 g of a white oil. This was dissolved in 4 mL of IPA and neutralized with concentrated HCl to an end-point determined by damp external pH paper. There was the immediate formation of solids which were removed by filtration and washed first with IPA and then with Et2O. This provided 1.0 g of 3,5-diethoxy-4-methoxyphenethylamine hydrochloride (SB) as white crystals, with a mp of 186-187 deg C. Anal. (C13H22ClNO3) C,H.

 

DOSAGE: above 240 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 120 mg) There were no effects. Sleep that evening was strange, however, and I was fully awake at 4:00 AM, alert, and mentally restless. And there was a strange outburst of anger in the mid-morning. Might these be related to the material the previous day?

 

(with 240 mg) There was a slight chill that reminded me that I had taken symbescaline a half hour earlier. There was what might be called a vague threshold for about three hours, then nothing more. This material had a God-awful taste that lingers in the mouth far too long. If ever again, it will be in a gelatin capsule.

 

EXTENSIONS AND COMMENTARY: It must be concluded that SB is "probably" not active. There was no convincing evidence for much effect at levels that would clearly be active for mescaline. This is the kind of result that puts some potentially ambiguous numbers in the literature. One cannot say that it is inactive, for there might well be something at 400 or 800 or 1200 milligrams. But since it has been tried only up to 240 milligrams, I have used the phrase that the activity is greater than 240 milligrams. This will be interpreted by some people as saying that it is active, but only at dosages higher than 240 milligrams. What is meant, is that there was no activity observed at the highest level tried, and so if it is active, the active dose will be greater than 240 milligrams, and so the potency will be less than that of mescaline. However you phrase it, someone will misinterpret it.      

 

 

 

#145 TA; 2,3,4,5-TETRAMETHOXYAMPHETAMINE

 

SYNTHESIS: To a solution of 50 g 2,3,4-trimethoxybenzaldehyde in 157 mL glacial acetic acid which was well stirred and preheated to 25 deg C there was added 55.6 g 40% peracetic acid in acetic acid. The rate of addition was adjusted to allow the evolved heat of the exothermic reaction to be removed by an external ice bath at a rate that kept the internal temperature within a degree of 25 deg C. When the addition was complete and there was no more heat being evolved, the reaction mixture was diluted with 3 volumes of H2O, and neutralized with solid K2CO3. All was extracted with 3x250 mL Et2O, and the removal of the solvent from the pooled extracts under vacuum gave 42 g of residue that appeared to be mainly phenol, with a little formate and aldehyde. This was dissolved in 200 mL of 10% NaOH, allowed to stand for 2 h at ambient temperature, washed with 2x75 mL CH2Cl2, acidified with HCl, and extracted with 3x100 mL Et2O. The pooled extracts were washed with saturated NaHCO3, and the solvent removed to give 34.7 g of 2,3,4-trimethoxyphenol as an amber oil which was used without further purification. The infra-red spectrum showed no carbonyl group, of either the formate or the starting aldehyde.

 

A solution of 11.4 g flaked KOH in 100 g EtOH was treated with 33.3 g 2,3,4-trimethoxyphenol and 21.9 g allyl bromide. The mixture was held at reflux for 1.5 h, then poured into 5 volumes of H2O, made basic with the addition of 25% NaOH, and extracted with 3x200 mL CH2Cl2. Removal of the solvent from the pooled extracts gave about 40 g of a crude 2,3,4-trimethoxy-1-allyloxybenzene that clearly had unreacted allyl bromide as a contaminant.

 

A 39 g sample of crude 2,3,4-trimethoxy-1-allyloxybenzene in a round-bottomed flask with an immersion thermometer was heated with a soft flame. At 225 deg C there was a light effervescence and at 240 deg C an exothermic reaction set in that raised the temperature immediately to 265 deg C. It was held there for 5 min, and then the reaction was allowed to cool to room temperature. GC and IR analysis showed the starting ether to be gone, and that the product was largely 2,3,4-trimethoxy-6-allylphenol. It weighed 34.4 g.

 

To a solution of 9.4 g KOH in 100 mL MeOH, there was added 33.3 g of 2,3,4-trimethoxy-6-allylphenol and 21.2 g methyl iodide and the mixture was held on the steam bath for 2 h. This was poured into aqueous base, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave 30 g of an amber oil residue that was distilled at 100-125 deg C at 0.5 mm/Hg to provide 23.3 g of nearly colorless 2,3,4,5-tetramethoxyallylbenzene.

 

The total distillation fraction, 23.3 g 2,3,4,5-tetramethoxyallylbenzene, was dissolved in a solution of 25 g flaked KOH in 25 mL EtOH and heated at 100 deg C for 24 h. The reaction mixture was poured into 500 mL H2O, and extracted with 2x100 mL CH2Cl2. The aqueous phase was saved. The pooled organic extracts were stripped of solvent under vacuum to give 13.8 g of a fluid oil that was surprising pure 2,3,4,5-tetramethoxypropenylbenzene by both GC and NMR analysis. The basic aqueous phase was acidified, extracted with 2x100 mL CH2Cl2, and the solvent stripped to give 7.5 g of an oil that was phenolic, totally propenyl (as opposed to allyl), and by infra-red the phenolic hydroxyl group was adjacent to the olefin chain. This crude 2-hydroxy-3,4,5-trimethoxypropenylbenzene was methylated with methyl iodide in alcoholic KOH to give an additional 5.6 g of the target 2,3,4,5-tetramethoxypropenylbenzene. This was identical to the original isolate above. The distilled material had an index of refraction, nD24 = 1.5409.

 

A well stirred solution of 17.9 g 2,3,4,5-tetramethoxypropenylbenzene in 80 mL distilled acetone was treated with 6.9 g pyridine, and cooled to 0 deg C with an external ice bath. There was then added 14 g tetranitromethane over the course of a 0.5 min, and the reaction was quenched by the addition of a solution of 4.6 g KOH in 80 mL H2O. As the reaction mixture stood, there was a slow deposition of yellow crystals, but beware, this is not the product. This solid weighed 4.0 g and was the potassium salt of trinitromethane. This isolate was dried and sealed in a small vial. After a few days standing, it detonated spontaneously. The filtrate was extracted with 3x75 mL CH2Cl2, and the removal of the solvent from these extracts gave a residue of 20.8 g of crude 2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene which did not crystallize.

 

A solution was made of 20.3 g of the crude 2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene in 200 mL anhydrous Et2O, and this was filtered to remove some 2.7 g of insoluble material which appeared to be the potassium salt of trinitromethane by infra-red analysis. A suspension of 14 g LAH in 1 L anhydrous Et2O was stirred, placed under an inert atmosphere, and brought up to a gentle reflux. The above clarified ether solution of the propene was added over the course of 1 h, and the mixture was held at reflux for 24 h. After cooling, the excess hydride was destroyed by the cautious addition of 1 L 1.5 N H2SO4 (initially a drop or two at a time) and when the two phases were complete clear, they were separated. The aqueous phase was treated with 350 g potassium sodium tartrate, and brought to a pH >9 with base. This was extracted with 3x150 mL CH2Cl2, and the removal of the solvent from the pooled extracts gave a residue that was dissolved in 200 mL anhydrous Et2O, and saturated with anhydrous HCl gas. An Et2O-insoluble oil was deposited and, after repeated scratching with fresh Et2O, finally gave a granular white solid. This product was recrystallized from acetic anhydride, giving white crystals that were removed by filtration, Et2O washed, and air dried. The yield of 2,3,4,5-tetramethoxyamphetamine hydrochloride (TA) was 1.9 g and had a mp of 135.5-136.5 deg C.

 

DOSAGE: probably above 50 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 30 mg) Definite threshold. There was eye dilation, and some unusual humor Q a completely wild day with chi-square calculations on the PDP-7 that were on the edge of bad taste. But I was definitely baseline in the afternoon during the Motor Vehicle Department interactions.

 

(with 35 mg) I had some gastric upset, but nonetheless there was a distinct intoxication. The next morning I had a foul headache.

 

EXTENSIONS AND COMMENTARY: This is pretty thin stuff from which to go out into a world that is populated by pharmacological sharks and stake out claims as to psychedelic potency. The structure of this molecule has everything going for it. It is an overlay of TMA (active) and TMA-2 (even more active) so it is completely reasonable that it should be doing something at a rational dosage. But that dosage might well be in the many tens of milligrams.

 

Tens of milligrams. Now there is a truly wishy-washy phrase. There is an art to the assignment of an exact number or, as is sometimes desperately needed, a fuzzy number, to a collection of things. In my youth (somewhere way back yonder in the early part of the century) I had been taught rules of grammer that were unquestionably expected of any well-educated person. If you used a Latin stem, you used a Latin prefix. And if you used a Greek stem, you used a Greek prefix. Consider a collection of things with simple geometric sides (a side is a latus in Latin). One would speak of a one-sided object as being unilateral, and a bilateral object has two sides. A trilateral, and quadrilateral, and way up there to multilateral objects, are referred to as having three or four or a lot of sides, respectively. Just the opposite occurs with geometric objects with faces. A face is a hedra in Greek, so one really should use the Greek structure. If one has just one face, one has a monohedron, a dihedron has two faces, and there are trihedron, tetrahedron, and polyhedron for things that have three, four, or a lot of faces. Actually, the prefix "poly" swings both ways. It was initially a Greek term, but as was the fate of many Greek words, it wandered its way from East to West, and ended up as a Latin term as well.

 

But back to the problem of how to refer to something that is more than one or two, but not as much as a lot? If you know exactly how many, you should use the proper prefix. But what if you don't know how many? There are terms such as "some." And there is "several." There is a "few" and a "number of" and "numerous" and "a hand full." One desperately looks for a term that is a collective, but which carries the meaning of an undefined number. There are English gems such as a pride of lions and a host of daffodils. But without a specific animal or plant of reference, one must have a target collective that is appropriate, to let the term "many" or "few" imply the proper size. There were many hundreds of persons (a few thousands of persons) at the rally. Several dozen hunters (a few score hunters) were gathered at the lake. A wonderful prefix is "oligo" which means a few, not a lot, and it means that I am not sure just how many are meant. Say, for example, that you have synthesized something in a biochemical mixture that contains three or four peptides. Di-and tri- and tetrapeptides are exact terms, but they do not describe what you have done. Polypeptide is way too big. However, an oligopeptide means that there are a few peptide units, I'm not sure how many. This may well be the most accurate description of just what you have.

 

I love the British modesty that is shown by hiding a person's physical weight by referring to it with the dimension known as the stone. This is, as I remember, something like 14 pounds. So, if stones were the weight equivalent of 10 milligrams, the activity of TA would be several stone. And since the synthetic intermediate 1-allyl-2,3,4,5-tetramethoxybenzene is one of the ten essential oils, the amination step from our hypothetical reaction in the human liver would make TA one of the so-called Ten Essential Amphetamines.      

 

 

 

#146 3-TASB; 3-THIOASYMBESCALINE;

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