BENZODIOXOL-5-YL)-2-BUTANAMINE

 

SYNTHESIS: The Grignard reagent of propyl bromide was made by the dropwise addition of 52 g 1-bromopropane to a stirred suspension of 14 g magnesium turnings in 50 mL anhydrous Et2O. After the addition, stirring was continued for 10 min, and then a solution of 50 g piperonal in 200 mL anhydrous Et2O was added over the course of 30 min. The reaction mixture was heated at reflux for 8 h, then cooled with an external ice bath. It was quenched with the addition of a solution of 75 mL cold, saturated aqueous ammonium chloride. The formed solids were removed by filtration, and the two-phase filtrate separated. The organic phase was washed with 3x200 mL dilute HCl, dried over anhydrous MgSO4, and the solvent removed under vacuum. The crude 62.2 g of 1-(3,4-methylenedioxyphenyl)-2-butanol, which contained a small amount of the olefin that formed by dehydration, was distilled at 98 deg C at 0.07 mm/Hg to give an analytical sample, but the crude isolate served well in the next reaction. Anal. (C11H14O3) C,H.

 

A mixture of 65 g crude 1-(3,4-methylenedioxyphenyl)-2-butanol and 1 g finely powdered potassium bisulfate was heated with a soft flame until the internal temperature reached 170 deg C and H2O was no longer evolved. The entire reaction mixture was then distilled at 100-110 deg C at 0.8 mm/Hg to give 55 g of 1-(3,4-methylenedioxyphenyl)-1-butene as a colorless oil. Anal. (C11H12O2) C,H.

 

To 240 mL of stirred and cooled formic acid there was added 30 mL H2O followed, slowly, by 45 mL of 35% hydrogen peroxide. There was then added a solution of 48 g 1-(3,4-methylenedioxyphenyl)-1-butene in 240 mL acetone at a rate that maintained the internal temperature at less than 40 deg C. After the addition, the reaction mixture was allowed to stand and stir for several additional days. The excess volatiles were removed under vacuum with the temperature never allowed to exceed 40 deg C. The residue was dissolved in 90 mL MeOH and diluted with 450 mL 15% H2SO4. This mixture was heated on the steam bath for 2.5 h, cooled, and then extracted with 3x100 mL Et2O. The extracts were pooled, washed with 2x200 mL H2O, 2x200 mL 5% NaOH, 2x200 mL brine, and then dried over anhydrous MgSO4. After removal of the solvent under vacuum, the residue was distilled at 105-135 deg C at 0.3 mm/Hg to give 28.2 g 1-(3,4-methylenedioxyphenyl)-2-butanone as an amber oil. Redistillation gave a colorless oil, with a bp of 98 deg C at 0.11 mm/Hg. Anal. (C11H12O3) C,H. This intermediate ketone could be prepared by the Wittig reaction between piperonal and the derivative of triphenylphosphonium propyl bromide and dibutyldisulfide, followed by hydrolysis in a HCl/acetic acid mixture, but the yields were no better, Efforts to prepare this ketone by the iron and acid reduction of the appropriate nitrostyrene (1-(3,4-methylenedioxyphenyl)-2-nitro-1-butene, mp 64-65 deg C) were thwarted by the consistently unsatisfactory yield of the precursor from the reaction between piperonal and 1-nitropropane.

 

A stirred solution of 20 g anhydrous ammonium acetate and 4.6 g 1-(3,4-methylenedioxyphenyl)-2-butanone in 50 mL MeOH was treated with 1.57 g sodium cyanoborohydride. Droplets of HCl were added as needed to maintain the pH at approximately 6. The reaction mixture was made basic with the addition of 250 mL dilute NaOH and extracted with 3x100 mL CH2Cl2. The pooled organic extracts were extracted with 2x100 mL dilute H2SO4, the pooled aqueous extracts made basic again, and extracted again with 2x100 mL CH2Cl2. Removal of the solvent gave a residue which was distilled to give 2.6 g of a colorless oil which was dissolved in 15 mL IPA, neutralized with concentrated HCl, and diluted with an equal volume of anhydrous Et2O. Crystals of 2-amino-1-(3,4-methylenedioxyphenyl)butane hydrochloride (J) separated slowly. After filtering, Et2O washing, and air drying there was obtained 2.8 g of white crystals that melted at 159-161 deg C. Anal. (C11H16ClNO2) C,H,N.

 

DOSAGE: 150 - 230 mg.

 

DURATION: 4 - 8 h.

 

QUALITATIVE COMMENTS: (with 175 mg) The first stirrings were evident in a half hour, pleasant feelings, and without any untoward body effects. Within another half hour I was at a plus 2 and there it leveled off. I would be reluctant to drive a car, but I could were it necessary. There were no visual distortions, no giddiness, no introspective urges, and no rise to a psychedelic intoxication of any significance. After about an hour and a half at this level, I gradually dropped back over another two hours. Afterwards I was quite fatigued and languorous.

 

(with 200 mg and a 75 mg supplement) RA very strong climb, and a very good, interior feeling. It has some of the MDMA properties, but it is difficult to concentrate on any one point. There is a tendency to slide off. Excellent emotional affect; music is fine but not gripping. Someone had used the phrase, mental nystagmus, and there is something valid there. The supplement was taken at the 2 hour point when I was already aware of some dropping, and its action was noticed in about a half hour.

 

(with 230 mg) Physically, there was a bit of dry mouth but no teeth clenching, some nystagmus, maybe the slightest bit of dizziness, very anorexic, and it is not a decongestant. Mentally, it is extremely benign and pleasant, funny and good-humored. No visuals. Peaceful. Easy silences, easy talking. More stoning than MDMA.

 

EXTENSIONS AND COMMENTARY: In general, all subjects who have explored J have accepted it and commented favorably. Perhaps those who have used supplements (in an imitation of the common MDMA procedure) achieved an additional period of effect, but also tended to drop to baseline afterwards more rapidly. The physical side effects, such as teeth clench and nystagmus, were infrequent. The consensus is that J is a bit more "stoning" than MDMA, more like MDA, but with a chronology that is very much the same.

 

Two nomenclature problems have to be faced in the naming of these compounds. One deals with the Chemical Abstracts terminology as contrasted with the logical and intuitive terminology. The other invokes the concept of the Muni-Metro, delightfully simple, but neither Chemical Abstracts-approved nor intuitive in form. The first problem is addressed here; the second is discussed where it better belongs, under the N-methyl homologue of J (see under METHYL-J).

 

In short, the two-ring system of J, or of any of the MDA-MDMA family of drugs, can be named as one ring being attached to the other, or by a single term that encompasses both. The first procedure, an old friend with chemists and the one that had been used for years in the abstracting services, calls the combination methylenedioxybenzene and, as a prefix, it becomes methylenedioxyphenyl-something. The benzene or the phenyl-something is the foundation of the name, and there happens to be a methylenedioxy-ring attached to it. On this basis, this compound J should be named as if it had no methylenedioxy ring anywhere, and then simply attach the new ring as an afterthought. So, the one-ring parent of J is 1-phenyl-2-aminobutane, and J is 1-(3,4-methylenedioxyphenyl)-2-aminobutane (or, to be a purist, the amino should alphabetically come first, to give 2-amino-1-(3,4-methylene-dioxyphenyl)butane). The synthesis of the chemical intermediates given above uses this old-fashioned nomenclature.

 

But the name currently in vogue for this two-ring system is 1,3-benzodioxole. As a prefix it becomes 1,3-benzodioxol-5-yl-something, and so J would be called 1-(1,3-benzodioxol-5-yl)-2-aminobutane. This is the source of the code name BDB. And the N-methyl homologue, the alpha-ethyl analogue of MDMA, is named MBDB, or METHYL-J, and is with its own separate entry in this footnote.

 

There is a psychological nuance to this new nomenclature. The virtues and potential medical value of MDMA lie in its most remarkable property of facilitating communication and introspective states without an overlay of psychedelic action. This property has prompted the coining of a new pharmacological class name, Entactogen, which comes from the Greek roots for "touching within." But MDMA has been badly smeared in both the public and the scientific view, by its wide popular misuse, its precipitous placement into a Schedule I category of the Federal Drug Law, and a flood of negative neurotoxicological findings in animal studies. There are some properties of both this compound and its methyl-homologue that suggest this "entactogen" world, so why not avoid the "MD" prefix that, in many eyes, is pejorative? Stick with the totally obscure chemical names, and call them BDB and MBDB. Or, even more simply, J and METHYL-J.      

 

 

 

#95 LOPHOPHINE; 3-METHOXY-4,5-METHYLENEDIOXYPHENETHYLAMINE

 

SYNTHESIS: A solution of 50 g myristicinaldehyde (3-methoxy-4,5-methylenedioxybenzaldehyde, see under MMDA for its preparation) in 200 mL acetic acid was treated with 33 mL nitromethane and 17.4 g anhydrous ammonium acetate and held on the steam bath for 5 h. The reaction mixture was diluted with a little H2O and cooled in an external ice-acetone bath. A heavy crop of yellow crystals formed, which were removed by filtration, washed with cold acetic acid, and dried to constant weight. There was thus obtained 19.3 g 3-methoxy-4,5-methylenedioxy-beta-nitrostyrene with a mp of 210-212 deg C. The mother liquors were diluted with H2O, and extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with 5% NaOH, and the solvent removed under vacuum yielding 34 g of a dark residue that was largely unreacted aldehyde. This residue was reprocessed in acetic acid with nitromethane and ammonium acetate, as described above, and provided an additional 8.1 g of the nitrostyrene with the same mp.

 

A suspension of 25 g LAH in 1.5 L anhydrous Et2O in an inert atmosphere was stirred magnetically, and brought up to a gentle reflux. Through a Soxhlet condenser modified to allow Et2O to return continuously to the reaction mixture, there was added 27.0 g of 3-methoxy-4,5-methylenedioxy-beta-nitrostyrene. The addition require many h, and when it was completed, the reaction was held at reflux for an additional 9 days. After cooling the reaction mixture in an external ice bath, the excess hydride was destroyed by the cautious addition of dilute H2SO4. The final amount used was 1800 mL H2O containing 133 g H2SO4. The phases were separated, and the aqueous phase was washed with 2x100 mL Et2O. To it was then added 625 g potassium sodium tartrate, and sufficient base to bring the pH to >9. This was extracted with 3x250 mL CH2Cl2, and the pooled extracts stripped of solvent under vacuum. The residue was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas, giving a heavy crystallization of salts. These were removed by filtration, Et2O washed, and air dried, to give 17.7 g 3-methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE) as an off-white solid with a mp of 160-161 deg C. This was dissolved in CH3CN containing 5% EtOH, decolorized with activated charcoal, filtered, and the removed charcoal washed with boiling CH3CN. Slow cooling of the solution provided 11.7 g of a white product which melted at 164-164.5 deg C.

 

DOSAGE: greater than 200 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 150 mg) Between two and five hours, very peaceful and euphoric mood elevation, similar to mescaline, but without any visual distortion. Mild enhancement of color perception, possibly a function of mood elevation. There was no nausea, no eyes-closed vision. Slept easily that evening.

 

(with 250 mg) Possibly something of a threshold effect from 2:30 to 4:30 of the experiment. Intangible, and certainly there is nothing an hour later.

 

EXTENSIONS AND COMMENTARY: It looks as if this compound is not active. There is an excellent argument as to why it really should be, and the fact that it is not active is completely unexpected. Let me try to explain.

 

Quite simply, mescaline is a major component and a centrally active alkaloid of the Peyote plant. It is a phenethylamine, which can undergo a cyclization within the plant to produce a pile of derivatives (tetrahydroisoquinolines) such as anhalonine and O-methylanhalonidine that are marvelously complex alkaloids, all natural components of this magical cactus. But there is another pile of derivatives (tetrahydroisoquinolines) such as anhalonine, and lophophorine, and peyophorine which are the logical cyclization products of another phenethylamine which does not exist in the cactus. It should be there, but it is not. If it were there it would be the natural precursor to a host of bicyclic alkaloids, but it is absent. This is 3-methoxy-4,5-methylenedioxyphenethylamine. I feel that some day it will be discovered as a plant component, and when it is it can be given a name that reflects the generic binomial of the plant. And since the plant has been known as Lophophora williamsii, why not give a name to this compound (which should be in the plant), one derived from the Latin name, but one that has never before been used? What about LOPHOPHINE? And so, I have named it, but I have not found it, nor has anyone else. Yet.

 

It is inevitable that this simple and most appealing precursor will be found to be present in the cactus, at some future time when we will have tools of sufficient sensitivity to detect it. And certainly, it would be reasonable to expect it to be an active psychedelic, and to be as interesting in man as its close cousin, mescaline. But, at the present time, LOPHOPHINE is not known to be present in the plant, and it is not known to be active in man. I am confident that both statuses will change in the future.      

 

 

 

#96 M; MESCALINE; 3,4,5-TRIMETHOXYPHENETHYLAMINE

 

SYNTHESIS: A solution of 20 g 3,4,5-trimethoxybenzaldehyde, 40 mL nitromethane, and 20 mL cyclohexylamine in 200 mL of acetic acid was heated on the steam bath for 1 h. The reaction mixture was then diluted slowly and with good stirring, with 400 mL H2O, which allowed the formation of a heavy yellow crystalline mass. This was removed by filtration, washed with H2O, and sucked as dry as possible.

 

Recrystallization from boiling MeOH (15 mL/g) yielded, after filtration and air drying, beta-nitro-3,4,5-trimethoxystyrene as bright yellow crystals weighing 18.5 g. An alternate synthesis was effective, using an excess of nitromethane as solvent as well as reagent, if the amount of ammonium acetate catalysis was kept small. A solution of 20 g 3,4,5-trimethoxybenzaldehyde in 40 mL nitromethane containing 1 g anhydrous ammonium acetate was heated on the steam bath for 4 h. The solvent was stripped under vacuum and the residual yellow oil was dissolved in two volumes of hot MeOH, decanted from some insolubles, and allowed to cool. The crystals formed are removed by filtration, washed with MeOH and air dried yielding 14.2 g. of bright yellow crystals of beta-nitro-3,4,5-trimethoxystyrene. The use of these proportions but with 3.5 g ammonium acetate gave extensive side-reaction products even when worked up after only 1.5 h heating. The yield of nitrostyrene was, in this latter case, unsatisfactory.

 

To a gently refluxing suspension of 2 g LAH in 200 mL Et2O, there was added 2.4 g beta-nitro-3,4,5-trimethoxystyrene as a saturated Et2O solution by use of a Soxhlet extraction condenser modified to allow the continuous return of condensed solvent through the thimble. After the addition was complete, the refluxing conditions were maintained for another 48 h. After cooling the reaction mixture, a total of 150 mL of 1.5 N H2SO4 was cautiously added, destroying the excess hydride and untimately providing two clear phases. These were separated, and the aqueous phase was washed once with 50 mL Et2O.  There was then added 50 g potassium sodium tartrate, followed by sufficient NaOH to bring the pH >9. This was then extracted with 3x75 mL CH2Cl2, and the solvent from the pooled extracts was removed under vacuum. The residue was distilled at 120-130 deg C at 0.3 mm/Hg giving a white oil that was dissolved in 10 mL IPA and neutralized with concentrated HCl. The white crystals that formed were diluted with 25 mL Et2O, removed by filtration, and air dried to provide 2.1 g 3,4,5-trimethoxyphenethylamine hydrochloride (M) as glistening white crystals. The sulfate salt formed spectacular crystals from water, but had a broad and uncharacteristic mp. An alternate synthesis can employ 3,4,5-trimethoxyphenylacetonitrile, as described under beta-D.

 

DOSAGE: 200-400 mg (as the sulfate salt), 178-256 mg (as the hydrochloride salt).

 

DURATION: 10-12 h

 

QUALITATIVE COMMENTS: (with 300 mg) I would have liked to, and was expecting to, have an exciting visual day, but I seemed to be unable to escape self-analysis. At the peak of the experience I was quite intoxicated and hyper with energy, so that it was not hard to move around. I was quite restless. But I spent most of the day in considerable agony, attempting to break through without success. I learned a great deal about myself and my inner workings. Everything almost was, but in the final analysis, wasn't. I began to become aware of a point, a brilliant white light, that seemed to be where God was entering, and it was inconceivably wonderful to perceive it and to be close to it. One wished for it to approach with all one's heart. I could see that people would sit and meditate for hours on end just in the hope that this little bit of light would contact them. I begged for it to continue and come closer but it did not. It faded away not to return in that particular guise the rest of the day. Listening to Mozart's Requiem, there were magnificent heights of beauty and glory. The world was so far away from God, and nothing was more important than getting back in touch with Him. But I saw how we created the nuclear fiasco to threaten the existence of the planet, as if it would be only through the threat of complete annihilation that people might wake up and begin to become concerned about each other. And so also with the famines in Africa. Many similar scenes of joy and despair kept me in balance. I ended up the experience in a very peaceful space, feeling that though I had been through a lot, I had accomplished a great deal. I felt wonderful, free, and clear.

 

(with 350 mg) Once I got through the nausea stage, I ventured out-of-doors and I was aware of an intensification of color and a considerable change in the texture of the cloth of my skirt and in the concrete of the sidewalk, and in the flowers and leaves that were handed me by an observer. I experienced the desire to laugh hysterically at what I could only describe as the completely ridiculous state of the entire world. Although I was afraid of motion, I was persuaded to take a ride in a car. The driver turned on the radio and suddenly the music 'The March of the Siamese Children' from 'The King and I' became the most perfect background music for the parody of real life which was indeed the normal activity of Telegraph Avenue on any Saturday morning. The perfectly ordinary people on their perfectly ordinary errands were clearly the most cleverly contrived set of characters all performing all manners of eccentric activities for our particular hilarity and enjoyment. I felt that I was at the same time both observing and performing in an outrageous moving picture. I experienced one moment of transcendant happiness when, while passing Epworth Hall, I looked out of the window of the car and up at the building and I was suddenly in Italy looking up at a gay apartment building with its shutters flung open in sunshine, and with its window boxes with flowers. We stopped at a spot overlooking the bay, but I found the view uninteresting and the sun uncomfortable. I sat there on the seat of the car looking down at the ground, and the earth became a mosaic of beautiful stones which had been placed in an intricate design which soon all began to move in a serpentine manner. Then I became aware that I was looking at the skin of a beautiful snake Q all the ground around me was this same huge creature and we were all standing on the back of this gigantic and beautiful reptile. The experience was very pleasing and I felt no revulsion. Just then, another automobile stopped to look at the view and I experienced my first real feeling of persecution and I wanted very much to leave.

 

(with 400 mg) During the initial phase of the intoxication (between 2 and 3 hours) everything seemed to have a humorous interpretation. People's faces are in caricature, small cars seem to be chasing big cars, and all cars coming towards me seem to have faces. This one is a duchess moving in regal pomp, that one is a wizened old man running away from someone. A remarkable effect of this drug is the extreme empathy felt for all small things; a stone, a flower, an insect. I believe that it would be impossible to harm anything Q to commit an overt harmful or painful act on anyone or anything is beyond one's capabilities. One cannot pluck a flower Q and even to walk upon a gravel path requires one to pick his footing carefully, to avoid hurting or disturbing the stones. I found the color perception to be the most striking aspect of the experience. The slightest difference of shade could be amplified to extreme contrast. Many subtle hues became phosphorescent in intensity. Saturated colors were often unchanged, but they were surrounded by cascades of new colors tumbling over the edges.

 

(with 400 mg) It took a long time to come on and I was afraid that I had done it wrong but my concerns were soon ended. The world soon became transformed where objects glowed as if from an inner illumination and my body sprang to life. The sense of my body, being alive in my muscles and sinews, filled me with enormous joy. I watched Ermina fill to brimming with animal spirit, her features tranformed, her body cat-like in her graceful natural movement. I was stopped in my tracks. The world seemed to hold its breath as the cat changed again into the Goddess. As she shed her clothes, she shed her ego and when the dance began, Ermina was no more. There was only the dance without the slightest self-consconciousness. How can anything so beautiful be chained and changed by other's expectations? I became aware of myself in her and as we looked deeply into one another my boundaries disappeared and I became her looking at me.

 

EXTENSIONS AND COMMENTARY: Mescaline is one of the oldest psychedelics known to man. It is the major active component of the small dumpling cactus known as Peyote. It grows wild in the Southwestern United States and in Northern Mexico, and has been used as an intimate component of a number of religious traditions amongst the native Indians of these areas. The cactus has the botanical name of Lophophora williamsii or Anhalonium lewinii and is immediately recognizable by its small round shape and the appearance of tufts of soft fuzz in place of the more conventional spines. The dried plant material has been classically used with anywhere from a few to a couple of dozen of the hard tops, called buttons, being consumed in the course of a ceremony.

 

Throughout the more recently published record of clinical human studies with mescaline, it has been used in the form of the synthetic material, and has usually been administered as the sulfate salt. Although this form has a miserable melting point (it contains water of crystallization, and the exact melting point depends on the rate of heating of the sample) it nonetheless forms magnificent crystals from water. Long, glistening needles that are, in a sense, its signature and its mark of purity. The dosages associated with the above "qualitative comments" are given as if measured as the sulfate, although the actual form used was usually the hydrochloride salt. The conversion factor is given under "dosage" above.

 

Mescaline has always been the central standard against which all other compounds are viewed. Even the United States Chemical Warfare group, in their human studies of a number of substituted phenethylamines, used mescaline as the reference material for both quantitative and qualitative comparisons. The Edgewood Arsenal code number for it was EA-1306. All psychedelics are given properties that are something like "twice the potency of mescaline" or "twice as long-lived as mescaline." This simple drug is truly the central prototype against which everything else is measured. The earliest studies with the "psychotomimetic amphetamines" had quantitative psychological numbers attached that read as "mescaline units." Mescaline was cast in concrete as being active at the 3.75 mg/kg level. That means for a 80 kilogram person (a 170 pound person) a dose of 300 milligrams. If a new compound proved to be active at 30 milligrams, there was a M.U. level of 10 put into the published literature. The behavioral biologists were happy, because now they had numbers to represent psychological properties. But in truth, none of this represented the magic of this material, the nature of the experience itself. That is why, in this Book II, there is only one line given to "dosage," but a full page given to "qualitative comments".

 

Four simple N-modified mescaline analogues are of interest in that they are natural and have been explored in man.

 

The N-acetyl analogue has been found in the peyote plant, and it is also a major metabolite of mescaline in man. It is made by the gentle reaction of mescaline with acetic anhydride (a bit too much heat, and the product N-acetyl mescaline will cyclize to a dihydroisoquinoline, itself a fine white crystalline solid, mp 160-161 deg C) and can be recrystallized from boiling toluene. A number of human trials with this amide at levels in the 300 to 750 milligrams range have shown it to be with very little activity. At the highest levels there have been suggestions of drowsiness. Certainly there were none of the classic mescaline psychedelic effects.

 

If free base mescaline is brought into reaction with ethyl formate (to produce the amide, N-formylmescaline) and subsequently reduced (with lithium aluminum hydride) it is converted to the N-methyl homologue. This base has also been found as a trace component in the Peyote cactus. And the effects of N-methylation of other psychedelic drugs have been commented upon elsewhere in these recipes, all with consistently negative results (with the noteworthy exception of the conversion of MDA to MDMA). Here, too, there is no obvious activity in man, although the levels assayed were only up to 25 milligrams.

 

N,N-Dimethylmescaline has been given the trivial name of Trichocerine as it has been found as a natural product in several cacti of the Trichocereus Genus but, interestingly, never in any Peyote variant. It also has proven inactive in man in dosages in excess of 500 milligrams, administered parenterally. This observation, the absence of activity of a simple tertiary amine, has been exploited in the development of several iodinated radiopharmaceuticals that are mentioned elsewhere in this book.

 

The fourth modification is the compound with the nitrogen atom oxidatively removed from the scene. This is the mescaline metabolite, 3,4,5-trimethoxyphenylacetic acid, or TMPEA. Human dosages up to 750 milligrams orally failed to produce either physiological or psychological changes.

 

One additional manipulation with some of these structures has been made and should be mentioned. These are the analogues with an oxygen atom inserted between the aromatic ring and the aliphatic chain. They are, in essence, aminoethyl phenyl ethers. The first is related to mescaline itself, 2-(3,4,5-trimethoxyphenoxy)ethylamine. Human trials were conducted over the dose range of 10 to 300 milligrams and there were no effects observed. The second is related to trichocerine, N,N-dimethyl-2-(3,4,5-trimethoxyphenoxy)ethylamine. It was inactive in man over the range of 10 to 400 milligrams. Mescaline, at a dose of 420 milligrams, served as the control in these studies.     

 

 

 

#97 4-MA; PMA; 4-METHOXYAMPHETAMINE

 

SYNTHESIS: A solution of 27.2 g anisaldehyde and 18.0 g nitroethane in 300 mL benzene was treated with 2.0 mL cyclohexane and refluxed using a Dean Stark trap until H2O ceased to accumulate. A total of 3.8 mL was generated over about 5 days. After the removal of the solvent under vacuum, the viscous red oily residue was cooled and it spontaneously crystallized. This was ground under an equal volume of MeOH, producing lemon-yellow crystals of 1-(4-methoxyphenyl)-2-nitropropene. The final yield was 27.4 g of product with a mp of 45-46 deg C. Recrystallization from 4 volumes MeOH did not improve the mp. An excellent alternate synthesis with a comparable yield involved letting a solution of equimolar amounts of the aldehyde and nitro-ethane and a tenth mole of n-amylamine stand in the dark at room temperature for a couple of weeks. The product spontaneously crystal-lized, and could be recrystallized from MeOH. The more conventional synthesis involving acetic acid as a solvent and ammonium acetate as a catalyst, produced a poor yield of the nitrostyrene and it was difficult to separate from the white diacetate of the starting anisaldehyde, mp 59-60 deg C.

 

A suspension of 32 g LAH in 1 L anhydrous Et2O was well stirred and 32.6 g 1-(4-methoxyphenyl)-2-nitropropene in Et2O was added at a rate that maintained a reflux. After the addition was complete, reflux was continued for 48 h. The reaction mixture was cooled, and the excess hydride was destroyed by the cautious addition of dilute H2SO4. The Et2O was separated, and extracted with additional aqueous H2SO4. A solution of 700 g potassium sodium tartrate in 600 mL H2O was added, and the pH brought to >9 with 25% NaOH. This aqueous phase was extracted with 3x200 mL CH2Cl2 which provided, after removal of the solvent, 32.5 g of a clear amber oil. This was dissolved in 100 mL IPA, neutralized with concentrated HCl, and then diluted with 300 mL anhydrous Et2O. There was obtained white crystals of 4-methoxyamphetamine hydrochloride (4-MA) that weighed, after filtering, Et2O washing and air drying, 22.2 g and had a mp of 208-209 deg C. The amphetamine metabolite, 4-hydroxyamphetamine hydrochloride (4-HA), was prepared by heating 5.0 g 4-MA in 20 mL concentrated HCl at 15 lbs/in. After recrystal-lization from aqueous EtOH, the product weighed 3.8 g and had a mp of 171-172 deg C.

 

DOSAGE: 50 - 80 mg.

 

DURATION: short.

 

QUALITATIVE COMMENTS: (with 60 mg) At just over an hour, there was a sudden blood pressure rise, with the systolic going up 55 mm. This was maintained for another hour. I found the effects reminiscent of DET, distinct after-images, and some parasthesia.  I was without any residue by early evening (after 5 hours).

 

(with 70 mg) It hit quite suddenly. I had a feeling of druggedness, almost an alcohol-like intoxication, and I never was really high in the psychedelic sense.

 

EXTENSIONS AND COMMENTARY: This is another of the essential amphetamines, because of the appearance of the 4-methoxy group in two most important essential oils. These are the allylbenzene (estragole or esdragol) and the propenyl isomer (anethole). Their natural sources have been discussed under TMA.

 

Two comments are warranted concerning 4-MA, one of scientific interest, and the other about a social tragedy.

 

A major metabolites of amphetamine is 4-hydroxyamphetamine, from oxidation at the 4-position. It has been long known that with chronic amphetamine usage there is the generation of tolerance, which encourages ever-increasing doses to be used. When the daily load gets up around one or two hundred milligrams, the subject can become quite psychotic. The question was asked: might the chronic amphetamine user be methylating his endogenously produced 4-hydroxyamphet-amine to produce 4-methoxyamphetamine (4-MA), and maybe this is the agent that promotes the psychosis? To address this question, several studies were done with normal subjects, about 20 years ago, to see if 4-MA might produce a psychotic state (it didn't at the highest levels tried, 75 milligrams) and to see if it was excreted to some extent unchanged in the urines of these normal subjects (it was seen even at the lowest dosage tried, 10 milligrams). It produced excitation and other central effects, it produced adrenergic pressor effects, and it consistently produced measur-able quantities of 4-MA in the urine, but it produced no amphetamine-like crazies. And since the administration of up to 600 milligrams of amphetamine produced no detectable 4-MA in the urine, this theory of psychotomimesis is not valid.

 

On the tragic side, a few years later, 4-MA became widely distributed in both the US (as the sulfate salt) and in Canada (as the hydrochloride), perhaps in-spired by some studies in rats that had reported that it was second only to LSD in potency as a hallucinogen. The several deaths that occurred probably followed overdose, and it was clear that 4-MA was involved as it had been isolated from both urine and tissue during post mortems. It had been sold under the names of Chicken Power and Chicken Yellow, and was promoted as being MDA. I could find no record of a typical street dosage, but comments collected in association with the deaths implied that the ingested quantites were in the hundreds of milligrams. Rrecently, the ethoxy homologue, 4-EA, appeared on the streets of Canada. The dosage, again, was not reported. It was promptly illegalized there.

 

The two positional analogues of 4-MA are known; vis., 2-MA and 3-MA. Their synthesis is straightforward, in imitation of that for 4-MA above. The meta-compound, 3-MA, has been metabolically explored in man, but no central effects were noted at a 50 milligram dose (2x25 milligrams, separated by three hours). There appears to be no report of any human trial of 2-MA. The N-methyl homologue of 2-MA is a commercial adrenergic bronchodilator called Methoxyphenamine, or Orthoxine. It has been used in the prevention of acute asthma attacks in doses of up to 200 milligrams, with only slight central stimulation. The N-methyl homologues of 3-MA and 4-MA are known, and the latter compound is the stuff of a separate entry in this book.     

 

#98 MADAM-6; 2,N-DIMETHYL-4,5-METHYLENEDIOXYAMPHETAMINE

 

SYNTHESIS: A mixture of 102 g POCl3 and 115 g N-methylformanilide was allowed to stand for 0.5 h at room temperature during which time it turned a deep claret color. To this there was added 45 g 3,4-methylenedioxytoluene and the mixture was held on the steam bath for 3 h. It was then added to 3 L H2O. Stirring was continued until the oil which had separated had become quite firm. This was removed by filtration to give a greenish, somewhat gummy, crystalline solid, which was finely ground under 40 mL MeOH and again filtered giving, when air dried, 25 g of an almost white solid. Recrystallization of a small sample from methylcyclopentane gave ivory-colored glistening crystals of 2-methyl-4,5-methylenedioxybenzaldehyde with a mp of 88.5-89.5 deg C. In the infra-red, the carbonyl was identical to that of the starting piperonal (1690 cm-1) but the fingerprint was different and unique, with bands at 868, 929, 1040 and 1052 cm-1.

 

A solution of 23 g 2-methyl-4,5-methylenedioxybenzaldehyde in 150 mL nitroethane was treated with 2.0 g anhydrous ammonium acetate and heated on the steam bath for 9 h. The excess solvent was removed under vacuum to give a dark yellow oil which was dissolved in 40 mL hot MeOH and allowed to crystallize. The solids were removed by filtration, washed modestly with MeOH and air dried, to give 21.2 g of 1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene as beautiful yellow crystals with a mp of 116-118 deg C. Recrystallization of an analytical sample from MeOH gave lustrous bright yellow crystals with a mp of 120-121 deg C. Anal. (C11H11NO4) C,H,N.

 

A suspension of 54 g electrolytic elemental iron in 240 g glacial acetic acid was warmed on the steam bath, with frequent stirring. When the reaction between them started, there was added, a portion at a time, a solution of 18.2 g 1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene in 125 mL warm acetic acid. The orange color of the nitrostyrene solution became quite reddish, white solids of iron acetate appeared, and a dark tomato-colored crust formed which was continuously broken back into the reaction mixture. Heating was continued for 1.5 h, and then all was poured into 2 L H2O. All the insolubles were removed by filtration, and these were washed well with CH2Cl2. The filtrate and washes were combined, the phases separated, and the aqueous phase extracted with 2x100 mL additional CH2Cl2. The combined organics were washed with 5% NaOH, and the solvent removed under vacuum. The residue weighed 15.9 g, and was distilled at 90-110 deg C at 0.4 mm/Hg to give 13.9 g of 2-methyl-4,5-methylenedioxyphenylacetone that spontaneously crystallized. A small sample from methylcyclopentane had a mp of 52-53 deg C, another from hexane a mp of 53-54 deg C, and another from MeOH a mp of 54-55 deg C. Anal. (C11H12O3) H; C calcd, 68.73; found 67.87, 67.84.

 

To a stirred solution of 30 g methylamine hydrochloride in 200 mL warm MeOH there was added 13.5 g 2-methyl-4,5-methylenedioxyphenylacetone followed, after returning to room temperature, by 7 g sodium cyanoborohydride. There was added HCl as needed to maintain the pH at approximately orange on external damp universal pH paper. After a few days, the reaction ceased generating base, and all was poured into 2 L dilute H2SO4 (caution, HCN evolved). This was washed with 3x75 mL CH2Cl2, made basic with 25% NaOH, and the resulting mixture extracted with 3x100 CH2Cl2. The pooled extracts were stripped of solvent under vacuum and the residue, 15 g of a pale amber oil, was distilled at 95-110 deg C at 0.4 mm/Hg. There was obtained 12.3 g of a white oil that was dissolved in 60 mL IPA, neutralized with approximately 5.5 mL concentrated HCl, and crystals of the salt formed spontaneously. These were loosened with the addition of another 10 mL IPA, and then all was diluted by the addition of an equal volume of anhydrous Et2O. The white crystals were separated by filtration, Et2O washed, and air dried to give 14.1 g of 2,N-dimethyl-4,5-methylenedioxyamphetamine hydrochloride (MADAM-6) as a brilliant white powder with a mp of 206-207 deg C. Anal. (C12H18ClNO2) C,H.

 

DOSAGE: greater than 280 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 180 mg) There is a hint of good things there, but nothing more than a hint. At four hours, there is no longer even a hint.

 

(with 280 mg) I took 150 milligrams, waited an hour for results, which was niente, nada, nothing. Took supplements of 65 milligrams twice, an hour apart. No effect. Yes, we giveth up.

 

EXTENSIONS AND COMMENTARY: The structure of MADAM-6 was designed to be that of MDMA, with a methyl group attached at what should be a reasonably indifferent position. In fact, that is the genesis of the name. MDMA has been called ADAM, and with a methyl group in the 6-position, MADAM-6 is quite understandable. And the other ortho-position is, using this nomenclature, the 2-position, and with a methyl group there, one would have MADAM-2. I should make a small apology for the choice of numbers. MDMA is a 3,4-methylenedioxy compound, and the least ambiguous numbering scheme would be to lock the methylenedioxy group inescapably at the 3,4-place, letting the other ring position numbers fall where they may. The rules of chemistry ask that if something is really a 3,4,6-orientation it should be renumbered as a 2,4,5-orientation. Let's quietly ignore that request here.

 

How fascinating it is, that a small methyl group, something that is little more than one more minor bump on the surface of a molecule that is lumpy and bumpy anyway, can so effectively change the action of a compound. A big activity change from a small structure change usually implies that the bump is at a vital point, such as a target of metabolism or a point of critical fit in some receptor site. And since 6-MADAM can be looked upon as 6-bump-MDMA, and since it is at least 3x less potent than MDMA, the implication is that the action of MDMA requires some unbumpiness at this position for its particular action. There are suggestions that the body may want to put a hydroxyl group right there (a 6-hydroxy-dopamine act), and it couldn't if there was a methyl group right there. The isopropylamine side chain may want a certain degree of swing-around freedom, and this would be restricted by a methyl bump right next to it. And there are all kinds of other speculations possible as to why that position should be open.

 

Anyway, MADAM-6 is not active. And the equally intriguing positional isomer, the easily made MADAM-2, will certainly contribute to these speculations. A quiz for the reader! Will 2,N-dimethyl-3,4-methylenedioxyamphetamine (MADAM-2) be: (1) Of much reduced activity, akin to MADAM-6, or (2) Of potency and action similar to that of MDMA, or (3) Something unexpected and unanticipated? I know only one way of finding out. Make the Schiffs' base between piperonal and cyclohexylamine, treat this with butyl lithium in hexane with some TMEDA present, add some N-methylformanilide, convert the formed benzaldehyde to a nitrostyrene with nitroethane, reduce this with elemental iron to the phenylacetone, reduce this in the presence of methylamine with sodium cyanoborohydride, then taste the result.      

 

 

 

#99 MAL; METHALLYLESCALINE;

⇐ Предыдущая12345678910Следующая ⇒

Поделиться: