METHYLENEDIOXY-N-(2-HYDROXYETHYL)AMPHETAMINE

 

SYNTHESIS: To a well stirred solution of 25 g ethanolamine hydrochloride in 75 mL MeOH there was added 4.45 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.1 g sodium cyanoborohydride. Concentrated HCl in MeOH was added as required, over the next few days, to maintain the pH at about 6 as determined with external, dampened universal pH paper. The reaction mixture was added to 300 mL H2O and made strongly acidic with an excess of HCl. After washing with 3x100 mL CH2Cl2 the aqueous phase was made basic with 25% NaOH, and extracted with 4x100 mL CH2Cl2. Removal of the solvent under vacuum yielded 3.5 g of a viscous off-white oil that was distilled at 160 deg C at 1.3 mm/Hg to give 2.0 g of a white viscous oil. The pot residue remained fluid, but was discarded. This distillate was dissolved in 8.0 mL IPA to give, eventually, a clear solution. This was neutralized with concentrated HCl and diluted with 100 mL anhydrous Et2O. The loose white crystals of 3,4-methylenedioxy-N-(2-hydroxy-ethyl)amphetamine hydrochloride (MDHOET) that formed were removed by filtration, washed with Et2O, and air dried. These weighed 2.3 g, and had a mp of 147-148 deg C. Anal. (C12H18ClNO3) N.

 

DOSAGE: greater than 50 mg.

 

DURATION: unknown.

 

EXTENSIONS AND COMMENTARY: Most compounds with bare, exposed polar groups like hydroxyls are not centrally active, as they simply do not have any way of getting into the brain. MDHOET is certainly not very active, if it is active at all.

 

There was one report that at very high doses some central effects were indeed observed. With quantities in the several hundreds of milligrams a picture emerged of changes in perceived color and depth perception, but without euphoria. It was said to resemble a mild dose of ketamine. This is an interesting comment, in that ketamine has found its major medical use as an anesthetic, and MDHOET is among the most effective of all the N-substituted MDA derivatives assayed in several animal analgesia models.        

 

#108 MDIP; N-ISOPROPYL-MDA;

(3,4-METHYLENEDIOXY-N-ISOPROPYLAMPHETAMINE)

 

SYNTHESIS: To a well stirred and cooled solution of 14.75 g isopropylamine in 100 mL MeOH there was added 4.45 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by a 1:1 mixture of concentrated HCL and MeOH, sufficient to bring the pH to about 4. This was followed with 1.1 g sodium cyanoborohydride, and stirring was continued overnight. When the pH increased to over 6 there was added an additional 0.5 g of the borohydride, and additional methanolic HCl was added as needed to maintain the pH there. When the pH became stable, the reaction mixture was brought soundly acid with the addition of yet additional HCl, and all solvents were removed under vacuum. The residues were added to 500 mL H2O and washed with 3x100 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 4x100 mL CH2Cl2. Removal of the solvent under vacuum yielded 2.8 g of an amber liquid that was distilled at 95-110 deg C at 0.3 mm/Hg. There was obtained about 2 mL of a white oil that was dissolved in 10 mL of IPA, neutralized with about 20 drops of concentrated HCl producing spontaneous crystals. These were diluted with some 40 mL of anhydrous Et2O, removed by filtration, washed with Et2O, and then air dried. There was obtained 1.6 g of 3,4-methylenedioxy-N-isopropylamphetamine hydrochloride (MDIP) with a mp of 186-186.5 deg C with prior sintering at 185 deg C. Anal. (C13H20ClNO2) N.

 

DOSAGE: greater than 250 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 250 mg) At 35 minutes there was an

extremely slight head disturbance which increased over the next few

minutes. I would have missed it if there had been any sensory input

at all. At the one hour point there was a slight physical malaise,

but no 'open window' of any kind, either like MDMA or like LSD. At

the most, this was a threshold, and in another half hour, I was

completely baseline.

 

EXTENSIONS AND COMMENTARY: The structure of MDIP can be looked at as

exactly that of MDE but with an additional methyl group (one carbon)

hanging off the ethyl that is on the nitrogen. And with that slight

additional weight, the activity has disappeared. On those occasions

where research has shown a compound to be inactive, there has been

some study made that could be called a "primer" experiment. Why not

take advantage of the fact that an "inactive" compound might well be

sitting in some receptor site in the brain without doing anything?

Might its presence, wherever it might be, have some effect if only a

person were to explore it in the correct way? Might it augment or

interfere with the action of another compound? Many experiments of

this kind have been performed, geared to milk additional information

out of a new trial of a new material.

 

Here is an example of a primer experiment that involved MDIP. Some

five hours following an inactive trial with 120 milligrams of MDIP

(maybe a slight disturbance at one hour, nothing at two hours) a

calibration dose of 80 milligrams of MDMA was taken. The effects of

the MDMA were noted at the 33 minute point, and an honest plus one was

achieved at one hour. At this point a second 80 milligrams was added

to the inventory that was already on board, and the general

intoxication and the eye effects that followed were completely

explained by the MDMA alone. It was obvious that the two drugs did

not see one-another.

 

Sometimes an experiment can involve the assay of an unknown material at the supplement time of an active drug. This has been called "piggybacking." Here is an example. At the five hour point of an experiment with 140 milligrams of MDE (this had been a light experience, a plus one which had not laster more than two hours) a dosage of 200 milligrams of MDIP rekindled a +1 experience, a pleasant intoxication of the MDE sort, but one that was quite invested with tremor and some feelings of eye-popping. It was almost as if the physical toxic effects outweighed the mental virtues. Imagine an iceberg, with the bulk of its mass underwater. The MDE had had its own modest effects, and had submerged into invisibility, and the response to a little bit of an otherwise inactive MDIP was to refloat a bit of the otherwise unseeable MDE.      

 

#109 MDMA; MDM; ADAM; ECSTASY; 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE

 

SYNTHESIS: (from MDA) A solution of 6.55 g of 3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8 mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap until no further H2O was generated (about 20 h was sufficient, and 1.4 mL H2O was collected). Removal of the solvent gave an 8.8 g of an amber oil which was dissolved in 100 mL CH2Cl2, washed first with dilute HCl, then with dilute NaOH, and finally once again with dilute acid. The solvent was removed under vacuum giving 7.7 g of an amber oil that, on standing, formed crystals of N-formyl-3,4-methylenedioxyamphetamine. An alternate process for the synthesis of this amide involved holding at reflux for 16 h a solution of 10 g of MDA as the free base in 20 mL fresh ethyl formate. Removal of the volatiles yielded an oil that set up to white crystals, weighing 7.8 g.

 

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL anhydrous THF was added dropwise to a well stirred and refluxing solution of 7.4 g LAH in 600 mL anhydrous THF under an inert atmosphere. The reaction mixture was held at reflux for 4 days. After being brought to room temperature, the excess hydride was destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4 mL of 15% NaOH and then another 22 mL H2O. The solids were removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in 200 mL CH2Cl2. This solution was extracted with 3x100 mL dilute HCl, and these extracts pooled and made basic with 25% NaOH. Extraction with 3x75 mL CH2Cl2 removed the product, and the pooled extracts were stripped of solvent under vacuum. There was obtained 6.5 g of a nearly white residue which was distilled at 100-110 deg C at 0.4 mm/Hg to give 5.0 g of a colorless oil. This was dissolved in 25 mL IPA, neutralized with concentrated HCl, followed by the addition of sufficient anhydrous Et2O to produce a lasting turbidity. On continued stirring, there was the deposition of fine white crystals of 3,4-methylenedioxy-N-methylamphetamine hydrochloride (MDMA) which were removed by filtration, washed with Et2O, and air dried, giving a final weight of 4.8 g.

 

(from 3,4-methylenedioxyphenylacetone) This key intermediate to all of the MD-series can be made from either isosafrole, or from piperonal via 1-(3,4-methylenedioxyphenyl)-2-nitropropene. To a well stirred solution of 34 g of 30% hydrogen peroxide in 150 g 80% formic acid there was added, dropwise, a solution of 32.4 g isosafrole in 120 mL acetone at a rate that kept the reaction mixture from exceeding 40 deg C. This required a bit over 1 h, and external cooling was used as necessary. Stirring was continued for 16 h, and care was taken that the slow exothermic reaction did not cause excess heating. An external bath with running water worked well. During this time the solution progressed from an orange color to a deep red. All volatile components were removed under vacuum which yielded some 60 g of a very deep red residue. This was dissolved in 60 mL of MeOH, treated with 360 mL of 15% H2SO4, and heated for 3 h on the steam bath. After cooling, the reaction mixture was extracted with 3x75 mL Et2O, the pooled extracts washed first with H2O and then with dilute NaOH, and the solvent removed under vacuum The residue was distilled (at 2.0 mm/108-112 deg C, or at about 160 deg C at the water pump) to provide 20.6 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil. The oxime (from hydroxylamine) had a mp of 85-88 deg C. The semicarbazone had a mp of 162-163 deg C.

 

An alternate synthesis of 3,4-methylenedioxyphenylacetone starts originally from piperonal. A suspension of 32 g electrolytic iron in 140 mL glacial acetic acid was gradually warmed on the steam bath. When quite hot but not yet with any white salts apparent, there was added, a bit at a time, a solution of 10.0 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in 75 mL acetic acid (see the synthesis of MDA for the preparation of this nitrostyrene intermediate from piperonal and nitroethane). This addition was conducted at a rate that permitted a vigorous reaction free from excessive frothing. The orange color of the reaction mixture became very reddish with the formation of white salts and a dark crust. After the addition was complete, the heating was continued for an additional 1.5 h during which time the body of the reaction mixture became quite white with the product appeared as a black oil climbing the sides of the beaker. This mixture was added to 2 L H2O, extracted with 3x100 mL CH2Cl2, and the pooled extracts washed with several portions of dilute NaOH. After the removal of the solvent under vacuum, the residue was distilled at reduced pressure (see above) to provide 8.0 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil.

 

To 40 g of thin aluminum foil cut in 1 inch squares (in a 2 L wide mouth Erlenmeyer flask) there was added 1400 mL H2O containing 1 g mercuric chloride. Amalgamation was allowed to proceed until there was the evolution of fine bubbles, the formation of a light grey precipitate, and the appearance of occasional silvery spots on the surface of the aluminum. This takes between 15 and 30 min depending on the freshness of the surfaces, the temperature of the H2O, and the thickness of the aluminum foil. (Aluminum foil thickness varies from country to country.) The H2O was removed by decantation, and the aluminum was washed with 2x1400 mL of fresh H2O. The residual H2O from the final washing was removed as thoroughly as possible by shaking, and there was added, in succession and with swirling, 60 g methylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145 mL 25% NaOH, 53 g 3,4-methylenedioxyphenylacetone, and finally 350 mL IPA. If the available form of methylamine is the aqueous solution of the free base, the following sequence can be substituted: add, in succession, 76 mL 40% aqueous methylamine, 180 mL IPA, a suspension of 50 g NaCl in 140 mL H2O that contains 25 mL 25% NaOH, 53 g 3,4-methylenedioxyphenylacetone, and finally 350 mL IPA. The exothermic reaction was kept below 60 deg C with occasional immersion into cold water and, when it was thermally stable, it was allowed to stand until it had returned to room temperature with all the insolubles settled to the bottom as a grey sludge. The clear yellow overhead was decanted and the sludge removed by filtration and washed with MeOH. The combined decantation, mother liquors and washes, were stripped of solvent under vacuum, the residue suspended in 2400 ml of H2O, and sufficient HCl added to make the phase distinctly acidic. This was then washed with 3x75 mL CH2Cl2, made basic with 25% NaOH, and extracted with 3x100 mL of CH2Cl2. After removal of the solvent from the combined extracts, there remained 55 g of an amber oil which was distilled at 100-110 deg C at 0.4 mm/Hg producing 41 g of an off-white liquid. This was dissolved in 200 mL IPA, neutralized with about 17 mL of concentrated HCl, and then treated with 400 mL anhydrous Et2O. After filtering off the white crystals, washing with an IPA/Et2O mixture, (2:1), with Et2O, and final air drying, there was obtained 42.0 g of 3,4-methylenedioxy-N-methylamphetamine (MDMA) as a fine white crystal. The actual form that the final salt takes depends upon the temperature and concentration at the moment of the initial crystallization. It can be anhydrous, or it can be any of several hydrated forms. Only the anhydrous form has a sharp mp; the published reports describe all possible one degree melting point values over the range from 148-153 deg C. The variously hydrated polymorphs have distinct infrared spectra, but have broad mps that depend on the rate of heating.

 

DOSAGE: 80 - 150 mg.

 

DURATION: 4 - 6 h.

 

QUALITATIVE COMMENTS: (with 100 mg) MDMA intrigued me because everyone I asked, who had used it, answered the question, 'What's it like?' in the same way: 'I don't know.' 'What happened?' 'Nothing.' And now I understand those answers. I too think nothing happened. But something seemed changed. Before the 'window' opened completely, I had some somatic effects, a tingling sensation in the fingers and temples Q a pleasant sensation, not distracting. However, just after that there was a slight nausea and dizziness similar to a little too much alcohol. All these details disappeared as I walked outside. My mood was light, happy, but with an underlying conviction that something significant was about to happen. There was a change in perspective both in the near visual field and in the distance. My usually poor vision was sharpened. I saw details in the distance that I could not normally see. After the peak experience had passed, my major state was one of deep relaxation. I felt that I could talk about deep or personal subjects with special clarity, and I experienced some of the feeling one has after the second martini, that one is discoursing brilliantly and with particularly acute analytical powers.

 

(with 100 mg) Beforehand, I was aware of a dull, uncaring tiredness that might have reflected too little sleep, and I took a modest level of MDMA to see if it might serve me as a stimulant. I napped for a half hour or so, and woke up definitely not improved. The feeling of insufficient energy and lack of spark that I'd felt before had become something quite strong, and might be characterized as a firm feeling of negativity about everything that had to be done and everything I had been looking forward to. So I set about my several tasks with no pleasure or enjoyment and I hummed a little tune to myself during these activities which had words that went: 'I shouldn't have done that, oh yes, I shouldn't have done that, oh no, I shouldn't have done that; it was a mistake.' Then I would start over again from the beginning. I was stuck in a gray space for quite a while, and there was nothing to do but keep doing what I had to do. After about 6 hours, I could see the whole mental state disintegrating and my pleasant feelings were coming back. But so was my plain, ornery tiredness. MDMA does not work like Dexedrine.

 

(with 120 mg) I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great, or believed this to be possible. The cleanliness, clarity, and marvelous feeling of solid inner strength continued throughout the rest of the day, and evening, and through the next day. I am overcome by the profundity of the experience, and how much more powerful it was than previous experiences, for no apparent reason, other than a continually improving state of being. All the next day I felt like 'a citizen of the universe' rather than a citizen of the planet, completely disconnecting time and flowing easily from one activity to the next.

 

(with 120 mg) As the material came on I felt that I was being enveloped, and my attention had to be directed to it. I became quite fearful, and my face felt cold and ashen. I felt that I wanted to go back, but I knew there was no turning back. Then the fear started to leave me, and I could try taking little baby steps, like taking first steps after being reborn. The woodpile is so beautiful, about all the joy and beauty that I can stand. I am afraid to turn around and face the mountains, for fear they will overpower me. But I did look, and I am astounded. Everyone must get to experience a profound state like this. I feel totally peaceful. I have lived all my life to get here, and I feel I have come home. I am complete.

 

(with 100 mg of the "R" isomer) There were the slightest of effects noted at about an hour (a couple of paresthetic twinges) and then nothing at all.

 

(with 160 mg of the "R" isomer) A disturbance of baseline at about forty minutes and this lasts for about another hour. Everything is clear by the third hour.

 

(with 200 mg of the "R" isomer) A progression from an alert at thirty minutes to a soft and light intoxication that did not persist. This was a modest +, and I was at baseline in another hour.

 

(with 60 mg of the "S" isomer) The effects began developing in a smooth, friendly way at about a half-hour. My handwriting is OK but I am writing faster than usual. At the one hour point, I am quite certain that I could not drive, time is slowing down a bit, but I am mentally very active. My pupils are considerably dilated. The dropping is evident at two hours, and complete by the third hour. All afternoon I am peaceful and relaxed, but clear and alert, with no trace of physical residue at all. A very successful ++.

 

(with 100 mg of the "S" isomer) I feel the onset is slower than with the racemate. Physically, I am excited, and my pulse and blood pressure are quite elevated. This does not have the 'fire' of the racemate, nor the rush of the development in getting to the plateau.

 

(with 120 mg of the "S" isomer) A rapid development, and both writing and typing are impossible before the end of the first hour. Lying down with eyes closed eliminates all effects; the visual process is needed for any awareness of the drug's effects. Some teeth clenching, but no nystagmus. Excellent sleep in the evening.

 

EXTENSIONS AND COMMENTARY: In clinical use, largely in psychotherapeutic sessions of which there were many in the early years of MDMA study, it became a common procedure to provide a supplemental dosage of the drug at about the one and a half hour point of the session. This supplement, characteristically 40 milligrams following an initial 120 milligrams, would extend the expected effects for about an additional hour, with only a modest exacerbation of the usual physical side-effects, namely, teeth clenching and eye twitching. A second supplement (as, for instance, a second 40 milligrams at the two and a half hour point) was rarely felt to be warranted. There are, more often than not, reports of tiredness and lethargy on the day following the use of MDMA, and this factor should be considered in the planning of clinical sessions.

 

With MDMA, the usual assignments of activity to optical isomers is reversed from all of the known psychedelic drugs. The more potent isomer is the "S" isomer, which is the more potent form of amphetamine and methamphetamine. This was one of the first clear distinctions that was apparent between MDMA and the structurally related psychedelics (where the "R" isomers are the more active). Tolerance studies also support differences in mechanisms of action. In one study, MDMA was consumed at 9:00 AM each day for almost a week (120 milligrams the first day and 160 milligrams each subsequent day) and by the fifth day there were no effects from the drug except for some mydriasis. And even this appeared to be lost on the sixth day. At this point of total tolerance, there was consumed (on day #7, at 9:00 AM) 120 milligrams of MDA and the response to it was substantially normal with proper chronology, teeth clench, and at most only a slight decrease in mental change. A complete holiday from any drug for another 6 days led to the reversal of this tolerance, in that 120 milligrams of MDMA had substantially the full expected effects. The fact that MDMA and MDA are not cross-tolerant strengthens the argument that they act in different ways, and at different sites in the brain.

 

A wide popularization of the social use of MDMA occurred in 1984-1985 and, with the reported observation of serotonin nerve changes in animal models resulting from the administration of the structurally similar drug MDA, an administrative move was launched to place it under legal control. The placement of MDMA into the most restrictive category of the Federal Controlled Substances Act has effectively removed it from the area of clinical experimentation and human research. The medical potential of this material will probably have to be developed through studies overseas.

 

A word of caution is in order concerning the intermediate 3,4-methylene-dioxyphenylacetone, which has also been called piperonylacetone. A devilish ambiguity appeared in the commercial market for this compound, centered about its name. The controversy focused on the meaning of the prefix, piperonyl, which has two separate chemical definitions. Let me try to explain this fascinating chaos in non-chemical terms. Piperonyl is a term that has been used for a two-ring system (the methylenedioxyphenyl group) either without, or with, an extra carbon atom sticking off of the side of it. Thus, piperonylacetone can be piperonyl (the two-ring thing without the extra carbon atom attached) plus acetone (a three carbon chain thing); the total number of carbons sticking out, three. Or, piperonylacetone can be piperonyl (the two-ring thing but with the extra carbon atom attached) plus acetone (a three carbon chain thing); the total number of carbons sticking out, four.

 

Does this make sense?

 

The three carbon sticking out job gives rise to MDA and to MDMA and to many homologues that are interesting materials discussed at length in these Book II comments. This is the usual item of commerce, available from both domestic and foreign suppliers. But the four-carbon sticking out job will produce totally weird stuff without any apparent relationship to psychedelics, psychoactives or psychotropics whatsoever. I know of one chemical supply house which supplied the weird compound, and they never did acknowledge their unusual use of the term piperonyl. There is a simple difference of properties which might be of value. The three carbon (correct) ketone is an oil with a sassafras smell that is always yellow colored. The four carbon (incorrect) ketone has a weak terpene smell and is white and crystalline. There should be no difficulties in distinguishing these two compounds. But unprincipled charlatans can always add mineral oil and butter yellow to otherwise white solids to make them into yellow oils. Caveat emptor.        

 

 

#110 MDMC; EDMA; 3,4-ETHYLENEDIOXY-N-METHYLAMPHETAMINE

 

SYNTHESIS: To a solution of 27.6 g protocatechualdehyde (3,4-dihydroxybenzaldehyde) in 250 mL acetone there was added 57 g finely powdered anhydrous K2CO3 and 43 g 1,2-dibromoethane. The mixture was held at reflux for 16 h, and then the acetone removed by evaporation. The remaining tar-like goo was distributed between equal volumes of H2O and CH2Cl2, and the phases separated by centrifugation. The organic phase was washed with 2x50 mL 5% NaOH, and the solvent removed under vacuum. The residue (22.0 g with the smell of the starting halide) was distilled to give a fraction that boiled at 110 deg C at 0.25 mm/Hg to yield 3,4-ethylenedioxybenzaldehyde (1,4-benzodioxane-6-carboxaldehyde) as a white oil weighing 6.88 g. This spontaneously crystallized to give white solids that melted at 50-51 deg C.

 

A solution of 6.64 g 3,4-ethylenedioxybenzaldehyde in 40 mL nitroethane was treated with 0.26 g anhydrous ammonium acetate and held at reflux for 3 days. TLC analysis showed that there was much aldehyde remaining unreacted, so an additional 0.7 g ammonium acetate was added, and the mixture held at reflux for an additional 6 h. The excess nitroethane was removed under vacuum. The residue was dissolved in 30 mL hot MeOH which, with patience and slow cooling, finally deposited a heavy yellow-gold powder. This product 1-(3,4-ethylenedioxyphenyl)-2-nitro-propene melted at 95-96 deg C and weighed 6.03 g when air dried to constant weight. Recrystallization from either MeOH or EtOAc gave the product as a yellow solid, but without any improvement in mp.

 

A solution of 4.0 g of 1-(3,4-ethylenedioxyphenyl)-2-nitropropene was made in 30 mL warm acetic acid. This was added to a suspension of 16 g elemental electrolytic iron in 75 mL acetic acid. The mixture was heated on the steam bath, and an exothermic reaction set in at about 70 deg C. Heating was continued and the reaction allowed to proceed until the mass was a thick gray color and a dirty scum had been formed on the surface. After about 2 h, the entire mix was poured into 2 L H2O and filtered free of a little residual unreacted iron which was washed with CH2Cl2. The filtrate and washes were extracted with 3x100 mL CH2Cl2 and the pooled organic extracts washed with 2x50 mL 5% NaOH. Removal of the solvent gave 3.38 g of an amber oil which was distilled. The product 1-(3,4-ethylenedioxyphenyl)-2-propanone distilled as a white oil, at 105-110 deg C at 0.2 mm/Hg. It weighed 2.74 g.

 

To 2.0 g. of 1 inch squares of light-weight aluminum foil there was added a solution of 50 mg mercuric chloride in 70 mL water. After standing at room temperature for 30 min, the H2O was drained away, and the amalgamated aluminum washed twice with H2O, and shaken as dry as possible. There was then added, promptly and in immediate sequence, a solution of 3 g methylamine hydrochloride in 3 mL H2O, 9 mL IPA, 7.25 mL 25% NaOH, 2.70 g of 1-(3,4-ethylenedioxyphenyl)-2-propanone, and 18 mL IPA. The mixture was heated on the steam bath until an exothermic reaction set in, and then it was continuously swirled as the reaction proceeded. When the aluminum was consumed, there was a colorless gray sludge, and this was filtered and washed with 2x10 mL MeOH. The combined mother liquors and washes were stripped of solvent under vacuum. The two phase residue was suspended in 400 mL H2O containing sufficient H2SO4 to make the resulting water solution acidic to pH paper. This was washed with 3x50 mL CH2Cl2, made basic with 25% NaOH, and the product extracted with 3x50 mL CH2Cl2. The resulting 3.01 g slightly amber residue oil was distilled at 110-120 deg C at 0.25 mm/Hg to give 2.53 g of a white oil, which did not appear to absorb carbon dioxide. This was dissolved in 12 mL IPA, neutralized with 1 mL concentrated HCl and diluted with anhydrous Et2O to the point of initial turbidity. There separated white crystals of 3,4-ethylenedioxy-N-methylamphetamine hydrochloride (MDMC) which weighed, when air dried to constant weight, 2.53 g.

 

DOSAGE: 200 or more mg.

 

DURATION: 3 - 5 h.

 

QUALITATIVE COMMENTS: (with 150 mg) A flood of paresthesia at the 30 minute point, and then nothing. There was the development of a plus one-and-a half effect over the next hour with the tendency to drift into a dozing state with hypnogogic imagery. There were colored letters in the periphery of my visual field. There was no appetite loss nor was there any blood pressure rise. And no eye jiggle or teeth clenching. I was out of the experience in 4 to 5 hours. A repeat of this level a few days later gave a bare possible threshold with no other effects.

 

(with 200 mg) There was something unmistakable at 45 minutes, with hints of nystagmus. Possibly MDMA-like, with no indicators of anything psychedelic. Subtle return to baseline, and there were no after-effects.

 

(with 250 mg) Alert at 40 minutes, and to a clear ++ at an hour. Slight something in the eye muscles. Dropping thirty minutes later, and baseline at three hours.

 

(with 250 mg) I am at a bare threshold at best.

 

EXTENSIONS AND COMMENTARY: What a strange and completely unsatisfactory compound! In the original run-up from low levels to increasing higher levels, there never was a dosage that was a minus, that had no effect. At every level, something was thought to be there, usually at a level of a single plus or thereabouts. But with different people, different responses. There is no way of guessing what an active level might be, or how consistent that level might be between different people, or for that matter what the responses are that might be expected at that level.

 

This was yet one more effort to find an MDMA-like substitute by the miniscule manipulation of the MDMA molecule. Perhaps a small molecular change might leave the particular magic of the MDMA action alone, but eliminate the serotonin neuron problem in test animals. Maybe the serotonin neuron change is essential for MDMA to have the action it has. Who can tell?

 

The original name that this compound got, during the several explorations of MDMA analogues, was based on the nickname for MDMA which was Adam. HAD'EM was mentioned with the hydroxy compound, MADAM with the 6-methyl homologue, and FLADAM with the 6-fluoro analogue. This compound got the sobriquet MACADAM from that horrible black gooey mess generated at the aldehyde stage. This was shortened to RCS and eventually the RCS was added to the MDMA parent name. Thus, MDMC. It doesn't really make sense; EDMA is more reasonable. But then there is no reason why MDMC should make sense.      

 

 

 

#111 MDMEO; N-METHOXY-MDA; 3,4-METHYLENEDIOXY-N-METHYOXYAMPHETAMINE

 

SYNTHESIS: To a solution of 20.9 g methoxyamine hydrochloride in 75 mL MeOH (a strongly acidic solution) there was added 4.45 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.10 g sodium cyanoborohydride. There was the immediate formation of a solid phase, and the evolution of what appeared to be hydrogen cyanide. To this there were added about 4 mL 5% NaOH which brought the pH to the vicinity of 3 or 4. Another 1.0 g of sodium cyanoborohydride was added (no gas evolution this time) and stirring was continued at ambient temperature for 6 days. All was added to 500 mL H2O, acidified with 10 mL HCl, and extraction with 3x100 mL CH2Cl2 removed almost all the color. The aqueous phase was made basic with 25% NaOH, and extracted with 4x100 mL CH2Cl2. Evaporation of the solvent from these extracts yielded 1.8 g of a pale yellow oil which, on distillation at 90-95 deg C at 0.5 mm/Hg, gave a 1.6 g fraction of an absolutely white, viscous, clear oil. This was dissolved in 8 mL IPA and neutralized with concentrated HCl. The product was an exceptionally weak base, and appropriate end points must be respected on the external pH paper (yellow to red, rather than purple to orange). Anhydrous Et2O was added to the point of turbidity, and as soon as crystallization had actually started, more Et2O was added with stirring, for a net total of 200 mL. After a couple of h standing, the fine white crystalline 3,4-methylenedioxy-N-methoxyamphetamine hydrochloride (MDMEO) was removed by filtration, Et2O washed, and air dried to constant weight. There was obtained 1.7 g of a product with a mp of 143-146 deg C. The proton NMR was excellent with the N-methoxyl group a sharp singlet at 4.06 ppm. Anal. (C11H16ClNO3) N.

 

DOSAGE: greater than 180 mgs.

 

DURATION: unknown

 

EXTENSIONS AND COMMENTARY: Why the interest in the N-methoxy analogue of MDA? There are several reasons. One, this is an isostere of MDE and it would be interesting to see if it might serve as a primer to the promotion of the effectiveness of other drugs (see primer discussion under MDPR). In one experiment, wherein a 60 microgram dosage of LSD was used an hour and a half after a 180 milligram load of MDMEO, there was no augmentation of effects. Thus, it would appear not to be a primer. Another reason for interest was that the material, although having an extremely similar overall structure to most of the active MD-series compounds, is very much a weaker base. And MDOH, which is also a very much weaker base than MDA, still shows the action and potency of MDA. And, as this compound appears to be inactive, base strength is not a sole predictor of activity.

 

The ultimate reason for making MDMEO was, of course, that it could be made. That reason is totally sufficient all by itself.     

 

#112 MDMEOET; N-METHOXYETHYL-MDA;

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