Книга I: история любви 18
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| #22 2C-C; 2,5-DIMETHOXY-4-CHLOROPHENETHYLAMINE SYNTHESIS: (from 2C-H) The free base of 2,5-dimethoxyphenethylamine was generated from its salt (see recipe for 2C-H for the preparation of this compound) by treating a solution of 16.2 g of the hydrochloride salt in 300 mL H2O with aqueous NaOH, extraction with 3x75 mL CH2Cl2, and removal of the solvent from the pooled extracts under vacuum. The colorless residue was dissolved in 75 mL glacial acetic acid (the solids that initially formed redissolved completely) and this was cooled to 0 deg C with an external ice bath. With vigorous stirring, there was added 4.0 mL of liquid chlorine, a little bit at a time with a Pasteur pipette. The theoretical volume was 3.4 mL, but some was lost in pipetting, some on contact with the 0 deg C acetic acid, and some was lost by chlorination of the acetic acid. The reaction turned a dark amber color, was allowed to stir for an additional 10 min, then quenched with 400 mL H2O. This was washed with 3x100 mL CH2Cl2 (which removed some of the color) then brought to neutrality with dilute aqueous NaOH and treated with a small amount of sodium dithionite which discharged most of the color (from deep brown to pale yellow). The reaction was made strongly basic with aqueous KOH, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed once with H2O and the solvent was removed under vacuum leaving about 10 mL of a deep amber oil as residue. This was dissolved in 75 mL IPA and neutralized with concentrated HCl which allowed spontaneous crystallization. These crystals were removed by filtration, washed with an additional 20 mL IPA, and air-dried to constant weight. There was thus obtained 4.2 g 2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) with a mp of 218-221 deg C. Recrystallization from IPA increased this to 220-222 deg C. The position of chlorination on the aromatic ring was verified by the presence of two para-protons in the NMR, at 7.12 and 7.20 ppm from external TMS, in a D2O solution of the hydrochloride salt. Synthesis from 2C-B. To a solution of 7.24 g 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 4.5 g phthalic anhydride in 100 mL anhydrous DMF there was added molecular sieves. After 16 h reflux, the reaction mixture was cooled and the sieves removed by filtration. The addition of a little CH2Cl2 prompted the deposition of yellow crystals which were recrystallized from EtOH. The resulting 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane weighed 7.57 g and had a mp of 141-142 deg C. Anal. (C18H16BrNO4) C,H,N,Br. A solution of 14.94 g of 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane and 4.5 g cuprous chloride in 300 mL anhydrous DMF was heated for 5 h at reflux. The cooled mixture was poured into 20 mL H2O that contained 13 g hydrated ferric chloride and 3 mL concentrated HCl. The mixture was maintained at about 70 deg C for 20 min, and then extracted with CH2Cl2. After washing the pooled organic extracts with dilute HCl and drying with anhydrous MgSO4, the volatiles were removed under vacuum to provide a solid residue. This was recrystallized from EtOH to provide 12.18 g of 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane as yellow needles that had a mp of 138-140 deg C. Anal. (C18H16ClNO4) C,H,N,Cl. To 60 mL absolute EtOH there was added 12.2 g 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane and 2.9 mL of 100% hydrazine. The solution was held at reflux for 15 min. After cooling, the cyclic hydrazone by-product was removed by filtration, and the alcoholic mother liquors taken to dryness under vacuum. The residue was distilled at 145-155 deg C at 0.05 mm/Hg to give 5.16 g of a clear, colorless oil. This was dissolved in anhydrous Et2O and treated with hydrogen chloride gas, producing 2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) as white crystals with a mp of 220-221 deg C. Anal. (C10H15Cl2NO2) C,H,N. DOSAGE: 20 - 40 mg. DURATION: 4 - 8 h. QUALITATIVE COMMENTS: (with 20 mg) This is longer lived than 2C-B, and there is a longer latency in coming on. It took an hour and a half, or even two hours to get there. It had a slight metallic overtone. (with 24 mg) I was at a moderately high and thoroughly favorable place, for several hours. It seemed to be a very sensual place, but without too much in the way of visual distraction. (with 40 mg) There were a lot of visuals Q something that I had noted at lower levels. There seems to be less stimulation than with 2C-B, and in some ways it is actually sedating. And yet I was up all night. It was like a very intense form of relaxation. EXTENSIONS AND COMMENTARY: Other reports mention usage of up to 50 milligrams which seems to increase yet further the intensity and the duration. I have one report of an intravenous administration of 20 milligrams, and the response was described as overwhelming. The effects peaked at about 5 minutes and lasted for perhaps 15 minutes. The halogens represent a small group of atoms that are unique for a couple of reasons. They are all located in a single column of the periodic table, being monovalent and negative. That means that they can be reasonably stable things when attached to an aromatic nucleus. But, being monovalent, they cannot be modified or extended in any way. Thus, they are kind of a dead end, at least as far as the 2C-X series is considered. The heaviest, iodine, was explored as the phen-ethylamine, as 2C-I, and as the amphetamine as DOI. These are the most potent. The next lighter is bromine, where the phenethylamine is 2C-B and the amphetamine is DOB. These two are a bit less potent, and are by far the most broadly explored of all the halides. Here, in the above recipe, we have the chlorine counterpart, 2C-C. There is also the corresponding amphetamine DOC. These are less potent still, and much less explored. Why? Perhaps because chlorine is a gas and troublesome to handle (bromine is a liquid, and iodine is a solid). The fluorine analogue is yet harder to make, and requires procedures that are indirect, because fluorine (the lightest of all the halides) is not only a gas, but is dangerous to handle and does not react in the usual halogen way. There will be mention made of 2C-F, but DOF is still unexplored. The treatment of the 2C-B phthalimide described above, with cuprous cyanide rather than cuprous chloride, gave rise to the cyano analog which, on hydrolysis with hydrazine, yielded 2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with hot, strong base gave the corresponding acid, 2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of either of these compounds has been made in the human animal, as far as I know. #23 2C-D; LE-25; 2,5-DIMETHOXY-4-METHYLPHENETHYLAMINE SYNTHESIS: Into 1 L H2O that was being stirred magnetically, there was added, in sequence, 62 g toluhydroquinone, 160 mL 25% NaOH, and 126 g dimethyl sulfate. After about 2 h, the reaction mixture was no longer basic, and another 40 mL of the 25% NaOH was added. Even with stirring for a few additional days, the reaction mixture remained basic. It was quenched in 2.5 L H2O, extracted with 3x100 mL CH2Cl2 and the pooled extracts stripped of solvent under vacuum. The remaining 56.4 g of amber oil was distilled at about 70 deg C at 0.5 mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The aqueous residues, on acidification, provided a phenolic fraction that distilled at 75-100 deg C at 0.4 mm/Hg to give 5.8 g of a pale yellow distillate that partially crystallized. These solids (with mp of 54-62 deg C) were removed by filtration, and yielded 3.1 g of a solid which was recrystallized from 50 mL hexane containing 5 mL toluene. This gave 2.53 g of a white crystalline product with a mp of 66-68 deg C. A second recrystallization (from hexane) raised this mp to 71-72 deg C. The literature value given for the mp of 2-methyl-4-methoxyphenol is 70-71 deg C. The literature value given for the mp of the isomeric 3-methyl-4-methoxyphenol is 44-46 deg C. This phenol, on ethylation, gives 2-ethoxy-5-methoxytoluene, which leads directly to the 2-carbon 2CD-5ETO (one of the Tweetios) and the 3-carbon Classic Lady IRIS. A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide was heated for 10 min on the steam bath, and then there was added 30.4 g of 2,5-dimethoxytoluene. Heating was continued for 2.5 h, and the viscous, black, ugly mess was poured into 600 mL of warm H2O and stirred overnight. The resulting rubbery miniature-rabbit-droppings product was removed by filtration and sucked as free of H2O as possible. The 37.2 g of wet product was extracted on the steam-bath with 4x100 mL portions of boiling hexane which, after decantation and cooling, yielded a total of 15.3 g of yellow crystalline product. This, upon recrystallization from 150 mL boiling hexane, gave pale yellow crystals which, when air dried to constant weight, represented 8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde, and had a mp of 83-84 deg C. Anal. (C8H12O3) C,H,N. The Gattermann aldehyde synthesis gave a better yield (60% of theory) but required the use of hydrogen cyanide gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3 g malononitrile in absolute EtOH, treated with a drop of triethylamine, was an orange crystalline product. A sample recrystallized from EtOH gave a mp of 138.5-139 deg C. A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde in 30 g nitromethane was treated with 1.1 g anhydrous ammonium acetate and heated for 50 min on the steam bath. Stripping off the excess nitromethane under vacuum yielded orange crystals which weighed 12.2 g. These were recrystallized from 100 mL IPA providing yellow crystals of 2,5-dimethoxy-4-methyl-beta-nitrostyrene which weighed, when dry, 7.70 g. The mp was 117-118 deg C, and this was increased to 118-119 deg C upon recrystallization from benzene/heptane 1:2. To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under an inert atmosphere, there was added 7.7 g 2,5-dimethoxy-4-methyl-beta-nitrostyrene in 35 mL THF over the course of 0.5 h. This reaction mixture was held at reflux for 24 h, cooled to room temperature, and the excess hydride destroyed with 25 mL IPA. There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The granular gray mass was filtered, and the filter cake washed with 2x50 mL THF. The combined filtrate and washes were stripped of their volatiles under vacuum to give a residue weighing 7.7 g which was distilled at 90-115 deg C at 0.3 mm/Hg to provide 4.90 g of a clear, white oil, which crystallized in the receiver. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl which produced immediate crystals of the salt. These were dispersed with 80 mL anhydrous Et2O, filtered, and washed with Et2O to give, after air drying to constant weight, 4.9 g of fluffy white crystals of 2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D). The mp was 213-214 deg C which was not improved by recrystallization from CH3CN/IPA mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 deg C. The acetamide, from the free base in pyridine treated with acetic anhydride, was a white crystalline solid which, when recrystallized from aqueous MeOH, had a mp of 116-117 deg C. DOSAGE: 20 - 60 mg. DURATION: 4 - 6 h. QUALITATIVE COMMENTS: (with 10 mg) There is something going on, but it is subtle. I find that I can just slightly redirect my attention so that it applies more exactly to what I am doing. I feel that I can learn faster. This is a `smart' pill! (with 20 mg) Butterflies in stomach whole time. OK. This is about the right level. In retrospect, not too interesting. Primarily a stimulant, not entirely physically pleasant. The visual is not too exciting. I am easily distracted. One line of thought to another. I feel that more would be too stimulating. (with 30 mg) I was into it quite quickly (not much over three-quarters of an hour) and got up to a ++ by the end of an hour. There is something unsatisfactory about trying to classify this level. I had said that I was willing to increase the dose to a higher level, to break out of this not-quite-defined level into something psychedelic. But I may not want to go higher. Under different circumstances I would not mind trying it at a considerably lower dosage, perhaps at the 10 or 15 milligrams. I do not have a comfortable label on this material, yet. (with 45 mg) There was a rocket from the half-hour to the one and a half hour, from nothing up to a +++. Somehow the intimacy and the erotic never quite knit, and I feel that I am always waiting for the experience to come home. Talking is extremely easy, but something is missing. Appetite is good. I am down by the fifth hour, and sleep is comfortable. This compound will take some learning. (with 75 mg) This is a +++, but the emphasis is on talking, not on personal interacting. I am putting out, but my boundaries are intact. I was able to sleep at the sixth hour. Communication was excellent. This is fast on, but not too long lived. Maybe a therapy tool? (with 150 mg) A truly remarkable psychedelic, one which could compare favorably with 2C-B. There are intense colors, and I feel that more would be too much. EXTENSIONS AND COMMENTARY: Wow! This particular compound is what I call a pharmacological tofu. It doesn't seem to do too much by itself, always teasing, until you get to heroic levels. But a goodly number of experimental therapists have said that it is excellent in extending the action of some other materials. It seems to boost the waning action of another drug, without adding its own color to the experience. Yet, the comment above, on the high level of 150 milligrams, is a direct quote from the use of this compound in Germany (where it is called LE-25) in therapeutic research. This is probably the most dramatic example of the loss of potency from an amphetamine (DOM, active at maybe 3 milligrams) to a phenethylamine (only one tenth as active). It is so often the case that the first of a series is not the most interesting nor the most potent member. As intriguing and as difficult-to-define as the 2C-D story might be, the next higher homologue of this set, 2C-E, is maximally active at the 15 to 20 milligram level, and is, without any question, a complete psychedelic. The N-monomethyl and the N,N-dimethyl homologues of 2C-D have been synthesized from 2C-D. The N-monomethyl compound was obtained by the quaternization of the Schiff's base formed between 2C-D and benzaldehyde with methyl sulfate, followed by hydrolysis; the hydrochloride salt had a melting point of 150-151 deg C, from EtOH. The N,N-dimethyl compound resulted from the action of formaldehyde-formic acid on 2C-D; the hydrochloride salt had a melting point of 168-169 deg C from EtOH/ether. These two compounds were some ten times less effective in interfering with conditioned responses in experimental rats. There is no report of their having been explored in man. I have learned of an extensive study of ethoxy homologues of a number of the phenethylamines in the 2C-X series; they have been collectively called the "Tweetios." This Sylvester and Tweety-bird allusion came directly from the compulsive habit of trying to alleviate the boredom of driving long distances (not under the influence of anything) by the attempt to pronounce the license plates of cars as they passed. The first of this series of compounds had a name that indicated that there was an ethoxy group at the 2-position, or 2-EtO, or Tweetio, and the rest is history. In every compound to be found in the 2C-X family, there are two methoxy groups, one at the 2-position and one at the 5-position. There are thus three possible tweetio compounds, a 2-EtO-, a 5-EtO- and a 2,5-di-EtO-. Those that have been evaluated in man are included after each of the 2C-X's that has served as the prototype. In general, the 2-EtO- compounds have a shorter duration and a lower potency, the 5-EtO- compounds have a relatively unchanged potency and a longer time duration; the 2,5-di-EtO- homologues are very weak, if active at all. The 2-EtO-homologue of 2C-D is 2-ethoxy-5-methoxy-4-methylphenethylamine, or 2CD-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-tolualdehyde) had a melting point of 60.5-61 deg C, the nitrostyrene intermediate a melting point of 110.5-111.5 deg C, and the final hydrochloride a melting point of 207-208 deg C. The hydrobromide salt had a melting point of 171-173 deg C. At levels of 60 milli-grams, there was the feeling of closeness between couples, without an appreciable state of intoxication. The duration was about 4 hours. The 5-EtO- homologue of 2C-D is 5-ethoxy-2-methoxy-4-methylphenethylamine, or 2CD-5ETO. The benzaldehyde (5-ethoxy-2-ethoxy-4-tolualdehyde) had a melting point of 81-82 deg C, and the details of this synthesis are given in the recipe for IRIS. The nitrostyrene intermediate had a melting point of 112.5-113.5 deg C and the final hydrochloride salt had a melting point of 197-198 deg C. The hydro-bromide salt had a melting point of 158-159 deg C. At dosage levels of 40 to 50 milli-grams, there was a slow, gradual climb to the full effects that were noted in about 2 hours. The experience was largely free from excitement, but with a friendly openness and outgoingness that allowed easy talk, interaction, humor, and a healthy appetite. The duration of effects was 12 hours. The 2,5-di-EtO- homologue of 2C-D is 2,5-diethoxy-4-methylphenethylamine, or 2CD-2,5-DIETO. The benzaldehyde (2,5-diethoxy-4-tolualdehyde) had a melting point of 102-103 deg C, the nitrostyrene intermediate a melting point of 108-109 deg C, and the final hydrochloride salt a melting point of 251-252 deg C. At a level of 55 milligrams, a plus one was reached, and what effects there were, were gone after four hours. |
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