Книга I: история любви 18
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| #169 2-TOET; 4-ETHYL-5-METHOXY-2-METHYLTHIOAMPHETAMINE SYNTHESIS: A mixture of 24.4 g ortho-ethylphenol and 18.9 mL methyl iodide was added to a solution of 15.6 g 85% KOH in 100 mL hot MeOH. The mixture was kept at reflux temperature overnight, stripped as much as possible of the MeOH, and poured into 1 L H2O. An excess of 5% NaOH was added and this was extracted with 3x75 mL CH2Cl2. The pooled extracts were washed with 1% NaOH, and the solvent removed under vacuum to give 32.8 g of a pale amber oil. This was distilled at 55-65 deg C at 0.4 mm/Hg to yield 22.0 g of 2-ethylanisole as a colorless oil. To a 21.7 g sample of 2-ethylanisole, well stirred but without solvent, there was added, 1 mL at a time, 21 mL of chlorosulfonic acid. The color progressed from white to yellow, and finally to deep purple, with the evolution of much HCl. The exothermic reaction mixture was allowed to stir until it had returned to room temperature (about 0.5 h). It was then poured over 400 mL cracked ice with good mechanical stirring, which produced a mass of pale pink solids. These were removed by filtration, washed well with H2O, and air dried to give about 27 g of 3-ethyl-4-methoxybenzenesulfonyl chloride as an off-white solid that retained some H2O. A sample recrystallized from cyclohexane had a mp of 44-46 deg C. A sample treated with ammonium hydroxide provided white crystals of 3-ethyl-4-methoxybenzenesulfonamide which could be recrystallized from H2O to give tufts of crystals with a mp of 97-98 deg C. Anal. (C9H13NO3S) C,H. In a 2 L round bottomed flask equipped with a mechanical stirrer there was added 200 mL cracked ice, 45 mL of concentrated H2SO4, 26.7 g of still moist 3-ethyl-4-methoxybenzenesulfonyl chloride, and 45 g elemental zinc dust. With external heating, an exothermic reaction set in and the temperature was maintained at reflux conditions for 4 h. After cooling to room temperature, the reaction mixture was filtered and the insolubles washed alternately with H2O and with CH2Cl2. The mother liquors and washings were diluted with sufficient H2O to allow CH2Cl2 to become the lower phase. These phases were separated, and the aqueous phase extracted with 3x100 mL CH2Cl2. The original organic phase and the extracts were pooled, washed with H2O, and the solvent removed to give 15.7 g of a smelly amber oil. This was distilled at 72-84 deg C at 0.3 mm/Hg to give 12.1 g of 3-ethyl-4-methoxythiophenol as a water-white oil. The infra-red was perfect (with the SH stretch at 2562, OCH3 at 2837 and 1061, and with fingerprint peaks at 806, 880, 1052, (1061), 1142 and 1179 cm-1). Anal. (C9H12OS) C,H. To a solution of 11.7 g of 3-ethyl-4-methoxythiophenol and 6.5 mL methyl iodide in 100 mL MeOH there was added, with good stirring and a bit at a time, a solution of 5.5 g 85% KOH in 25 mL hot MeOH. The mixture was held at reflux on the steam bath for 1.5 h, and then stripped of volatiles under vacuum. The residues were added to 400 mL H2O, made strongly basic with 5% NaOH, and extracted with 3x75 mL CH2Cl2. The pooled extracts were back-washed with 1% NaOH, and the solvent removed under vacuum. The 13.2 g residue was distilled giving 2-ethyl-4-(methylthio)anisole as a fraction boiling at 78-85 deg C at 0.2 mm/Hg. The weight was 11.6 g for an isolated yield of over 90% of theory. The mp was at about 0 deg C. The infra-red showed no SH or other functionality, but an OCH3 at 2832 and 1031, and a fingerprint spectrum with peaks at 808, 970, (1031), 1051, 1144 and 1179 cm-1. Anal. (C10H14OS) C,H. A solution of 11.2 g 2-ethyl-4-(methylthio)anisole and 9 g dichloro-methyl methyl ether in 200 mL dry CH2Cl2 was treated with 13 g anhydrous aluminum chloride, added a bit at a time. The color progressed from pink to claret to deep claret, with a modest evolution of HCl. Stirring was continued for 1 h, then the reaction was quenched by the cautious addition of 250 mL H2O. The two phase mixture was stirred an additional hour and then separated. The aqueous phase was extracted with 2x100 mL CH2Cl2. The organics were pooled, washed with 5% NaOH, then with saturated brine, and the solvent removed under vacuum. The residue was an amber oil weighing 13.7 g. This was distilled at 0.2 mm/Hg. A first fraction was a yellow oil boiling at 90-100 deg C, and weighing 2.9 g. It was a mixture of starting anisole and the desired benzaldehyde. A second fraction, boiling at 100-130 deg C was a viscous yellow oil weighing 4.8 g. By TLC it was free of starting anisole, and contained a sizeable quantity of a second benzaldehyde. From this fraction, seed crystal was obtained, and when the oil was dissolved in an equal volume of MeOH, the seed took, producing a yellow solid. This was filtered and air dried, to give 2.2 g of 4-ethyl-5-methoxy-2-(methylthio)benzaldehyde with a mp of 62-63 deg C. A small sample from MeOH was almost white, and melted at 61-62 deg C. The mixed mp with 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde (57-58 deg C) was severely depressed (37-44 deg C). A cooled solution of the first fraction of the distillation, in MeOH, provided an additional 1.6 g product, with a mp 59-61 deg C. The combined mother liquors gave additional product for an overall weight of 5.3 g. Anal. (C11H14O2S) C,H. A solution of 1.9 g 4-ethyl-5-methoxy-2-(methylthio)benzaldehyde in 75 mL nitroethane was treated with 0.3 g anhydrous ammonium acetate, and held on the steam bath for 2.5 h. The excess solvent/reagent was removed under vacuum, and the deep orange oil residue was dissolved in 10 mL boiling MeOH. As this cooled, there was the spontaneous generation of crystals. After cooling in an ice bath for a few h, these were removed by filtration, washed with MeOH, and air dried to constant weight. A total of 1.4 g of 1-(4-ethyl-5-methoxy-2-methylthiophenyl)-2-nitropropene was obtained as canary-yellow crystals melting at 83-84 deg C which was not improved by recrystallization from MeOH. Anal. (C13H17NO3S) C,H. To a solution of 1.5 g LAH in 30 mL anhydrous THF that was cooled to 0 deg C and stirred under a He atmosphere, there was added, slowly, 1.05 mL freshly prepared 100% H2SO4 (prepared by adding 0.9 g 20% fuming H2SO4 to 1.0 g 96% concentrated H2SO4). This was followed by the addition of a solution of 1.4 g 1-(4-ethyl-5-methoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF, over the course of 10 min. The color of the nitrostyrene solution was discharged immediately upon addition. With continued stirring, this was allowed to come to room temperature, and then to a gentle reflux for 2 h. After cooling again to room temperature, the excess hydride was destroyed by the addition of IPA. Sufficient 5% NaOH was added to generate the inorganic salts as a loose filterable mass, and these were removed by filtration. The filter cake was well washed with additional IPA, and the combined mother liquors and washes were stripped of solvent under vacuum. The residue was dissolved in 100 mL dilute H2SO4, washed with CH2Cl2, made basic with 5% NaOH, and extracted with 2x75 mL CH2Cl2. Removal of the solvent gave a residue that was distilled at 102-117 deg C at 0.15 mm/Hg. The colorless liquid that distilled (0.7 g) was dissolved in 6 mL IPA and neutralized with 11 drops of concentrated HCl. The solids that formed were dissolved by heating the mixture briefly to a boil, and this clear solution was diluted with 20 mL anhydrous Et2O. The white crystals of 4-ethyl-5-methoxy-2-methylthioamphetamine hydrochloride (2-TOET) weighed 0.6 g and had a mp of 164-167 deg C. Anal. (C13H22ClNOS) C,H. DOSAGE: greater than 65 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 50 mg) After about an hour and a half, I found myself a little light-headed. And maybe a feeling of being physically a bit fragile. I ate something, but there was not much joy in eating. And the next day there was some residual fragility, whatever that means. Ahead with caution. (with 65 mg) During the day this was barely noticeable, but pleasant. EXTENSIONS AND COMMENTARY: It seems as if the sulfur in the 2-position makes things less interesting, and less potent, than when it is in the 5-position. 2-TOM required twice the dosage of 5-TOM, and here it appears that it could well take a dosage of twice that required for 5-TOET, to get 2-TOET off the ground. There is an understandable reluctance to push on upwards in dosage with a new and unknown compound, when there are feelings of physical discomfort that outweigh the mental effects. There is nothing tangible here. In the complete report of the 50 milligram trial, there is a mention of an inability to effect erection, and this with the light-headedness and disinterest in food, all suggest some involvement with the sympathetic nervous system. And with these subtle effects persisting into the next day, why push higher? Instinct said to leave it alone. So I left it alone. The 2-carbon analogue, 2C-2-TOET, was made from the same aldehyde intermediate. The appropriate nitrostyrene came smoothly from the aldehyde and nitromethane, and gave glistening pumpkin-orange crystals from methanol, that melted at 93-94 deg C. Anal. (C12H15NO3S) C,H. The final phenethylamine hydrochloride salt was prepared from its reduction with aluminum hydride in THF, and was isolated in the usual manner. It was a white crystalline mass that melted at 226-227 deg C. It, as with the other 2-carbon analogues of the TOMs and TOETs, remains untasted as of the moment. #170 5-TOET; 4-ETHYL-2-METHOXY-5-METHYLTHIOAMPHETAMINE SYNTHESIS: A solution of 25 g 3-ethylphenol in 100 mL Et2O was equipped with a magnetic stirrer, and cooled to 0 deg C with an external ice bath. There was added 16 mL DMSO. Then, a total of 15 mL chlorosulfonic acid was added dropwise, over the course of 30 min. The reaction was allowed to return to room temperature and stirred overnight. The overhead Et2O phase was removed by decantation, and the light-colored residue was dissolved in 100 mL IPA. The clear solution spontaneously generated white crystals which were allowed to stand for 1 h, removed by filtration, and lightly washed with IPA. After air-drying, this crop of dimethyl-(2-ethyl-4-hydroxyphenyl)-sulfonium chloride weighed 20.0 g and had a mp of 168-170 deg C without obvious effervescence. A solution of 19.8 g of this sulfonium salt in 200 mL H2O was diluted with 500 mL MeOH, and there was added 30 g NaOH. This was heated to reflux on the steam bath. There was an initial deposition of some white solids, but after 36 h the solution was almost clear. The excess MeOH was removed under vacuum, and the non-volatiles were poured into 1 L H2O. This was acidified with HCl, and extracted with 3x100 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum. The residue, 12.6 g of an amber oil, was distilled at 95-120 deg C at 0.3 mm/Hg to give 10.0 g of 3-ethyl-4-(methylthio)phenol as an off-white oil. This spontaneously crystallized to a solid that had a mp of 47-49 deg C. Recrystallization of an analytical sample from cyclohexane gave a mp of 47-48 deg C. To a solution of 9.7 g 3-ethyl-4-(methylthio)phenol in 50 mL MeOH there was added a solution of 4.6 g 85% KOH in 50 mL hot MeOH. There was then added 5.4 mL methyl iodide and the mixture was held at reflux on the steam bath for 18 h. Removal of the solvent under vacuum gave a residue that was poured into 1 L H2O and made strongly basic by the addition of 5% NaOH. This was extracted with 3x75 mL CH2Cl2, and the extracts were pooled and the solvent removed under vacuum. There remained 11.0 g of an almost white oil with a startling apple smell. This oil was distilled at 78-88 deg C at 0.3 mm/Hg to give 7.9 g 3-ethyl-4-(methylthio)anisole as a white oil. Anal. (C10H14OS) C,H. A mixture of 7.8 g POCl3 and 6.9 g N-methylformanilide was heated on the steam bath for a few min, until there was the development of a deep claret color. This was added to 7.7 g 3-ethyl-4-(methylthio)anisole and the mixture was heated on the steam bath for 2 h. This was poured into 400 mL H2O and stirred overnight, which produced an oily phase with no signs of crystals. The entire reaction mixture was extracted with 3x75 mL CH2Cl2, and the pooled extracts washed with H2O. Removal of the solvent under vacuum gave 9.2 g of a residue. This was suspended in 25 mL hexane, and after 1 h standing, the overhead clear solution was decanted from the settled sludge. This hexane solution was stripped of solvent under vacuum, giving 7.7 g of an oil that by TLC was a mixture of starting ether and desired aldehyde. This was distilled at 0.25 mm/Hg to give three fractions, the first boiling at 75-100 deg C (2.7 g) and the second at 100-115 deg C (2.6 g). These were largely starting ether and aldehyde, and were chemically processed below. A third fraction, boiling at 120-140 deg C, solidified in the receiver, weighed 1.6 g, and was largely the desired aldehyde. Cuts #1 and #2 (5.3 g of what was mostly recovered aldehyde) were resubmitted to the Vilsmeier reaction. A mixture of 5.4 g POCl3 and 4.7 g N-methylformanilide was heated on the steam bath until it became claret-colored. The recovered aldehyde was added, and the mixture was heated overnight on the steam bath. This was poured into 500 mL H2O. The heavy tar that was knocked out was extracted with 3x75 mL CH2Cl2, and the solvent was removed from the pooled extracts under vacuum. Some 5.8 g of residue was obtained, and this was heated to 120 deg C at 0.2 mm/Hg to remove all materials lower boiling than the desired aldehyde. The very dark pot was extracted with 3x50 mL boiling hexane, and removal of the solvent from these pooled extracts under vacuum gave 0.9 g of a yellow oil. This was distilled at 0.2 mm/Hg to give a fraction boiling at 130-140 deg C which spontaneously crystallized. This pressed on a porous plate gave almost white crystals with a mp of 55-57 deg C. Recrystallization from 0.3 mL cyclohexane provided 0.3 g of 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde with a mp of 57-58 deg C. The total yield was 1.9 g. Anal. (C11H14O2S) C,H. To a solution of 1.2 g 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde in 25 mL nitroethane there was added 0.25 g anhydrous ammonium acetate and the mixture was heated on the steam bath. The initial color was green, but this quickly changed to the more usual yellow which darkened as the reaction mixture was heated. After 1.5 h heating, the excess solvent/reagent was removed in vacuo. The yellow residue was dissolved in 10 mL hot MeOH and allowed to stand in the refrigerator overnight. There was an orange oil layer formed underneath the MeOH. A small sample of this was scratched externally with dry ice, and seed was obtained. The orange oil layer slowly set to crystals which, after a few h, were removed by filtration to give 1.3 g of a slightly sticky orange solid with a mp of 43-45 deg C. This was recrystallized from 8 mL boiling MeOH to give, after cooling, filtering, and air drying to constant weight, 1.1 g of 1-(4-ethyl-2-methoxy-5-methylthiophenyl)-2-nitropropene as electrostatic yellow crystals melting at 59-60 deg C. Anal. (C13H17NO3S) C,H. A solution of 1.0 g LAH in 25 mL tetrahydrofuran was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 0.6 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 1.1 g of 1-(4-ethyl-2-methoxy-5-methylthio)-2-nitropropene in a small amount of THF. After 10 min further stirring, it was brought up to room temperature and allowed to stand for several days. The excess hydride was destroyed by the cautious addition of IPA followed by sufficient 15% NaOH to give a white granular character to the aluminum oxide, and to assure that the reaction mixture was basic. This was filtered, and the filter cake washed first with THF and then with IPA. The filtrate and washings were pooled and stripped of solvent under vacuum providing a pale amber residue. This was dissolved in 50 mL of dilute H2SO4 and washed with 2x50 mL CH2Cl2. The aqueous phase was made basic with 5% NaOH, and extracted wit 2x50 mL CH2Cl2. These extracts were pooled, stripped under vacuum, and distilled at 0.15 mm/Hg. The fraction with a bp of 102-128 deg C weighed 0.4 g and was a colorless liquid. This was dissolved in a small amount of IPA, neutralized with concentrated HCl and diluted with anhydrous Et2O to provide the 4-ethyl-2-methoxy-5-methylthioamphetamine hydrochloride (5-TOET) which weighed 0.6 g and melted at 146-147 deg C. Anal. (C13H22ClNOS) C,H. DOSAGE: 12 - 25 mg. DURATION: 8 - 24 h. QUALITATIVE COMMENTS: (with 8 mg) After my totally freaky experience on the very closely related compound in this series, 5-TOM, I intended to approach this with some caution. Three milligrams was without effects, so I tried eight milligrams. I was a little light-headed, and saw sort of a brightness around trees against the blue sky. Noticed movement on couch in living room, and there was some activity in the curtains, almost 2C-B like. In the evening writing was still difficult, and there was eye dilation but minimal nystagmus. My sleep was fitful, but certainly there was no hint of the 5-TOM storm. (with 18 mg) This was too much. There was an exhausting visual hallucinatory tinsel, continuous movement, and there was no escape. It popped into an LSD-like thing, strong, restless, constantly changing, with too much input. I had to take a Miltown to calm down enough for an attempt at sleep. In the morning, a day later, I was still 1.5 + and tired of it. It was the next day after that before I was completely clear. (with 20 mg) This has the makings of a superb, extraordinary material. I didn't get to a full plus two, maybe something around a plus one and three quarters. The eyes-closed fantasy was exceptional, with new dimensions. The nature of the fantasy, the feeling that one had about the fantasy figures and landscapes, was the essence of joy, beauty, lovingness, serenity. A glimpse of what true heaven is supposed to feel like. Or maybe a button in the brain was pushed which has not been pushed by previous chemicals. Insight? Don't know yet. I was able to function without difficulty with eyes closed or open. Erotic absolutely exquisite. In fact, the entire experience was exquisite. Next day, same sense of serene, quiet joy/beauty persisted for most of the day. A true healing potential. Onwards and upwards. This one could be extraordinary. (with 30 mg) Tried to focus on cosmic questions, and succeeded. Very little fantasy images for the first 2-3 hours. After that, lovely interacting, music okay but not vital. On this compound the Brahms Concerto #1 gave vivid 'memory' impressions of house and vegetable garden, like a primitive painting. Tremendous nostalgia for a place I've never seen. EXTENSIONS AND COMMENTARY: With the extraordinary experience that had been observed with one person with 5-TOM, this ethyl homologue was not only run up with special caution, but that individual ran his own personal titration. And he proved to be perhaps twice as sensitive to 5-TOET than any of the other subjects. An approach to what might just be some unusual metabolic idiosyncrasy on the part of his liver, is discussed in the recipe for TOMSO. The initials of TOET progressed quite logically from TOM, in an exact parallel with the relationship between the corresponding sulfur-free analogues, where the ethyl compound is DOET and the methyl counterpart is DOM. "T" for "thio" which is the chemical nomenclature term for the replacement of an oxygen atom with a sulfur atom. And, as has been discussed in the text of this volume, the peculiarities of pronunciation in this series are interesting, to say the least. TOM is no problem. But TOET could have any of several pronunciations such as "Two-it", or "Tow-it", or "Too-wet", but somehow the one syllable term "Twat" became regularly used, and the family was generally referred to as the "Toms and Twats." The almost-obscene meaning of the latter was progressively forgotten with usage, and has led to some raised eyebrows at occasional seminars when these compounds are discussed. And not only at seminars. Once at the between-acts intermission at the Berkeley Repertory Theater, the topic came up and the phrase was used. There was a stunned silence about us within the circle of hearing, and we seemed to have been given a little extra room immediately thereafter. As with the other members of the TOM's and TOET's, the phenethylamine homologue of 5-TOET was synthesized, but had never been started in human evaluation. The aldehyde from above, 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde, was condensed with nitroethane (as reagent and as solvent) and with ammonium acetate as catalyst to give the nitrostyrene as spectacular canary-yellow electrostatic crystals with a mp of 91-92 deg C. Anal. (C12H15NO3S) C,H. This was reduced with aluminum hydride (from cold THF-dissolved lithium aluminum hydride and 100% sulfuric acid) to the phenethylamine 4-ethyl-2-methoxy-5-methylthiophenethylamine (2C-5-TOET) which, when totally freed from water of hydration by drying at 100 deg C under a hard vacuum, had a mp of 216-217 deg C. Anal. (C12H20ClNOS) C,H. |
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