Книга I: история любви 18
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| #15 BOH; beta-METHOXY-3,4-METHYLENEDIOXYPHENETHYLAMINE SYNTHESIS: To a solution of 30 g piperonal in 100 mL acetic acid there was added 20 mL nitromethane and 10 mL cyclohexylamine. After heating on the steam bath for 1.5 h, the reaction mixture started to crystallize. The mixture was cooled in an ice bath, and the heavy mass of deposited crystals removed by filtration and washed with 20 mL acetic acid. All was supended in 100 mL warm MeOH, cooled again, and filtered to give 24.5 g of 3,4-methylenedioxy-beta-nitrostyrene as canary-yellow crystals, with a mp of 158-160 deg C. Reduction of this compound with LAH gives rise to MDPEA, which is a separate entry with a recipe of its own. To a vigorously stirred suspension of 20 g 3,4-methylenedioxy-beta-nitro -styrene in 100 mL anhydrous MeOH there was added a freshly prepared solution of 5.5 g elemental sodium in 100 mL MeOH. The nitrostyrene goes into solution over the course of 5 min. There was then added, first, 50 mL acetic acid with the stirring continued for an additional 1 min. There was then added 300 mL H2O. An oil separated and was extracted into 200 mL CH2Cl2. The organic extract was washed with 500 mL dilute aqueous NaHCO3, followed by 500 mL H2O. Removal of the solvent gave a residue that was distilled at 128-145 deg C at 0.4 mm/Hg, providing 16.6 g of a yellow viscous liquid which slowly crystallized. An analytical sample was recrystallized from four volumes of MeOH to give 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane as bright yellow crystals with a mp of 58-59 deg C. Anal. (C10H11NO5) C,H. A solution of LAH (100 mL of 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 2.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 12 g 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane over the course of 2 min. There was an immediate loss of color. After a few minutes further stirring, the temperature was brought up to a reflux with a heating mantle. There was a gentle gas evolution for a few min, followed by an exothermic reaction that exceeded the capacity of the condenser. Once the reaction had subsided, the unreacted hydride was destroyed with a minimum of IPA, and 15% NaOH was added to convert the inorganics to a loose white filterable mass. The reaction mixture was filtered, and the filter cake washed thoroughly with THF. The combined filtrate and washes were stripped of solvent under vacuum, providing an orange oil. This was dissolved in 400 mL dilute H2SO4, which was washed with 3x75 mL CH2Cl2. After making the aqueous phase basic, it was extracted with 2x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue distilled at 103-112 deg C at 0.5 mm/Hg. There was obtained 2.5 g of a colorless, viscous oil which was dissolved in 25 mL IPA, neutralized with 45 drops of concentrated HCl, and finally diluted with 30 mL anhydrous Et2O. There was thus formed beta-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (BOH) as a fine white crystalline product. The mp was 105-106.5 deg C, with bubbling and darkening. The mp properties proved to be inconsistent, as the salt was a hydrate. Recrystallization from CH3CN, or simply heating to 100 deg C in toluene, converted the salt to an anhydrous form, with mp of 152-153 deg C. Anal. (C10H14ClNO3) C,H. DOSAGE: 80 - 120 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 90 mg) Distinct body awareness in an hour. The threshold is mostly physical. Faint sense of inside warmth, skin prickling, cold feet, loose bowels, anorexia. By the fifth hour, I was on the downslope, and in retrospect I found it good humored but not insightful. (with 100 mg) There was a vague nausea, and a chilling of the feet. It reached a real plus two, with dilated pupils and quite a thirst. How can one describe the state? There were no visuals, and I was not even stoned. I was just very turned on. And I was completely back to baseline by hour number six. EXTENSIONS AND COMMENTARY: There are several reports of a nice, mild mood enhancement in the 20-40 milligram dosage area, but searches for psychedelic effects at higher levels gave a strange mix of some sort of an altered state along with bodily discomfort. The BOH name for this member of the BOX family follows the convention discussed in the BOD recipe Q with RHS for homopiperonylamine, the simplest of the muni-metro family, q.v. The demethylated homologue of BOH is BOHH, and is the methylenedioxy analogue of norepinephrine. It might well hydrolytically open up in the body to provide this neurotransmitter, and serve as some sort of transmitter in its own right. It is discussed under DME. Maybe there is something to the concept that when you imitate a neurotransmitter too closely, you get a hybrid gemisch of activity. The term "pro-drug" is used to identify a compound that may not be intrinsically active, but one which metabolizes in the body to provide an active drug. I feel the term should have been pre-drug, but pro-drug was the word that caught on. BOH may well act in the body as a pro-drug to norepinephrine, but with the temporary blocking of the polar functions with ether groups, it can gain access to the brain. And once there, it can be stripped of these shields and play a direct neurological role. I uncovered a very similar analogy in the tryptamine world some years ago. Just as norepinephrine is a neurotransmitter, so is serotonin. And I found that by putting an O-ether on the indolic phenol (to hide its polarity) and an alpha-methyl group next to the primary amine (to protect it from metabolic deaminase), it became an extremely potent, and most complex, psychedelic. This was the compound alpha,O-dimethylserotonin, or a,O-DMS. There is an uncanny analogy between this tryptamine and the phenethylamine BOH. Somehow the quiet voice deep inside me says, don't use too much, too quickly. Maybe one of the optical isomers is the body thing, and the other isomer is the mind thing. So far, only the racemic mixture has been tasted, to the best of my knowledge. #16 BOHD; 2,5-DIMETHOXY-beta-HYDROXY-4-METHYLPHENETHYLAMINE SYNTHESIS: A solution of 0.4 g 1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane (see preparation in the recipe for BOD) in 3.0 mL acetic acid was heated to 100 deg C on a steam bath. There was added 1.0 g powdered zinc, followed by additional acetic acid as needed to maintain smooth stirring. After 0.5 h there was added 1.0 mL concentrated HCl and, following an additional few minutes heating, the reaction mixture was poured into 300 mL H2O. After washing the aqueous phase with 3x75 mL CH2Cl2, the mixture was made basic with 25% NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent and distillation of the residue at 130-140 deg C 0.25 mm/Hg gave an oil that, on dissolving in IPA, neutralization with concentrated HCl, and the addition of anhydrous Et2O, gave beautiful white crystals of 2,5-dimethoxy-beta-hydroxy-4-methylphenethylamine hydrochloride (BOHD). The yield was 0.2 g, and the mp was 180-181 deg C. The infrared spectrum was that of an amine salt with a strong OH group present. Anal. (C11H18ClNO3) C,H. DOSAGE: greater than 50 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 50 mg) At about the two hour point, there was a precipitous drop of blood pressure (from 120/72 to 84/68) although the pulse stayed steady at 60. This trend had been apparent in earlier trials, and was being watched carefully. No further tests are planned. EXTENSIONS AND COMMENTARY: The usual method of making beta-ethanolamine such as this is through the reduction of the cyanohydrin of the corresponding benzaldehyde and, in fact, that method is described in the recipe for DME. This above procedure was actually part of an exploration of different agents that might be used in the reduction of the intermediate nitroalkane. This product was the unexpected result of trying zinc. Why the potent cardiovascular effect seen by this compound? There are a couple of points that might argue for some adrenolytic toxicity. This material is a beta-ethanolamine and, with maybe one or two exceptions, clinically used beta-receptor blockers are beta-ethanolamines. In fact, a few of these so-called beta-blockers actually have two methoxy groups on the aromatic rings, also a property of BOHD. The antidiabetic drug Butaxamine (BW 64-9 in the code of Burroughs Wellcome) is identical to BOHD except that the 4-methyl group is on the alpha-carbon instead, and there is a tertiary butyl group on the nitrogen atom. Another point involves the proximity of the beta-hydroxy group and the methoxyl oxygen atom in the 2-position of the ring. There is going to be a strong hydrogen-bonding with this orientation, with the formation of a stable six-membered ring. This might help obscure the hydrophilic nature of the free hydroxyl group and allow the compound to pass into the brain easily. If this group is masked by an easily removed group such as an acetate ester, one gets the compound beta-acetoxy-3,4-dimethoxy-4-methylphenethylamine (BOAD) which is similar to BOHD as a hypotensive. The code-naming procedure used here (and elsewhere here in Book II) is: (1) to use RBOS as the alert to there being an oxygen on the benzyl carbon of a phenethylamine (it is a benzyl alcohol); (2) if there is just one more letter (a third and last letter) it will identify the 2C-X parent from which it has been derived [RBS comes from 2C-B, RDS comes from 2C-D, RHS comes from homopiperonylamine (MDPEA) rather than from 2C-H, RMS comes from mescaline, and in every case the beta-substituent is a methoxy group]; and (3) if there are four letters, then the fourth letter is as above, and the third letter (the next to last letter) is the substituent on that benzylic oxygen. With a three letter code, the substituent is a methyl group, an RHS for a third letter of four makes it a hydroxyl group, and an RAS for the third letter is an acetyl group, and an RES is for an ethyl group. A similar sort of cryptographic music was composed by Du Pont in their three-number codes for the Freons. The first number was one less than the number of carbons in the molecule, the second number was one more than the number of hydrogens in the molecule, the third number was the exact number of fluorines in the molecule, and the rest of the bonds were filled with chlorines, Thus Freon 11 (really Freon 011) was trichlorofluoromethane and Freon 116 was hexafluoroethane. Complex, yes. But both systems are completely straightforward, and flexible for future creations. A few additional examples of similar beta-ethanolamines are scattered throughout Book II and they have, in general, proved to be uninteresting, at least as potential psychedelic compounds. #17 BOM; beta-METHOXYMESCALINE; 3,4,5,beta-TETRAMETHOXYPHENETHYLAMINE SYNTHESIS: To a vigorously stirred suspension of 9.0 g beta-nitro-3,4,5-trimethoxystyrene (see under the recipe for M for the preparation of this intermediate) in 50 mL anhydrous MeOH there was added a solution obtained from the addition of 2.0 g metallic sodium to 50 mL anhydrous MeOH. The bright orange color faded to a light cream as the nitrostyrene went into solution. After 3 min there was added 30 mL acetic acid, which produced white solids, and this was followed by further dilution with 150 mL H2O. The formed solids were removed by filtration, washed well with H2O, and recrystallized from 150 mL boiling MeOH. After removal of the product by filtration and air drying to constant weight, there was obtained 6.9 g of 1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane as fine, cream-colored crystals. The mp was 143-144 deg C, and the Rf by TLC (silica-gel plates and CH2Cl2 as moving phase) was identical to that of the starting aldehyde. Anal. (C12H17NO6) C,H. A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 6 g of solid 1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane over the course of 2 min. There was some gas evolution. After 5 min additional stirring, the temperature was brought up to a reflux with a heating mantle. There was a gentle gas evolution for a few minutes, followed by an exothermic reaction with vigorous gas evolution. Once everything had settled down, the reaction mixture was held at reflux temperature for an additional 2 h. The excess hydride was destroyed by the addition of IPA and 15% NaOH was added to convert the inorganic salts to a loose white filterable mass. The reaction mixture was filtered, and the filter cake washed thoroughly with THF. The combined filtrate and washes were stripped of solvent under vacuum which provided a red-brown liquid. This was dissolved in dilute H2SO4 and washed with 3x75 mL CH2Cl2. After making the aqueous phase basic with NaOH, it was extracted with 2x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the colorless residue distilled at 120-150 deg C at 0.3 mm/Hg. There was obtained 2.8 g of a colorless oil which was dissolved in 30 mL IPA and neutralized with concentrated HCl, allowing the spontaneous formation of the hydrochloride salt. This was diluted with 75 mL anhydrous Et2O, yielding 2.8 g 3,4,5,beta-tetramethoxyphenethylamine hydrochloride (BOM) as a white crystalline product. This had a mp of 198.5-199.5 deg C. Anal. (C12H20ClNO4) C,H. DOSAGE: greater than 200 mg. DURATION: unknown. EXTENSIONS AND COMMENTARY: There are some indicators of central activity with assays involving both the 120 milligram and the 180 milligram levels, but nothing that can be rated as over a plus one. It can be seen with the two active members of the BOX series (BOD and BOB) that the potency is about equal to, or a little more (up to a factor of maybe x2), than the analogue without the methoxyl group on the aliphatic chain. If this formula were to hold in the relationship between mescaline and BOM, the active level might well be in the 200-400 milligram range. But at the moment, it remains unknown. Again, the name of the compound (BOM) is from the RBO-S prefix of this family (from benzyl + oxy), plus the RMS of mescaline (which has provided the ring substitution pattern). #18 4-BR-3,5-DMA; 3,5-DIMETHOXY-4-BROMOAMPHETAMINE SYNTHESIS: The starting material 3,5-dimethoxy-4-bromobenzoic acid (made from the commercially available resorcinol by the action of methyl sulfate) was a white crystalline solid from aqueous EtOH with a mp of 248-250 deg C. Reaction with thionyl chloride produced 3,5-dimethoxy-4-bromobenzoyl chloride which was used as the crude solid product, mp 124-128 deg C. This was reduced with tri-O-(t)-butoxy lithium aluminum hydride to produce 3,5-dimethoxy-4-bromobenzaldehyde which was recrystallized from aqueous MeOH and had a mp of 112-114 deg C. Anal. (C9H9BrO3) C,H. This aldehyde, with nitroethane and anhydrous ammonium acetate in acetic acid, was converted to the nitrostyrene 1-(3,5-dimethoxy-4-bromophenyl)-2-nitropropene, with a mp of 121-121.5 deg C. Anal. (C11H12BrNO4) C,H,N. This was reduced at low temperature with just one equivalent of LAH, to minimize reductive removal of the bromine atom. The product 3,5-dimethoxy-4-bromoamphetamine hydrochloride (4-BR-3,5-DMA) was isolated in a 37% yield and had a mp of 221-222 deg C. Anal. (C11H17BrClNO2) C,H,N. DOSAGE: 4 - 10 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 3 mg) This is certainly no placebo. At about 2 hours I felt some analgesia and numbing in my extremities, but if there were any sensory distortions, they were barely perceptible. (with 6 mg) There is a very shallow threshold, no more. (with 10 mg) I can certainly confirm the indications of anesthesia that were hinted at. It was for me central in nature, however. I could (this at three hours) pierce a skin pinch on my left arm with no bother except for the emerging of the needle due to skin resistance. There was little bleeding. And multiple needle prickings into the thumb abductor were not felt. A quick plunge of the tip of my little finger into boiling water elicited reflex response, but no residual pain. Judgment was OK, so I stayed out of physical trouble, luckily! The perhaps ++ was dropping in the fourth or fifth hour, and by the tenth hour there were few effects still noted, except for some teeth-rubbiness and a burning irritation at the pin-prick area, so feeling is back. No sleep problems at just past midnight. EXTENSIONS AND COMMENTARY: Here is a complex and, at the moment, totally undefined drug. There were two independent reports of analgesia, yet a thorough screen in experimental animals, conducted by a major pharmaceutical house, failed to confirm any of it. A ++ report does not necessarily reflect a psychedelic effect, since this quantitative measure of the level of activity represents the extent of impairment of function, regardless of the nature of the drug producing it. In other words, if you were experiencing the effects of a drug that would in your judgment interfere with safe and good driving, this would be a ++ whether your performance was being limited by a psychedelic, a stimulant, a hypnotic or a narcotic. None of the quantitative reports ever mentioned any sensory distortion (analgesia is a loss, not a distortion) or visual effect. Perhaps 4-BR-3,5-DMA showed its ++ as a narcotic. But then, the rats had said no. |
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