Pihkal
Page 78
followed, in turn, by sufficient additional THF to make the suspension of inorganic salts loose and filterable. The reaction mixture was filtered, and the filter cake washed with additional THF. The filtrate and washings were combined and stripped of solvent under vacuum providing 4.6 g of a pale amber oil. This was dissolved in dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent under vacuum yielded 2.3 g of residue which was distilled at 115-125 !C at 0.3 mm/Hg to give 0.94 g of a clear white oil. This was dissolved in 5 mL IPA, neutralized with 12 drops of concentrated HCl, and diluted with 10 mL anhydrous Et2O. White crystals of 2,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (2C-O-4) separated, and were removed by filtration, Et2O washed, and air dried.
The final weight was 0.58 g.
DOSAGE: greater than 60 mg.
DURATION: unknown
QUALITATIVE COMMENTS: (with 60 mg) I became aware of something in the front part of my head, and there was a lot of yawning. The body was aware of the experiment. But also there was a general exhilaration and excitement, which lasted for a few hours. At best, I am at a plus one.
EXTENSIONS AND COMMENTARY: The full activity of 2C-O-4 is yet to be discovered. It represents an interesting hybrid lying in between several fascinating compounds.
First and foremost, all these carry the 2,4,5-trisubstitution which has consistently proven to be the most interesting and the most active of the phenethylamines. And with very few exceptions, the 2- and the 5- are methoxyl groups.
The sulfur analogues in this area, compounds with an alkylthio group at the 4-position of the 2,5-dimethoxyphenethylamine backbone, are the 2C-T things. The replacement of a sulfur with an oxygen, quite rightly, should give rise to the 2C-O counterparts. And they have been given the same numbering system that was bestowed upon the RTS
series. 2C-T-4 was the 4-isopropylthio compound and one of the most interesting of this family. And so, quite reasonably, the oxygen coun-terpart should be the 2C-O-4 analogue, and should be one of the first explored.
The extension of the 4-alkoxy-group led to the discovery of the TMA-2
Q MEM Q MIPM Q MPM Q MBM series of amphetamine analogues. The 2-carbon counterparts of these would be a fascinating series to explore, I thought, if there was some encouragement to be had from a preliminary try in this field.
This was a first shot in the dark, the actual trial example, and it certainly didnUt provide much encouragement. The three-carbon analogue, MIPM, was made (q.v.) but not explored, following the disappointing trials of MPM. If this area is ever re-opened, the numbering should reasonably follow the sulfur materials. The 4-ethoxy material would be 2C-O-2, the 4-(n)-propoxy compound 2C-O-7, and the 4-(n)-butoxy compound 2C-O-19. These are the exact analogues of 2C-T-2, 2C-T-7, and 2C-T-19, resp., and the 2-carbon homologues of MEM, MPM, and MBM. The simplest member of this series, the methyl counterpart, is 2C-O, and it is the obvious analogue of 2C-T. This is also called 2,4,5-TMPEA, and its story is presented elsewhere.
But, with the probable low eventual potency of 2C-O-4, I feel that the 2C-O series will not be an exciting one.
36 2C-P; 2,5-DIMETHOXY-4-(n)-PROPYLPHENETHYLAMINE
SYNTHESIS: To a stirred solution of 138 g p-dimethoxybenzene in 400 mL
CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL
CH2Cl2 which contained 92.5 g propionyl chloride. After stirring for 1.5 h the reaction mixture was poured into 2 L H2O containing ice.
The phases were separated, and the aqueous fraction was extracted with 2x100 mL CH2Cl2. The organic phase and the extracts were pooled, washed once with H2O, and then with 2x100 mL 5% NaOH. The solvent from the organic phase was removed under vacuum, yielding a deeply colored residue. This was distilled at 150-165 !C at 20 mm/Hg yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored oil. Acidification of the sodium hydroxide extract, extraction with CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that slowly crystallized. These solids, on recrystallization from MeOH, provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a mp of 47-48
!C. The same Friedel Crafts reaction, conducted on the same scale in CS2 rather than in CH2Cl2, required reduced temperature (5 !C) and a 24 h reaction period. This solvent variation, with the same workup and isolation, gave 76 g of 2,5-dimethoxypropiophenone as a pale amber oil boiling at 130-137 !C at 4 mm/Hg.
A total of 150 g mossy zinc was amalgamated by treatment with a solution of 15 g mercuric chloride in 1 L H2O. After swirling for 0.5
h, the H2O phase was removed by decantation and the zinc added to a 1
L three neck flask. To this there was added 20 mL H2O and 20 mL
concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone dissolved in 50 mL EtOH. This mixture was held at reflux with a heating mantle overnight, with the occasional addition of HCl as needed to maintain acidic conditions. After cooling to room temperature, the residual solids were removed by filtration, and the filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase).
Sufficient H2O was then added to allow extraction with 2x100 mL
additional CH2Cl2 with the organic solvent being the lower phase. The combined organic extracts were washed twice with 5% NaOH, followed by one washing with dilute acid. Removal of the solvent under vacuum yielded 18 g of a dark brown oil that was distilled at the water pump to yield 7.2 g of 2,5-dimethoxypropylbenzene as a light yellow oil boiling at 90-130 !C.
A mixture of 22 g 2,5-dimethoxypropylbenzene, 23 g POCl3 and 22 g N-methylformanilide was heated on the steam bath for 1.5 h. The hot, dark reaction mass was poured into 1 L H2O, which allowed the eventual separation of 2,5-dimethoxy-4-(n)-propylbenzaldehyde as a clear yellow oil weighting 14 g. Although the homologous 4-ethyl and 4-butyl benzaldehydes were clean crystalline solids, this propyl homologue remained an oil. Gas chromatographic analysis showed it to be about 90% pure, and it was used as obtained in the nitrostyrene steps with either nitromethane (here) or nitroethane (under DOPR).
To a solution of 13 g 2,5-dimethoxy-4-(n)-propylbenzaldehyde in 100 mL
nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture held at reflux for 1 h. Removal of the solvent/reactant under vacuum yielded a spontaneously crystallizing mass of orange solids that was removed with the help of a little MeOH. After filtering and air drying there was obtained 7.5 g
2,5-dimethoxy-'-nitro-4-(n)-propylstyrene with a mp of 118-122 !C.
Recrystallization from CH3CN gave an analytical sample with a mp 123-124 !C. Anal. (C13H17NO4) N.
In a 1 L round bottomed flask with a magnetic stirrer under a He atmosphere there was added 120 mL 1 M LAH in tetrahydrofuran. This stirred solution was cooled with an external ice bath, and there was added, dropwise, 3.2 mL of 100% H2SO4, freshly made by the addition of 13.5 g 20% fuming H2SO4 to 15.0 g of ordinary 96% concentrated H2SO4.
When the addition was complete, a total of 7.2 g of dry 2,5-dimethoxy-'-nitro-4-(n)-propylstyrene was introduced as solids in several batches, against a flow of He, over the course of 20 min. The reaction mixture was allowed to come to room temperature, and stirred for an additional 0.5 h, then brought to reflux for 10 min on the steam bath. The excess hydride was destroyed with 18 mL IPA, and then sufficient 15% NaOH was added which made the aluminum oxides distinctly basic and of a filterable texture. The inorganics were removed by filtration, and the filter cake washed with additional THF.
The combined filrate and washes were stripped of solvent, yielding several g of a pale yellow oil that was suspended in a large quantity of dilute H2SO4. The aqueous phase was filtered free of insolubles, washed with a little CH2Cl2, and made basic with aqueous NaOH. This was extracted with 3x40 mL CH2Cl2 and, after the removal of the solvent under vacuum, the residual 2 g of off-white oil was distilled.
A fraction that distilled at 100-110 !C at 0.3 mm/Hg was water white, weighed 1.59 g and spontaneously crystallized. This fraction was dissolved in 7.
5 mL warm IPA and neutralized with 0.6 mL concentrated HCl. The spontaneous crystals of
2,5-di-methoxy-4-(n)-propylphenethylamine hydrochloride (2C-P) were suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air dried. The weight was 1.65 g and the mp was 207-209 !C with prior sintering at 183 !C., Anal. (C13H22ClNO2) N.
DOSAGE: 6 - 10 mg.
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 6 mg) I was not feeling so good.
Hangover, I guess. The material was so gentle in coming on, and soon my body became jangled. Thinking was easy. Verbalizing was easy.
Being comfortable with my body was not. My back hurt and then my legs hurt. My lower back was in spasm. At first I did not particularly like what this drug was doing to my body, but took a good look at it and decided that I was the culprit. Took a good look at my drinking so much, and decided that I didnUt need it. So much energy was going through me I didnUt know what to do with it. The whole day was spent in physical discomfort. Food tasted good, and we nibbled all day. My stomach was bloated. Next day I was more or less like a zombie. I was wiped out.
(with 8 mg) Comes on slowly, not feeling intently until into 2nd hour. I feel slight discomfort but override it responding to music.
I take in air, directing it inside to heal uncomfortable places, open up my clogged sinuses. Wonderful experience of clean, fresh, healing air. Find that discomfort zone is places where I think there is something wrong with me. I dissolve these places with the feeling IUm OK. Like myself better and better, and find more reasons to enjoy and appreciate myself. I find this material powerful, and an excellent working material. Under other circumstances, would probably spend more time working alone inside, where there were great openings, and some of the most beautiful visuals I have seen for a long time.
Usually I do not get visuals. I like the long action. I feel that this material worked for a good week after the experience, with internal processes taking place, many insights, and energy running.
At times the energy was a little uncom-fortable, but could always be quelled by taking a moment for deep relaxation or looking directly at the internal process. I feel that much good internal work has been done, a lot of it unconscious.
(with 9 mg) At the one hour point, I am barely off of baseline. It is not until almost the third hour that the experience is fully developed, and once there it is maintained for another four hours. I was well grounded but rather diffuse. I explored writing (which went quite well), interpretation (pictures and reading both OK) and talking (very good). This is an excellent level, and probably near the max.
(with 12 mg) Slow and even rise. At five minutes to seven (suddenly the clock time makes no sense at all) I am at a 3+ and feel that I have not yet plateauUd. Erotic was excellent. Music good.
Eyes-closed imagery very different place than usual experiences.
Slow, calm, strong images from an area that has no apparent connection with usual waking world, yet underlies all of it. A cool, wise place which has its own rules. All emotions and feeling available, but there is a cool perspective which informs all thinking. Talking superb and fun, and it was possible to feel our bodies healthy and full of determination to remain so, despite obvious faults and self-indulgences. Could do a lot of learning with this material, but probably not a group thing. It would lend itself too easily to hypnotic power-games, and it would be too easy to open up the shared consciousness level, which would be frightening to a lot of people and bring about necessary escapes such as sickness. Excellent feeling the next day.
EXTENSIONS AND COMMENTARY: There is certainly a broad mixture of experiences with 2C-P but, on the whole, probably more favorable than not. There was one report of an experience in which a single dosage of 16 mg was clearly an overdose, with the entire experiment labeled a physical disaster, not to be repeated. A consistent observation is that there may not be too much latitude in dosage between that which would be modest, or adequate, and that which would be excessive. The need for individual titration would be most important with this compound.
37 CPM; CYCLOPROPYLMESCALINE;
4-CYCLOPROPYLMETHOXY-3,5-DIMETHOXYPHENETHYLAMINE
SYNTHESIS: To a solution of 2.8 g homosyringonitrile (see under E for synthesis) in 20 ml acetone containing about 50 mg decyltriethylammonium iodide, there was added 3.0 g cyclopropylmethyl chloride and 5.0 g NaI. Stirring was continued during a color change from pale yellow to blue. There was then added 2.9 g of finely powdered anhydrous K2CO3, resulting in a beautiful turquoise color.
The mixture was held at reflux on the steam bath for 3 h, which discharged all color. The solvent was removed under vacuum, and the residues were added to 100 mL H2O. This solution was extracted with 3x75 mL CH2Cl2, the extracts were pooled, washed with 2x50 mL 5% NaOH, and the organic solvent removed under vacuum. The residual oil weighed 4.2 g, and was distilled at 140-155 !C at 0.4 mm/Hg to yield 4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile as a colorless oil weighing 2.8 g which spontaneously crystallized. Its mp was 44-44.5 !C after recrystallization from MeOH/H2O. Anal. (C14H17NO3) C,H.
A suspension of 1.3 g LAH in 65 mL anhydrous THF under He was cooled to 0 !C with stirring, and 0.85 mL of 100% H2SO4 was slowly added.
Then, with continued stirring, a THF solution of 2.7 g of 4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile in 50 mL THF was added dropwise. After the addition was complete, the mixture was brought to a boil briefly on the steam bath, cooled, and treated with sufficient IPA to destroy the excess hydride. Then there was added an amount of 15% NaOH sufficient to produce a loose filterable solid form of aluminum oxide. This was removed by filtration, and the filter cake washed with THF. The pooled filtrate and washes were stripped of solvent, and the residue was dissolved in dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 2x50 mL of CH2Cl2. After removal of the solvent, the residue was distilled at 128-140 !C at 0.4 mm/Hg to yield 2.5 g of a white oil.
This was dissolved in 10 mL IPA, and treated with 30 drops of concentrated HCl which was just sufficient to demonstrate acidity as judged by external dampened pH paper. The addition of 25 mL anhydrous Et2O to the stirred solution allowed, in a few minutes, the product 4-cyclopropylmethoxy-3,5-dimethoxyphenethylamine hydrochloride (CPM) to spontaneously crystallize as a fine white solid. The yield was 1.8
g, and a second crop of 0.8 g was obtained from the IPA/Et2O mother liquors. The mp was 172-173 !C. Anal. (C14H22ClNO3) C,H.
DOSAGE: 60 - 80 mg.
DURATION: 12 - 18 h.
QUALITATIVE COMMENTS: (with 70 mg) I was surprised at the fast development of this drug, with the knowledge that it was a long-laster. Twenty minutes into it I was aware of some changes, and by the end of one and a half hours there was a complete plus three.
The most remarkable property is the eyes-closed imagery. No, not just imagery but fantasy. It is not completely benign, but it locks into music with an extraordinary fit. I was at one moment keenly aware of my body touching the rug, the tactile aspects of my surroundings, and then I would find that my world was simply my personal sphere of reality that kept engulfing everything about me, all completely augmented by the music. Constructed by the music. I hoped that I wouldnUt offend anyone else around me with this growing world of mine.
Eyes open, there was not that much of note. Not much insight. Not much in the way of visuals. By the eighth hour an effort to sleep showed me how exposed and vunerable I was, and when I closed my eyes I needed my guards against this fantasy world. Even at the twelth hour there was no easy way to relax and sleep. Use higher dosages with caution.
(with 70 mg) There is a goodly amount of eyes-closed patterning but I found external sounds to be irritating. Voices, and even music, seemed to be intrusive. I didnUt want to share my space with anyone.
I was reminded of mescaline, in that I kept losing the awareness of the drug's role in my experience. Visual exaggerations are probably right around the corner. The residual effects were too much to ignor
e, but 100 milligrams of phenobarb at about the twelth hour allowed me to lie down quietly.
(with 80 mg) A wild day of profound philosophy, with discussions of the art of molecules, the origins of the universe, and similar weighty trivia. Much day-dreaming in erotic areas, but by and large, it went on a bit too long. I was tired.
EXTENSIONS AND COMMENTARY: In the literary world, the guy who is on your side, your leader, your champion, is the protagonist and the guy he battles, your enemy, is the antagonist. These same roles are played in the world of pharmacology, but the names are slightly changed. A drug which does the needed or expected thing is called the agonist rather than protagonist, but the drug that gets in its way is still called the antagonist.
The cyclopropylmethyl group plays an interesting role in the world of narcotics. There are numerous examples of opiates with a methyl group attached to a nitrogen atom which are famous for being valuable in producing analgesia and sedation. These run the gamut from natural alkaloids such as morphine and codeine, to synthetic variants such as Dilaudid and Percodan. And yet, with most of these narcotics, when the methyl on the nitrogen is removed, and a cyclopropylmethyl group put into its place, the agonist becomes an antagonist. Oxycodone (the active narcotic thing in Percodan) becomes Naltrexone, a drug that will immediately snap a heroin victim out of his overdose.
Cyclopropylmescaline (CPM) is a molecule that is very simply mescaline itself, with a methyl group removed from an oxygen atom and a cyclopropylmethyl group put on instead. Might CPM be not only inactive, but actually block the action of mescaline? Interesting concept. But it turned out to be entirely wrong.
The amphetamine analog of CPM should be easily made from the alkyl-ation of syringaldehyde with cyclopropyl chloride, followed by conventional reaction of the resulting aldehyde with nitroethane, and finally a reduction step. There is no reason to believe that the resulting compound 3,5-dimethoxy-4-cyclo-propyloxyamphetamine (3C-CPM) would be any shorter acting than CPM.