α,α-Dimethyl-3,4-methylenedioxyphenethylamine · 3,4-Methylenedioxyphentermine
SYNTHESIS: To 150 mL of THF, under an atmosphere of nitrogen, there was added 11.2 g diisopropylamine, and the solution was cooled with external dry ice/IPA. There was then added 48 mL of a 2.3 M solution of butyllithium in hexane, dropwise, with good stirring. This was warmed to room temperature, stirred for a few min, and then all was cooled again in the dry ice bath. Following the dropwise addition of 4.4 g of isobutyric acid there was added 10.5 mL hexamethylphosphoramide. Again, the stirred reaction mixture was brought to room temperature for about 0.5 h. There was then added, drop-wise, 8.5 g 3,4-methylenedioxybenzyl chloride and the mixture allowed to stir overnight at room temperature. The reaction mixture was poured into 100 mL 10% HCl, and the excess THF was removed under vacuum. The acidic aqueous residue was extracted with 2×150 mL Et2O. These extracts were pooled, washed with 10% HCl, and then extracted with 3×75 mL of 4 N Na2CO3. These extracts were pooled, made acidic with HCl, and again extracted with Et2O. After drying the pooled extracts with anhydrous MgSO4, the solvent was removed under vacuum to give a residue that spontaneously crystallized. Recrystallization from hexane yielded 6.5 g of 2,2-dimethyl-3-(3,4-methylenedioxyphenyl)propionic acid as white crystals with a mp of 71–73 °C. The NMR spectrum in CDCl3 showed the alpha-dimethyl groups as a sharp singlet at 1.18 ppm. Anal. (C12H14O4) C,H.
The triethylamine salt of 2,2-dimethyl-3-(3,4-methylenedioxyphenyl)propionic acid (5.4 g amine, 11.4 g acid) was dissolved in 10 mL H2O and diluted with sufficient acetone to maintain a clear solution at ice-bath temperature. A solution of 6.4 g ethyl chloroformate in 40 mL acetone was added to the 0 °C solution over the course of 30 min, followed by the addition of a solution of 4.1 g sodium azide in 30 mL H2O. Stirring was continued for 45 min while the reaction returned to room temperature. The aqueous phase was extracted with 100 mL toluene which was washed once with H2O and then dried with anhydrous MgSO4. This organic solution of the azide was heated on a steam bath until nitrogen evolution had ceased, which required about 30 min. The solvent was removed under vacuum and the residue was dissolved in 30 mL benzyl alcohol. This solution was heated on the steam bath overnight. Removal of the excess benzyl alcohol under vacuum left a residue 13.5 g of 1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane as an amber oil. The dimethyl group showed, in the NMR, a sharp singlet at 1.30 ppm in CDCH3. Anal. (C19H21NO4) C,H. This carbamate was reduced to the primary amine (below) or to the methylamine (see under
A solution of 3.27 g of 1-[N-(benzyloxycarbonyl)amino]-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane in 250 mL absolute ethanol was treated with 0.5 g 10% palladium on carbon. This mixture was shaken under hydrogen at 35 pounds pressure for 24 h. The carbon was removed by filtration through Celite, and the filtrate titrated with HCl. The solvent was removed under vacuum, and the residue allowed to crystallize. This produce was recrystallized from an EtOH/EtOAc mixture to provide α,α-dimethyl-3,4-methylenedioxyphenethylamine hydrochloride (MDPH). The white crystals weighed 1.63 g and had a mp of 180–181 °C. Anal. (C11H16ClNO2) C,H,N.
DOSAGE: 160–240 mg.
DURATION: 3–5 h.
QUALITATIVE COMMENTS: (with 120 mg) “The alert was felt in forty minutes and I was pretty much there at an hour and twenty. Quite like
(with 160 mg) “A very quiet development. There was no body load whatsoever. And no visual, and I saw it fading away all too soon. This might be a good promoter, like
(with 200 mg) “This has an inordinately foul taste. I felt slightly queasy. There were short daydreams which were quickly forgotten. I see no values that are worth the hints of physical problems, a little eye mismanagement and some clenching of teeth, and a tendency to sweat. I was able to sleep at only five hours into it, but there were a couple of darts. This is not as rewarding (stoning) as plus two.”
EXTENSIONS AND COMMENTARY: What is the train of thought that leads from the structure of a known compound (which is active) to the structure of an unknown one (which may or may not be active)? Certainly the extrapolations involve many what-if’s and maybe’s. The path can be humorous, it certainly can be tortuous, and it often calls for special things such as faith, insight, and intuition. But can one say that it is logical?
Logic is a tricky thing to evaluate. One of the earliest approaches was laid down by Aristotle, in the form of the syllogism. In it there are three lines consisting of two premises and a conclusion, a form that is called a “mood.” All are statements of relationships and, if the premises are true, there are only certain conclusions that may logically follow. For example:
- Every man is a lover.
- Every chemist is a man.
- Therefore, every chemist is a lover.
Letting lover be the major term “a” and letting chemist be the minor term “b” and letting man be the middle term “m”, this reduces to:
- Every m is a,
- Every b is m.
- Therefore, every b is a
and it is a valid mood called Barbara.
Of the 256 possible combinations of all’s and some’s and none’s and are’s and are-not’s, only 24 moods are valid. The reasoning here with MDPH goes:
- Some stimulants when given a methylenedioxy ring are MDMA-like.
- Some ring-unsubstituted 1,1-dimethylphenylethylamines are stimulants.
- Therefore, some ring-unsubstituted 1,1-dimethylphenylethylamines when given a methylenedioxy ring are MDMA-like.
In symbolic form this is:
- Some m is a, and
- Some b is m, then
- Some b is a
and this is not one of the 24 valid moods. Given the first premise as some m is a, there is only one valid syllogism form that can follow, and this is known as Disamis, or:
- Some m is a, and
- Every m is b, then
- Some b is a
which translates as:
- Some stimulants when given a methylenedioxy group are MDMA-like.
- Every stimulant is a ring-unsubstituted 1,1-dimethylphenylethylamine.
- Therefore, some ring-unsubstituted 1,1-dimethylphenylethylamines when given a methylenedioxy group are MDMA-like.
The conclusion is the same. But the second premise is false so the entire reasoning is illogical. What is the false second premise? It is not a fact that every stimulant is a phentermine. There are lots of stimulants that are not phentermines.
So much for applying syllogistics to pharmacology.
13 May 2016 · · Isomer Design
About PiHKAL · info
This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.
“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.
PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.Transform Press,
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