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Posts 1 - 15 of 36   Subject: alpha-benzylpiperidine & alpha-piperonylpiperidine   Page:  All  Last  Next  New   New  Down

 
    cattleprodder
(Hive Bee)
08-12-04 13:29
No 525033
      alpha-benzylpiperidine & alpha-piperonylpiperidine  Bookmark  Reply   

Have these two compounds ever been synthesized?  Are they psychoactive? 

The first is simply Ritalin without the
R-C02Me group while the second is the same compound plus a 3,4-methylenedioxy system attached to the phenyl ring.

How would you make them?  Any ideas?  Perhaps benzaldehyde (or piperonal) plus 2-MgBr-piperidine followed by removal of the resulting benzyl OH?
 
 
 
 
    josef_k
(Hive Bee)
08-12-04 17:55
No 525064
      I have thought about that compound sometime...  Bookmark  Reply   

I have thought about that compound sometime also, it does have the phenylisopropylamine structure so common among stimulants.

You can only run the grignard with tertiary amines, so your scheme won't work.
Perhaps you could run a Friedel-Crafts alkylation with benzyl chloride and pyridine, and then reduce the resulting compound to the piperidine. Or instead you could react 2-BrMg-pyridine with benzyl chloride, and then reduce.
 
 
 
 
    cattleprodder
(Hive Bee)
08-12-04 18:26
No 525066
      Unfortunately, I don't have the ...  Bookmark  Reply   

Unfortunately, I don't have the resources/connections to pull that synthesis off myself.  I emailed "Ask DrShulgin" about it hoping that he might be impelled to do it himself, but I seriously doubt he will.

Maybe one of you could pull it off?  Bandil or Barium perhaps???  You could conceivably create the next wonder drug (or two)!
 
 
 
 
    Rhodium
(Chief Bee)
08-13-04 00:53
No 525105
User Picture 
      N-methyl-alpha-benzhydryl-piperidine  Bookmark  Reply   

A related substance (2-benzhydryl-1-methyl-piperidine) is discussed here: Post 122779 (dormouse: "alpha-cyclohexyl amphetamine analogue  -Lilienthal", Serious Chemistry)














Molecule: N-methyl-alpha-benzhydryl-piperidine ("CN3C(CCCC3)CC(C2=CC=CC=C2)C1=CC=CC=C1")



The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Nicodem
(Hive Bee)
08-13-04 14:56
No 525245
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      What about reducing the size of that ring?
(Rated as: excellent)
 Bookmark  Reply   

First, just for the sake of an illustration:
cycloPEA.gif

2-benzylpiperidine and 3-phenylpiperidine might have some potentials as stimulants but I seriously doubt about their potential as serotonegics – in my opinion, adding a methylendioxy group to these would not result in MDMA-like activity.
I would also be very skeptical about the alleged amphetamine like activity of alpha-cyclohexyl-PEA mentioned in the link Rhodium provided. Its structure is somewhat similar to lefetamine and it might act trough NMDA blocking and opiate receptors (Post 499450 (Fastandbulbous: "Possible new dissociative (NMDA antagonist)", General Discourse)). Nevertheless it might be an interesting kind of psychoactivity.
Less bulky “ethylamine” side chain would be preferred for serotonergic activity. Reducing the size of the ring to 3-phenylpyrrolidines has more potential for some 5-HT2A affinity, though unfortunately it has even more potential for 5-HT1A affinity. Here is a paper where 3-phenylpyrrolidine based 5-HT1A antagonists show also some nanomolar affinity for 5-HT2A receptors. I assume if one would prepare some suitably substituted 3-phenylpyrrolidines without those annoying N-alkylamide side chains, so typical for 5-HT1A and 5-HT2A antagonists, the resulting compound would be an agonist:

N-Substituted-3-arylpyrrolidines: Potent and Selective Ligands at Serotonin 1A Receptor
Kyo Han Ahn, Seok Jong Lee, Chang-Ho Lee, Chang Y. Hong and Tae Kyo Park
Bioorganic & Medicinal Chemistry Letters 9 (1999) 1379-1384.

Abstract: 3-Arylpyrrolidines are synthesized through the coupling of N-benzyl-3-(methanesulfonyloxy)pyrrolidine with diarylcuprates. Pharmacological evaluation of a series of N-substituted-3-arylpyrrolidines toward several neurotransmitter receptors indicated that some of them are good ligands for serotonin 1A receptor. Particularly, N-[(N-saccharino)butyl]pyrrolidines were found to be potent and selective ligands. A preliminary biological evaluation for several selected compounds indicated that they are potentially effective antianxiety and antidepressant agents.

There are also some other papers on 3-phenylpyrrolidine derived compounds and their pharmacology referenced in the paper above (but at the moment I don’t have access to the full texts). Unfortunately none seam to target for 5-HT2A agonist activity:

Regioselective synthesis of 3-aryl substituted pyrrolidines via palladium catalyzed arylation: pharmacological evaluation for central dopaminergic and serotonergic activity.
Sonesson C, Wikstr6m H, Smith MW. Svensson K, Carlsson A, Waters N.
Bioorg. Med. Chem. Lett. 1997:7;241-246.  DOI:10.1016/S0960-894X(96)00618-X
Abstract: A series of 3-arylpyrrolidines has been synthesised via palladium catalyzed arylation and evaluated for dopaminergic and serotonergic activity in vitro and in vivo. Compounds substituted by electron withdrawing groups on the meta position of the aromatic ring, were found to be preferential dopamine autoreceptor antagonists.

Basha FZ, DeBernardis JF.
Pure & Appl. Chem. 1994:66;2201-2204.

Hancock AA, Buckner SA, Giardina WJ, Brune ME, Lee JY, Morse PA, Oheim KW, Stanisic DS, Warner RB, Kerkman D J, DeBernardis JF. J.
Pharmacol. Exp. Ther. 1995:272;1160-1169.

Patent DE19615232




Some 3-phenylpyrrolidines seam to have some potential for cocaine-like activity:

Actions of A-75200, a novel catecholamine uptake inhibitor, on norepinephrine uptake and release from bovine adrenal chromaffin cells.
Firestone JA, Gerhardt GA, DeBernardis JF, McKelvy JF, Browning MD.
J Pharmacol Exp Ther. 1993 Mar;264(3):1206-10.  Medline (PMID=8450458)

Abstract: The balance between catecholamine (CA) release and reuptake is closely regulated and determines the effective level of transmitter at the synaptic cleft. Drugs that block CA uptake have potential utility as antidepressant medications. One such drug is racemic (+/-)-(1' R*,3R*)-3-phenyl-1-[1',2',3',4'-tetrahydro-5',6'- methylenedioxy-1'-naphthalenyl-methyl]-pyrrolidine methanesulfonate (A-7500), a novel polycyclic compound developed at Abbott Laboratories. This compound is known to bind to CA transporters in the central nervous system, however, its effects on an intact neurosecretory system have not been studied. In this regard, norepinephrine (NE) release from bovine adrenal chromaffin cells (BACC) is a classic model system for CA release and is an excellent system in which to examine the effects of drugs which modulate neurotransmitter release. We compared the effects of A-75200 and its two constituent enantiomers, A-74111 and A-74112, to the effects of three well-characterized uptake inhibitors, desipramine (DMI), nomifensine and cocaine. We found that the Abbott compounds inhibit [3H]norepinephrine ([3H]NE) uptake with an EC50 comparable to cocaine. In addition, unlike nomifensine and cocaine, these compounds inhibited nicotine- and K(+)-stimulated NE release, whereas histamine-stimulated release was preserved. Thus, the Abbott compounds block the effects on secretion of two agonists (nicotine and K+) which depend on a depolarization-dependent influx of extracellular calcium. We conclude that in addition to blocking NE uptake by inhibiting the NE transporter, the Abbott compounds may modulate peripheral NE release by inhibiting calcium flux through voltage-gated channels. This study demonstrates the utility of bovine adrenal chromaffin cells for preclinical trials of drugs that affect catecholaminergic neurotransmission.

Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent alpha-2 antagonism with moderate NE uptake inhibition
Zelle RE, Hancock AA, Buchner SA, Basha FZ, Tietje K, DeBernardis JF, Meyer MD.
Bioorg. Med. Chem. Lett. 1994:4;1319-1322.  DOI:10.1016/S0960-894X(01)80353-X
Abstract: ABT-200, (±)-(1'R*,3R*)-3-phenyl-1-[(1',2',3',4'-tetrahydro-5',6'-methylenedioxy-1'-naphthalenyl)methyl]pyrrolidine, (1a/b) represents the first example of a new structural class of potent alpha-2 antagonists which possess the additional property of norepinephrine (NE) uptake inhibition. This profile of combined activities is expected to have utility in the treatment of depression.

The stimulant (R)-(+)-alpha,alpha-Diphenyl-2-pyrrolidinemethanol can be considered a 2-benzylpyrrolidine derivative: Post 483951 (blunts: "(R)-(+)-alpha,alpha-Diphenyl-2-pyrrolidinemethanol", General Discourse). Note the similarity of this one with the compound in the Rhodium’s post above.




Reducing the ring further down to the azetidine size is in my opinion most promising for hallucinogenic activity. I already posted about that in Post 514788 (Nicodem: "Pharmacology of the 3-phenylazetidines", General Discourse), but that did not raise any interest.

“The real drug-problem is that we need more and better drugs.” – J. Ott
 
 
 
 
    cattleprodder
(Hive Bee)
08-14-04 01:01
No 525316
      interesting  Bookmark  Reply   

Perhaps condensing benzene (or methylenedioxybenzene) with hypophosphorous acid and 2-carboxylic acid piperidine and then reducing the ketone would work.

BTW what is the IUPAC name for 2-carboxylic acid piperidine?  Is it commercially available?  If not, how would one make it?

I still have high hopes for alpha-piperonylpiperidine partly because 3,4-methylenedioxy-2-aminoindan doesn't have the traditional amphetamine structure framework but is still serotonergic, which is not to say that your idea about the reduced ring size analogues should not be investigated as well because I would like to do that as well.

Any takers?
 
 
 
 
    Nicodem
(Hive Bee)
08-14-04 12:14
No 525381
User Picture 
      I still doubt about it
(Rated as: good read)
 Bookmark  Reply   

Perhaps condensing benzene (or piperonal) with hypophosphorous acid and 2-carboxylic acid piperidine and then reducing the ketone would work.

I doubt you can acylate benzene or benzodioxole with piperidine-2-carboxylic acid (that’s its IPAC namesmile) without protecting the amine first. Even with protection I’m still skeptical that it can bee done with the (poly)phosphoric acid or P2O5, but it would not be a stupid thing to try. It would be more rational to use picolinic acid for such an attempt and reduce the resulting compound directly to 2-benzylpiperidine with H2/Pd-C. Such reduction can be done for 3-benzylpiperidine (see DOI:10.1016/j.tet.2003.08.023; the alcohol is an intermediate in the reduction of phenyl-pyrid-2-yl ketone anyway; using such a Grignard reaction on pyridin-2-al would also be a good alternative). Some 2-benzylpiperidines are pharmacologicaly active (unfortunately as dopamine antagonists, search Medline) so many syntheses are already known and described.

I still have high hopes for alpha-piperonylpiperidine partly because 3,4-methylenedioxy-2-aminoindan doesn't have the traditional amphetamine structure framework but is still serotonergic

Well, the aminoindane analogue is actually the less bulky one. The indane ring is fixed almost in one plane and its conformers don’t expand far from the benzene ring. As you can se bellow the conformers of the MDMA molecule can wag on a notably larger area (blue circle) and also considerably out of the benzene plane (not shown). Obviously the space required for the 2-benzylpiperidine to wag from different conformers to the potentially active conformation is quite larger. The restricted receptor site size might not allow for such changes.
Given that the aminoindane analogue is active* we can assume that the preferred ethylamine side chain conformation is to be in plane with the benzene ring (psychedelic amphetamines – 5-HT2A agonists – have very different requirements though). Also, the alpha methyl group in MDMA does not pose much steric interference to the acceptor group in the receptor site (red arc), while in the 2-benzylpiperidine the piperidine ring makes quite an interference and limits the access from many directions. The steric repulsion with the benzene ring would also make any conformation of the ethylamine chain, similar to the required one, energeticaly unfavorable.
You must also consider that the receptor site pockets often don’t allow much space and sometimes already an addition of a methyl group causes the loss of activity. As you probably know MBDB, the aminobutane analogue of MDMA, is slightly weaker and lacks the stimulant activity* and as far as I know the aminopentane analogue is probably already inactive. Now, the 2-benzylpiperidine analogue would have similar space requirements like the aminopentane analogue if not higher. Keep also in mind that the phentermine MDMA analogue (alpha-methyl-MDMA) is already inactive* even though it differ from MDMA by only one methyl group.
Furthermore the inertia of the piperidine ring is higher and the interaction with the acceptor molecule in the receptor site is more likely to lose grip much easier than with MDMA and obviously much, much easier than with the conformationaly restricted aminoindane.
I’m not saying that it would be useless to prepare and test the compound in question. It is quite possible that it is psychoactive. There are many other sites with which it might interact, like the dopamine receptors probably. I’m just saying that its interaction with the serotonin transporter in a MDMA-like fashion as well as with other relevant sites is not very feasible.
MDMA-space.gif

Further read:
* Structure-Activity Relationships of MDMA-Like Substances.
Nichols, Oberlender
http://www.nida.nih.gov/pdf/monographs/download94.html

“The real drug-problem is that we need more and better drugs.” – J. Ott
 
 
 
 
    longimanus
(Hive Bee)
08-14-04 12:34
No 525384
      IUPAC name + price  Bookmark  Reply   

IUPAC Name: Pipecolic acid
 CAS Number: 535-75-1 (the (R)-form)
 CAS Name: 2-Piperidinecarboxylic acid
 IUPAC Name: Piperidine-2-carboxylic acid
 Additional Names: Pipecolinic acid, Hexahydropicolinic acid, Homoproline, Dihydrobaikianine and many others
 
 Price:
 5 gr ~ $15-20
 25 gr ~ $40-70

 The l-form occurs in plants: Phillips, Chem. & Ind. (London) 1953, 127.
 Synthesis:
A. Ladenburg, Ber. 24, 640 (1891)
Stevens, Ellman, J. Biol. Chem. 182, 759 (1950)
V. Asher et al., Tetrahedron Letters 22, 141 (1981)
Synthesis of L-pipecolic acid from L-lysine: Fujii, Miyoshi, Bull. Chem. Soc. Japan 48, 1341 (1975) - actually biosynthesis
Synthesis of racemate: R. T. Shuman et al., J. Org. Chem. 55, 738 (1990)
 
 
 
 
    cattleprodder
(Hive Bee)
08-15-04 06:58
No 525471
      here's a rough 1st draft (needs input)  Bookmark  Reply   

Thanks for all the input.

So, if one were to try to see if the condensation reaction will be a go even without N protection, what procedure to use?

I have extrapolated this rough first draft based on the DOAM entry in PiHKAL.  I'm pretty sure that I got the stoichiometries right.  Note:  this is a highly experimental procedure write up and has not been attempted.

SYNTHESIS:  A solution of 62.4 g benzene (or 97.6 g
1,3-benzodioxole) and 129 g pipecolic acid in 168 g polyphosphoric acid are to be heated on a steam bath for 3 hours.  The strongly acidic solution is then to be poured into 1 L of water and extracted (how to extract without basifying enough to cause intramolecular imine formation while still getting rid of the water soluble acids is eluding me--Shulgin wasn't dealing with an amine and an amine with a ketone functionality at that in his procedure).

After that little kink is worked out, the pure ketone is to presumably undergo the following.  To 360 g mossy zinc there is to be added a solution of 7.2 g mercuric chloride in 200 mL warm water, and this solution is to be swirled periodically for 2 hours.  The water is to be drained off, and the amalgamated zinc added to a 2 L three-necked round bottomed flask, treated with 200 mL concentrated hydrochloric acid, and heated with an electic heating mantle.  Next, a solution of either 48.4 g of the benzene based ketone or 51.5 g of the piperonyl based ketone in 107 mL ethyl alcohol containing 30 mL concentrated hydrochloric acid is to be added dropwise over the course of 4 hours accompanied by 350 mL concentrated hydrochloric acid added batchwise over the same period.  The mixture is to be refluxed overnight, cooled and diluted with enough water to make methylene chloride be the lower phase (on bottom).  The phases are to be separated using a seperatory funnel and the aqueous phase extracted with two 200 mL increments more of methylene chloride.  Next, the two organic phases are to be combined, washed first with 5% sodium hydroxide, and then with water, and the solvent removed under vacuum.  The mother liquors are then distilled and the higher boiling of the 2 (presumably) fractions that come over saved, gassed with HCl or what not, and spread out under the heat lamp to dry.

Help!  This project needs more practical advice.  Thanks.

Oh yeah, can a methylenedioxybenzene ring system stand all the concentrated hydrochloric acid required in Step 2 (the Clemmenson reduction)?  If it can then that means they can make mdma from methylone, I suppose.

It would probably also be better to use racemic pipecolic acid if that is available.  I don't know if the R form is going to give the right or the wrong or a mixture of both products.  Does anyone know the stereochemical configuration of Focalin (dexmethylphenidate)?
 
 
 
 
    Nicodem
(Hive Bee)
08-15-04 13:24
No 525507
User Picture 
      Not good enough yet  Bookmark  Reply   

Cattleprodder, maybe you are not aware that polyphosphoric acid is one of the most powerful dehydrating reagents. This means that there is no way pipecolic acid would acylate benzene without side reactions. If you don’t protect that secondary amine, either as a triflate or as tertiary amine, you would more likely end up with an ugly tar-like polymerization product that could barely deserve to be called a coagulated polypeptide smile.

Secondary aminoketones are usually enough stable as freebases to allow for the extraction.
Anyway, let’s suppose you try with N-methyl-pipecolic acid and somehow end up with the N-methyl-2-benzoylpiperidine. Then you have the problem of the Clemmensen not working well with aminoketones. I have yet to see a successful Clemmensen for alpha-aminoketones. Even aminoketones with the amine group on a more distant position still give rearrangement products in some cases. A more promising method might be the Wolf-Kishner reduction.

However, don’t you think that before jumping on the synthesis propositions it might bee cleverer to first do a literature search for the pharmacology of the compound and its closest derivatives? I gave you a hint that these compounds are known and there is literature available for both synthesis and pharmacology. I was expecting you would follow that hint and post some really interesting info, since obviously they interest me as well (but I should be studying for an important exam instead of searching for literature tongue).

“The real drug-problem is that we need more and better drugs.” – J. Ott
 
 
 
 
    scarmani
(Hive Bee)
08-22-04 23:46
No 526803
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      Sort of Related?
(Rated as: excellent)
 Bookmark  Reply   

Rhodium posted about pyrrolidinopropiophenones which have supposedly appeared on the illicit drug market, including 4'-Methoxy-pyrrolidinopropiophenone (MOPPP) and 3',4'-Methylenedioxy-pyrrolidinopropiophenone (MDPPP).  Post 461388 (Rhodium: "Metabolism of of alpha-pyrrolidinopropiophenones", Serious Chemistry) Also mentioned in Post 377606 (Stonium: "Journal Ref Article Abstracts of Interest (3)", General Discourse) and Post 512763 (Rhodium: "3,4-MD-(alpha-pyrrolidino)propiophenon", Serious Chemistry)

There are some additional papers along the same lines for additional analogs alpha-pyrrolidinopropiophenone (PPP), 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP), and 4'-Methyl-alpha-pyrrolidinohexanophenone (MPHP).  These analogs are not too closely related to the rest of the thread, but they also include the nitrogen in a ring.  It would be interesting to see actual binding studies or bioassays.













Molecule: 4'-Methoxy--pyrrolidinopropiophenone (MOPPP) ("O=C(C1=CC=C(OC)C=C1)C(N2CCCC2)C")














Molecule: 3',4'-Methylenedioxy-pyrrolidinopropiophenone (MDPPP) ("O=C(C1=CC=C(OCO3)C3=C1)C(N2CCCC2)C")














Molecule: 4'-Methyl-alpha-pyrrolidinopropiophenone (MPPP) ("O=C(C1=CC=C(C)C=C1)C(N2CCCC2)C")














Molecule: 4'-Methyl-alpha-pyrrolidinohexanophenone (MPHP) (" CCCCC(N2CCCC2)C(C1=CC=C(C)C=C1)=O")



With the oxygen and nitrogen maybe this look a little bit alike












Molecule: alpha-pyrrolidinopropiophenone (PPP) ("O=C(C1=CC=CC=C1)C(N2CCCC2)C")














Molecule: 4-methylaminorex ("CC1N=C(N)OC1C2=CC=CC=C2")



______  _____  ____  ___  __  _


Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis.
Dietmar Springer, Giselher Fritschi, Hans H. Maurer, R. Staack.
Ther. Drug Monitor. 26(2), 127-31. (2004)

Abstract
Designer drugs of the amphetamine type (eg, MDMA, MDEA, MDA), of the new benzyl or phenyl piperazine type (eg, BZP, MDBP, mCPP, TFMPP, MeOPP), or of the pyrrolidinophenone type (eg, PPP, MOPPP, MDPPP, MPPP, MPHP) have gained popularity and notoriety as rave drugs. These drugs produce feelings of euphoria and energy and a desire to socialize. Although in the corresponding drug scene designer drugs have the reputation of being safe, studies in rats and primates in combination with human epidemiologic investigations indicate potential risks to humans. Thus, a variety of adverse effects have been associated with the use/abuse of this class of drugs in humans, including a life-threatening serotonin syndrome, hepatotoxicity, neurotoxicity, and psychopathology. Metabolites were suspected to contribute to some of the toxic effects. Therefore, knowledge of the metabolism is a prerequisite for toxicologic risk assessment. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are described for designer drugs of different groups. In summary, polymorphically expressed CYP2D6 was the major enzyme catalyzing the major metabolic steps of the studied piperazine- and pyrrolidinophenone-derived designer drugs. However, it cannot be concluded at the moment whether this genetic polymorphism is of clinical relevance.

______  _____  ____  ___  __  _


Metabolism of the new designer drug alpha-pyrrolidinopropiophenone (PPP) and the toxicological detection of PPP and 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP) studied in rat urine using gas chromatography-mass spectrometry.
Dietmar Springer, Giselher Fritschi and Hans H. Maurer
Journal of Chromatography B 796(2), 253-66 (2003)
Medline (PMID=14581066)
Abstract
R,S-alpha-pyrrolidinopropiophenone (PPP) is a new designer drug with assumed amphetamine-like effects which has appeared on the illicit drug market. The aim of this study was to identify the PPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and gas chromatography-mass spectrometry (GC-MS). Analysis of urine samples of rats treated with PPP revealed that PPP was extensively metabolized by hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam, hydroxylation of the aromatic ring in position 4' or double dealkylation of the pyrrolidine ring to the corresponding primary amine (cathinone) partly followed by reduction of the keto group to the corresponding secondary alcohol (norephedrines). As cathinone and the norephedrine diastereomers are also formed after intake of other drugs of abuse or medicaments, special attention must be paid to the detection of the unequivocal metabolite 2"-oxo-PPP as an unambiguous proof for the intake of PPP. The hydroxy groups were found to be partly conjugated. Based on these data, PPP could be detected in urine via its metabolites by full-scan GC-MS using mass chromatography for screening and library search for identification by comparison of the spectra with reference spectra. The same toxicological detection procedure can be applied to other designer drugs of the pyrrolidinophenone type, like MOPPP, MDPPP, MPHP, and MPPP. The detection of the latter will also be presented here.

______  _____  ____  ___  __  _


Studies on the metabolism and toxicological detection of the new designer drug 4'-methyl-alpha-pyrrolidinopropiophenone in urine using gas chromatography-mass spectrometry.
Dietmar Springer, F. Peters, Giselher Fritschi and Hans H. Maurer
Journal of Chromatography B 773(1), 25-33 (2002)
Medline (PMID=12015267)
Abstract
4'-Methyl-alpha-pyrrolidinopropiophenone (MPPP) is a new designer drug which has appeared on the illicit drug market. The aim of our study was to identify the MPPP metabolites and to develop a toxicological detection procedure in urine using solid-phase extraction, ethylation and GC-MS. In urine samples of rats treated with MPPP, MPPP was found to be completely metabolized by oxidative desamination, hydroxylation of the 4'-methyl group followed by oxidation finally to the corresponding carboxy compound and/or by hydroxylation of the pyrrolidine ring followed by dehydrogenation to the corresponding lactam. The carboxy groups were found to be partly conjugated. Based on these data, MPPP could be detected in urine via its metabolites by GC-MS using mass chromatography for screening and library search for identification.

______  _____  ____  ___  __  _


New designer drug 4'-methyl-alpha-pyrrolidinohexanophenone: studies on its metabolism and toxicological detection in urine using gas chromatography-mass spectrometry.
Dietmar Springer, F. Peters, Giselher Fritschi and Hans H. Maurer
Journal of Chromatography B 789(1), 79-91 (2003)
Medline (PMID=12726846)
Abstract
R,S-4'-Methyl-alpha-pyrrolidinohexanophenone (MPHP) is a new designer drug which has appeared on the illicit drug market. The aim of this study was to identify the MPHP metabolites using solid-phase extraction, ethylation or acetylation, as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and GC-MS. Analysis of urine samples of rats treated with MPHP revealed that MPHP was completely metabolized by hydroxylation of the tolyl methyl group followed by dehydrogenation to the corresponding carboxylic acid, hydroxylation of the side chain, hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam and/or reduction of the keto group. The carboxy and/or hydroxy groups were found to be only partly conjugated. Based on these data, MPHP could be detected in urine via its metabolites by GC-MS using mass chromatography for screening and library search for identification.

boot from the shadow of a broken mirror
 
 
 
 
    Fastandbulbous
(Hive Bee)
08-26-04 03:58
No 527379
User Picture 
      Most potent pipradrol deriv  Bookmark  Reply   

Nicodem, for the modification of the heterocyclic ring of 2-benzylpiperidine, I'm not sure quite how effective the structures without the phenylisopropyl structures would be (eg 3-phenylpiperidine). After searching several papers, I found a similar compound, which was stated to be a dopamine reuptake inhibitor (2-methyl-3-phenylquinuclidine), but as you can see, it has the required phenylisopropylskeleton.

Anyhow, main point:

From a paper about the effectiveness of analogues of pipradrol (will post ref when I find the CD-R I've stored it on)with regard to replacing one of the phenyl groups with other aryl compounds (2-thienyl etc), the hydroxy group with a hydrogen and using different nitrogen heterocyclics (ie replacing the piperidyl group with other heterocyclics).

They eventually discovered that the structure given below was the most potent from a wide range of substitutions

pip_deriv.jpeg

The advantage of the morpholines is that they can be made from aminoalcohols and 2-iodoethanol. Using that as a starting place, the appropriate aminoalcohol can be made from reducung diphenylalanine to diphenylalaninol. For the compound analogous to benzylpiperidine, it can be made by reducing phenylalanine to phenylalaninol (3-phenyl-2-aminopropanol), reacting it with 2-iodoethanol to give 3-phenyl-2-(2-hydroxyethyl)propanol, then finally dehydrating with conc sulphuric acid to give 3-benzylmorpholine
(the last two steps are from synthesis of phenmetrazine from phenylpropanolamine).

Although diphenylalanine might not be the easiest amino acid to obtain (for most potent derivative), phenylalanine is available from so many sources it's not worth listing them, and is cheap enough to allow for the synth of 3-benzylmorpholine for evaluation purposes

That is right, the Mascara Snake: Fast and bulbous
 
 
 
 
New: Posts 13 - 15 of 36   Subject: alpha-benzylpiperidine & alpha-piperonylpiperidine   Top   Down
 
 
    phenethyl_man
(Newbee)
08-29-04 00:37
No 528000
      Re: ... it can be made by reducing ...  Bookmark  Reply   


... it can be made by reducing phenylalanine to phenylalaninol (3-phenyl-2-aminopropanol), reacting it with 2-iodoethanol to give 3-phenyl-2-(2-hydroxyethyl)propanol, then finally dehydrating with conc sulphuric acid to give 3-benzylmorpholine ...



I think you mean "3-phenyl-2-(hydroxyethyl)aminopropanol" tongue

Diphenylmethane can be synthesized from the Friedel-crafts alkylation of benzene in the prescence of DCM and AlCl3.  Morpholine can be synthesized from the simple dehydration of diethanolamine which can be obtained from any photography store.  Surely there is some way to attach the amine to that alpha-carbon to obtain the target compound; but I'm too tired to think about it...

When you say this particular compound is the most potent, do you mean in a psychedelic (5-HT2x binding, etc.), or in a stimulatory sense?  I assume it is stimulatory due to the striking similiarity to methylphenidate..  blah, I can just go to my shrink for that; I even get the isolated dextro isomer all by it's lonesome.


- phenethylman -
 
 
 
 
    Fastandbulbous
(Hive Bee)
09-01-04 05:25
No 528671
User Picture 
      Re: phenethyl_man  Bookmark  Reply   

Yes, I meant 3-phenyl-2-(2-hydroxyethyl)aminopropanol, just my brain was 5 steps ahead of my typing, and yes, it's just a stimulant (DAT inhibitor, as is methylphenidate and cocaine), but it was found to be active at a much lower dose than either of the other two mentioned above (reckoned to be 0.5 - 1mg in man) so it's not a worthless compound

That is right, the Mascara Snake: Fast and bulbous
 
 
 
 
    phenethyl_man
(Newbee)
09-01-04 07:10
No 528742
      wow.. now that's potency in a stimulant..  Bookmark  Reply   

wow.. now that's potency in a stimulant.. you are right that doesn't sound worthless; it sounds down-right lethal!

.. and I thought I had a meth problem. There's no doubt I would kill myself w/that.  Hence the reason my ventures into clandestine chemistry are strictly limited to the psychedelic genre..

good luck.

- phenethylman -
 
 

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