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Posts 1 - 12 of 12 | Subject: alpha-benzylpiperidine & alpha-piperonylpiperidine | Down | ![]() |
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cattleprodder (Hive Bee) 08-12-04 13:29 No 525033 |
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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? |
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josef_k (Hive Bee) 08-12-04 17:55 No 525064 |
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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. |
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cattleprodder (Hive Bee) 08-12-04 18:26 No 525066 |
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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)! |
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Rhodium (Chief Bee) 08-13-04 00:53 No 525105 ![]() |
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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 |
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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) |
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First, just for the sake of an illustration: ![]() 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)pyrrolidi 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'-tetrahyd 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'- The stimulant (R)-(+)-alpha,alpha-Diphenyl-2-pyrrolidi 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 |
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cattleprodder (Hive Bee) 08-14-04 01:01 No 525316 |
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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? |
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Nicodem (Hive Bee) 08-14-04 12:14 No 525381 ![]() |
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I still doubt about it (Rated as: good read) |
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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 name ![]() 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. ![]() Further read: * Structure-Activity Relationships of MDMA-Like Substances. Nichols, Oberlender http://www.nida.nih.gov/pdf/monographs/d “The real drug-problem is that we need more and better drugs.” – J. Ott |
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longimanus (Hive Bee) 08-14-04 12:34 No 525384 |
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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) |
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cattleprodder (Hive Bee) 08-15-04 06:58 No 525471 |
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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)? |
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Nicodem (Hive Bee) 08-15-04 13:24 No 525507 ![]() |
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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 ![]() 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 ![]() “The real drug-problem is that we need more and better drugs.” – J. Ott |
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scarmani (Hive Bee) 08-22-04 23:46 No 526803 ![]() |
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Sort of Related? | Bookmark Reply | |||||
Rhodium posted about pyrrolidinopropiophenones which have supposedly appeared on the illicit drug market, including 4'-Methoxy-pyrrolidinopropiophenone (MOPPP) and 3',4'-Methylenedioxy-pyrrolidinopropioph There are some additional papers along the same lines for additional analogs alpha-pyrrolidinopropiophenone (PPP), 4'-methyl-alpha-pyrrolidinopropiophenone Molecule: 4'-Methoxy--pyrrolidinopropiophenone (MOPPP) ("O=C(C1=CC=C(OC)C=C1)C(N2CCCC2)C") Molecule: 3',4'-Methylenedioxy-pyrrolidinopropioph Molecule: 4'-Methyl-alpha-pyrrolidinopropiophenone Molecule: 4'-Methyl-alpha-pyrrolidinohexanophenone 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 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 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 ______ _____ ____ ___ __ _ New designer drug 4'-methyl-alpha-pyrrolidinohexanophenone 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-pyrrolidinohexanophe boot from the shadow of a broken mirror |
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Fastandbulbous (Hive Bee) 08-26-04 03:58 No 527379 ![]() |
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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 ![]() 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 |
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