09-09-04 03:45
No 530422
Has anyone had any dreams of phenylpiperidine analgesics? I was thinking that maybe the 1,3-dimethylpiperidinone could be synthed from 1-methylpiperidinone with LDA and CH3I? Maybe make a silyl enol ether with TMSCl to ensure that LDA only deprotonates 1 alpha carbon? Can PhMgCl be substituted for PhLi? With modern chromatography techniques and analytical methods there really is no danger of having possible MPTP contamination in what would be pharmaceutical grade yumminess.
Is this class of analgesics less adictive than morphine? Can they be used recreationally? There are a lot of papers on syntheses of prodine analogues which were bioassayed. This seems very interesting.
blessed...
(Hive Addict)
09-09-04 22:59
No 530526
Why can I not find any relevant literature on the named compound's pharmacodynamics? Can you provide anything?
(Chief Bee)
09-10-04 00:44
No 530545
(Rated as: excellent)
Alpha- and Beta-Prodine Type Compounds
A. H. Beckett, A. F. Casy, G. Kirk
J. Med. Chem. 1, 37-58 (1959) (../rhodium/pdf /alpha-beta.p
____ ___ __ _
Receptor binding of the analgetic aryl moiety. I. α-Prodine analogs
Khalid Sabih, Robert A. Wiley
J. Med. Chem. 12, 922-923 (1969) (../rhodium/pdf /alpha-prodin
____ ___ __ _
Relations between opiate receptor binding and analgetic properties of prodine-type compounds
M. A. Iorio, W. A. Klee
J. Med. Chem. 20, 309-310 (1977) (../rhodium/pdf /prodine.pote
Abstract
The receptor binding affinities of some diastereoisomeric prodine analogues have been compared with their analgetic activities determined by the hot-plate test in mice. The close correlation found between these potencies indicates that the relative analgetic activities of the α/β isomers are determined primarily by the appropriate association to the receptor sites.
One-step Prodine synthesis from α-ethylstyrene: Patent US2765315
This article contains a section on pethidine reversed esters, i.e. Prodines:
A. H. Beckett, A. F. Casy, Recent advances in pethidine-type analgesics, Bulletin in Narcotics, No. 4, pp. 37-54 (1957)
Reversed Esters of Pethidine, Synthesis and Stereochemistry (http://www.unodc.org/unodc/bulletin/bul
The Hive - Clandestine Chemists Without Borders
(Hive Bee)
09-10-04 11:46
No 530616
Maybe you don't realise that the molecule you have drawn IS prodine!
See: http://rhodium.ws/pdf/prodine.pdf for an interesting synthesis of this...
Looking in "Opioid Analgesics - Chemistry and Receptors" by Casy and Parfitt:
Page 252 contains a very similar diagram to the one you provided, they start with the 2nd compound you have pictured, then the arrow says "PhLi | (EtCO)2O" and the resulting compound is the same as the last molecule in your diagram with the methyl pointing both in and out.
The end product is referred to as "The original 3-methyl reversed esters derived from 1,3-dimethyl-4-piperidone" ... alpha-prodine and beta-prodine. It goes on to say alpha-prodine is equipotent to morphine, and beta-prodine is 5X morphine.
These 2 references are related:
L.O.Randall and G.Lehman, J. Pharmacol. Exp. Ther. 93, 314 (1948)
A.F.Casy in Guide to Molecular Pharmacology-toxicology, Part 1 (R.M.Featherstone, ed.), pg 217, Marcel Dekker, New York (1973)
On page 245 "Isoprodines (28), related to Beta-pethidine, are inactive in mice in doses up to 100mg/kg"
The molecule referred to by (28) looks exactly the same as the one you posted, except the Methyl is switched with the phenyl/OCOEt. The source is: M.A.Iorio, H.Michalek, and G.Damia, Chim. Therap. 2, 233 (1973)
Edit: Rhodium pretty much said what I said earlier and better, thats what I get for not hitting the "Submit Post" button for several hours...
(Hive Bee)
09-10-04 15:16
No 530632
If I remember correctly these synthetic pathways more or less create a side product thats known to cause chemically produced irreversible parkinsonism by the selective destruction of D2 dopamine receptors in man.
Please dont challenge your body with such unworthyness. Its the only thing that you really have. Be careful.
(Hive Bee)
09-10-04 15:57
No 530639
There is no problem with the product when going the path from alfa-ethylstyren as in the patent found by Epikur.
(Chief Bee)
09-11-04 06:02
No 530778
The Reaction of 2-Substituted Cyclohexanones with Organometallic Compounds
S. M. McElvain, Rodney B. Clampitt, J. Am. Chem. Soc. 81, 5590-5598 (1959)
Abstract
The reaction products of a series of 2-substituted cyclohexanones (III) with phenylmagnesium bromide and phenyllithium have been determined, When the 2-substituent is a carbethoxymethyl or a 2-carbethoxyethyl group, a major reaction product is the metal enolate of the original ketone. When this substituent is the dimethylaminornethyl group, normal addition of the organometallic compound to the ketone function occurs. If the amino function is separated from the ring by two or three methylene groups, the enolization reaction is the main or only reaction with phenylmagnesium bromide; with phenyllithium these substituents do not interfere with normal addition to the ketone. With non-polar alkyl groups as 2-substituents, both organometallic compounds give the normal addition reactions. A rationalization of these results is proposed. The propionates of two of the aminocarbinols (XIIIc and d) were prepared and screened for analgesic activity.
The Hive - Clandestine Chemists Without Borders
(Newbee)
09-11-04 22:47
No 530915
Thanks for the refs, Rhod!
Looks like PhMgBr will work fine with an alkyl substitution. The paper that I'm referencing is not in front of me at the moment. I will get it up soon. They actually prepare the piperidinone by a Dieckman condensation followed by decarboxylation. I agree. As I implied, do not try this reaction in an ill-equipped lab. A small amount of the dehydration will probably occur and insufficient purification could only lead to disaster. This is all for curiosity's purposes only.
I read somewhere that demerol-like analgesics can not be routinely administered anyway because buildup of the demethylated metabolite leads to seizures. bless... bless...