Alpha- and Beta-Prodine Type Compounds
A. H. Beckett, A. F. Casy, G. Kirk
J. Med. Chem. 1, 37-58 (1959) (https://www.thevespiary.org/rhodium/Rhodium/pdf/alpha-beta.prodines.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/alpha-beta.prodines.pdf)
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Receptor binding of the analgetic aryl moiety. I. ?-Prodine analogs
Khalid Sabih, Robert A. Wiley
J. Med. Chem. 12, 922-923 (1969) (https://www.thevespiary.org/rhodium/Rhodium/pdf/alpha-prodine.analogs.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/alpha-prodine.analogs.pdf)
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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) (https://www.thevespiary.org/rhodium/Rhodium/pdf/prodine.potency-affinity.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/prodine.potency-affinity.pdf)
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 ?/? isomers are determined primarily by the appropriate association to the receptor sites.
One-step Prodine synthesis from ?-ethylstyrene: Patent US2765315 (http://l2.espacenet.com/dips/viewer?PN=US2765315&CY=gb&LG=en&DB=EPD)
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/bulletin_1957-01-01_4_page006.html#s12)
(http://www.unodc.org/unodc/bulletin/bulletin_1957-01-01_4_page006.html#s12)
Maybe you don't realise that the molecule you have drawn IS prodine!
See: https://www.thevespiary.org/rhodium/Rhodium/pdf/prodine.pdf (https://www.thevespiary.org/rhodium/Rhodium/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...
The Reaction of 2-Substituted Cyclohexanones with Organometallic Compounds
S. M. McElvain, Rodney B. Clampitt, J. Am. Chem. Soc. 81, 5590-5598 (1959)
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/pdf.gif)
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.