A simple regioselective synthesis of ethyl 1,5‐diarylpyrazole‐3‐carboxylates

Murray, William V.; Wachter, Michael P.

doi:10.1002/jhet.5570260529

Cited by 33 publications

(17 citation statements)

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“…However, as we extended the scope to the reaction of Li-enolate (4) with differently substituted arylhydrazines, it was found that the regioselectivity in the pyrazole ring formation is very dependent on the aromatic substitution pattern of the applied arylhydrazine. This phenomenon 21) is exemplified in Chart 2 for the reaction of the Li-enolate (4) with 4-methoxyphenylhydrazine (9). This reaction yielded a mixture of three products (13), (14) and (15) in 15, 17 and 46% yield, respectively.…”

Section: Chemistrymentioning

confidence: 89%

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Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists.

et al. 2002

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Cannabinoids are present in the Indian hemp Cannabis sativa and have been used as medicinal agents for centuries.1,2) However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on CB receptors and their (endogenous) agonists. The discovery and the subsequent cloning 3,4) of two subtypes of cannabinoid receptor (CB 1 and CB 2 ) stimulated the search for novel cannabinoid antagonists and triggered the development of cannabinoid drugs for the treatment of diseases. 5,6) Several types of CB 1 receptor antagonists are known (Fig. 1). Sanofi disclosed 7-9) their selective CB 1 receptor antagonist SR141716A (rimonabant) which is currently undergoing clinical development for psychotic disorders and obesity treatment. Iodopravadoline AM-630 was introduced in 1995. AM-630 is a moderately active CB 1 receptor antagonist, but sometimes behaves as a weak partial agonist. 10) Researchers from Eli Lilly described 11) the selective CB 1 receptor antagonist LY-320135. 3-Alkyl-5,5Ј-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated 12) to be cannabinoid antagonists. CP-272871 is a pyrazole derivative, like SR141716A, but less potent and less CB 1 receptor subtype-selective 13) than SR141716A. Recently, Aventis Pharma claimed 14) diarylmethyleneazetidine analogs (1) as CB 1 receptor antagonists. Interestingly, many CB 1 receptor antagonists have been reported 15) to behave as inverse agonists in vitro. Several reviews describe the current status in the cannabinoid research area. [16][17][18][19] In this paper our approach to tricyclic selective CB 1 receptor antagonists of general formula (2) is described. 20) We envisioned that an additional ring constraint from the 4-methyl position in SR141716A to the ortho-position of its 5-aryl substituent would provide a novel class of considerably more rigid benzocycloheptapyrazoles (2), thereby having good prospects as potent CB 1 antagonists. Moreover, threedimensional comparison of SR141716A with the more rigid counterpart (2) and analysis of their pharmacological results is expected to provide a more detailed insight in the required bioactive conformation of such CB 1 receptor antagonists, which is expected to facilitate their rational structure optimisation. ChemistryThe four step synthesis route to the CB 1 antagonists (2) is exemplified by the preparation of 8 (Chart 1). Commercially available 1-benzosuberone (3) was deprotonated with lithium bis(trimethylsilyl)amide and subsequently reacted with diethyl oxalate to afford the lithiated keto ester adduct (4) as a solid in 99% yield. Subsequent reaction with the arylhydrazine (5) in acetic acid gave the benzocycloheptapyrazole ester (6) in 51% yield. Mild basic hydrolysis of the carboethoxy group in 6 to the corresponding carboxylic acid proceeded quantitatively. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC)-activated coupling to Naminoperhydroazepine (7) in dichloromethane furnished 8 in 68% yield.In this specific cas...

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Section: Chemistrymentioning

confidence: 89%

“…Our investigations started with compound (21). This compound is found less active than SR141716A in both assays.…”

Section: Biological Evaluation and Discussionmentioning

confidence: 99%

Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists.

et al. 2002

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“…In particular, owing to the excellent chelating ability of b-diketones, the en route lithium salt of benzoylpyruvate 1 can usually be isolated as a shelf-stabile solid by simple filtration [11]. Thus, sequential treatment of 10 with LDA and diethyl oxalate 11 was the preferred method to prepare the needed starting material (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

“…In general, the stipulated benzoylpyruvate 1 can readily be accessed by reacting the metal enolate of the V C 2010 HeteroCorporation 878 Vol 47 corresponding acetophenone 10 with diethyl oxalate 11 [9][10][11]. In particular, owing to the excellent chelating ability of b-diketones, the en route lithium salt of benzoylpyruvate 1 can usually be isolated as a shelf-stabile solid by simple filtration [11].…”

Section: Resultsmentioning

confidence: 99%

A simple and versatile protocol for the preparation of 1,3‐functionalized heterocycles utilizing benzoylpyruvates

Nolsöe

Ertan

Svensson

et al. 2010

Journal of Heterocyclic Chem

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magnified image Acid‐mediated condensation between benzoylpyruvates and various dinucleophiles in alcoholic solvent furnished the heterocyclic imprint in moderate to good yield. Combining a range of symmetric as well as nonsymmetric nitrogen/nitrogen or nitrogen/carbon centered dinucleophiles resulted in excellent regioselectivity. γ‐Difunctionalized fused pyrimidines, pyridazines, and pyridines were produced in this manner. The protocol was designed to obviate chromatographic purification. J. Heterocyclic Chem., (2010).

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“…The former is usually preferred due to initial attack of the unsubstituted hydrazine nitrogen at the more electrophilic 2-carbonyl of 2,4-diketo esters. 9,14 An nOe spectral determination was used to show the regiochemistry of the product SR141716 and by inference the structure of 8. The proximity of the two aryl rings in the 1,5-isomer suggests that an nOe interaction would exist between the ortho protons H a and H b on the respective aryl rings, thus identifying SR141716.…”

Section: Resultsmentioning

confidence: 99%

Tritiation of SR141716 by metallation–iodination–reduction: tritium‐proton nOe study

Seltzman

Carroll

Burgess

et al. 2001

Labelled Comp Radiopharmac

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SummaryThe central cannabinoid receptor antagonist SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, was synthesized from commercially available starting materials. Condensation of an aryl hydrazine with a diketone followed by base promoted isomerization/ cyclization of the intermediate anti-imine gave the pyrazole acid which was converted to the title hydrazide via its acid chloride. Facile iodination via metallation followed by in situ trapping with an iodine source gave a modest yield of the iodinated SR141716. The iodine was selectively reduced with tritium gas and catalyst while retaining the three aryl chlorine atoms in the structure. The tritiated SR141716 exhibited a tritium-proton nOe both definitively identifying the position of the tritium as well as the sought isomer of the diarylpyrazole. This work provides a direct method for the preparation of preferred iodinated aryl substrates that offer advantages where selectivity and high incorporation in catalytic reduction is sought.

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A simple regioselective synthesis of ethyl 1,5‐diarylpyrazole‐3‐carboxylates

Cited by 33 publications

References 5 publications

Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists.

Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists.

A simple and versatile protocol for the preparation of 1,3‐functionalized heterocycles utilizing benzoylpyruvates

Tritiation of SR141716 by metallation–iodination–reduction: tritium‐proton nOe study

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