Synthesis of 4‐hydroxyquinolin‐2(1H)‐one analogues and 2‐substituted quinolone derivatives

Abstract

A versatile synthetic method for preparing 4-hydroxyquinolone and 2-substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates were keto esters 4a-e, which could be transformed to 4-hydroxyquinolones 5a,b or 2-substituted quinolone ethyl esters 6a-c depending on the reaction conditions. 4-Hydroxyquinolone analogues were prepared and investigated for N-methyl-D-aspartate (NMDA) activity in vitro. Among these derivatives, 6,7-difluoro-3-nitro-4-hydroxyquinolin-2(1H)-one (9) exhibited moderate activity. A variety of routes for the synthesis of 4-hydroxyquinolone compounds have been reported in the literature [5][6][7][8]. Most of these methods have been based on the cyclization of malondianilides with aluminium trichloride [9] or poly phosphoric acid [10], which afforded the corresponding 4-hydroxyquinolone compounds in poor to moderate yields and made the product isolation considerably difficult. Our need for rapid access to 4-hydroxyquinolone compounds for large scale syntheses for 2-substituted quinolone compounds, prompted us to explore new methodology for the synthesis of these compounds.The present paper describes a convenient method for the preparing 4-hydroxyquinolones 5a,b and 2-substituted quinolone compounds 6a-c. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis [11] and reductive cyclization. Several derivatives of 4-hydroxyquinolone and 2-substituted quinolone were also prepared by simple method from 4-hydroxyquinolones 5a,b and 2-substituted (methyl or phenyl) quinolones 6a-c. These compounds were evaluated for N-methyl-D-aspartate (NMDA) glycine binding site activity and antibacterial activity in vitro, respectively.We have used 4,5-difluorobenzoic acid as starting material, which was nitrated to give 4,5-difluoro-2-nitrobenzoic acid (2b). Acids 2a,b were treated with thionyl chloride to give acid chlorides, which were subsequently treated with the anion of diethyl malonate, ethyl acetoacetate or phenyl acetoacetate to give keto esters 4a-e in excellent yields. In this condensation reaction, we found that magnesium ethoxide was the most effective among bases such as sodium ethoxide, sodium hydride and potassium t-butoxide. The keto diesters 4a,b were smoothly transformed to 4-hydroxyquinolone compounds 5a,b by reductive ring closure over palladium-on-charcoal with sodium borohydride under akaline reduction condition. Whereas, the diketo esters 4c-e were converted to N-hydroxy-2-substituted quinolone compounds 6a-c using the mild catalytic hydrogenation over palladium-oncharcoal in ethanol at room temperature (Scheme 1). Jan-Feb 2001 61 i) HNO 3 /H 2 SO 4 ; ii)SOCl 2 , urea/toluene; iii) Mg, EtOH/toluene; iv) NaBH 4 , Pd-C, NaOH (aq), 1,4-dioxane; v) H 2 , Pd-C, EtOH, 1 bar.

Novel 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New CB2 Cannabinoid Receptors Agonists: Synthesis, Pharmacological Properties and Molecular Modeling

“…N -alkylation of 2 in anhydrous DMF with appropriate alkyl bromides or benzylbromide in the presence of sodium hydride gave the 1-alkyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl esters 3 − 6 . Hydrolysis in 10% aqueous NaOH yielded the corresponding 1-alkyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids 7 − 10 …”

“…44 Hydrolysis in 10% aqueous NaOH yielded the corresponding 1-alkyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids 7-10. 45 To obtain some chemical diversity among 1-alkyl-4-oxo-1,4-dihydroquinoline-3-carboxamides, a solid phase procedure was set up using a previously reported polystyrene-supported HOBt as coupling reagent. 46,47 The reaction performed on a Quest 205 synthesizer according to the general reaction pathway outlined in Scheme 2 generated compounds 11-36.…”

Asmarines G and H and Barekol, Three New Compounds from the Marine Sponge Raspailia sp.

“…Reduction of Asmarine A (1) to Asmarine H(4). Asmarine A (10 mg) in 80% aqueous ethanol (5 mL) was treated with Na 2 S 2 O 3 (5 mg). After 3 h at 60 °C, the cooled solution was evaporated.…”

4‐Quinolone Derivatives and Their Activities Against Gram‐negative Pathogens

“…Several series 4‐quinolone derivatives with amino , methyl or phenyl , 2,3‐oxaborole‐fused , and pyridinium bromides at C‐2 position were screened for their activities against representative Gram‐negative organisms, in spite of the activity was weak for the majority of them, the SAR enriched.…”