4-hydroxy-2-quinolones. 94. Improved synthesis and structure of 1-hydroxy-3-oxo-5,6-dihydro-3h-pyrrolo[3,2,1-i,j]-quinoline-2-carboxylic acid ethyl ester

Abstract

A modified method is proposed for preparation and purification, and the special features of the spatial structure have been studied for the ethyl ester Keywords: heterocyclic derivatives of tricarbonylmethane, ethyl esters of 4-hydroxy-2-oxoquinoline-3-carboxylic acids, X-ray structural analysis.Esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids display interesting pharmacological properties [2][3][4] and in addition are widely used for obtaining the corresponding alkyl, aryl and heterylamides, and hydrazides. The various hetaryl-substituted quinol-2-ones possess antithyroidal [5], anti-inflammatory [6], local anesthetic [7], antinephritic [8], antitubercular [9], herbicidal [10], antitumor [11], and other forms of biological activity.Several methods of synthesizing such compounds are known today. However, only some of them are used, mostly for preparative purposes, and assume the interaction of alkylanthranilates [12], isatoic acid anhydrides [13,14], or 2-carbalkoxyphenyl isocyanates [15] with derivatives of malonic acid. Subsequent heterocyclization catalyzed by bases leads to esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids. On the whole these methods have been well studied, give excellent yields, and are limited only by the availability of the appropriate anthranilic acids.Comparatively recently a new variant has been proposed for assembling 4-hydroxy-3-carbalkoxy-2-oxoquinoline systems, based on the interaction of trialkyl methanetricarboxylates with N-substituted anilines, including cyclic derivatives. As an example may be given the synthesis of the ethyl ester of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-i,j]quinoline-2-carboxylic acid (1). This includes the condensation of indoline 2 with the triethyl ester of methanetricarboxylic acid (3) [16]. The advantage of this method is that it is one stage, and also it is possible in certain cases to synthesize successfully desired compounds difficult to obtain by other methods. Regrettably, it is not devoid of drawbacks, the most important of which is the formation of side products, acyclic methanetri-N-R-carboxamides. For the suppression of this undesirable reaction a double [16], and sometimes a triple [14], excess of triethyl methanetricarboxylate is used, which reduces the overall

Creation of New Local Anesthetics Based on Quinoline Derivatives and Related Heterocycles

“…In particular, in 1-propylsubstituted 4-hydroxy-quinolones-2 the ethyl fragment is placed perpendicular the plane of the quinolone nucleus, as a result the terminal methyl group is far from the bicycle more thansystem is much compact -in spite of the sofa conformation of the tetrahydropyridine ring, (6) atom deviates from its relative plane only in 0.56 Å (Ukrainets et al, 2008). Unlike 1-N-ethylsubstituted 4-hydroxyquinolones-2, in which the methyl group of ethyl substituent is never located in the quinolone cycle plane (Baumer et al, 2004;Ukrainets et al, 2007), tricyclic pyrrolo[3,2,1-ij]-quinoline system is practically flat (Ukrainets et al, 2006a). It is clear that transfer from 1-N-ethyl-and 1-N-propylsubtituted 3a,b to conformation limited pyrrolo-and pyridoquinolines 12-13 should be obligatory reflected to the biological properties.…”

Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine–Quinolone Carboxamides

“…The tricyclic dihydropyridine-quinolone core was synthesized using an elegant one-pot method developed by Ukrainets et al , A concerted nucleophilic addition–cyclization reaction of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline with triethylmethanetricarboxylate afforded the ester 1 , which was subsequently displaced with a variety of amines to yield analogues 2 (hit compound) through 57 (Scheme ). We began our SAR exploration by evaluating substituted pyridines (analogues 3 – 21 ), an examination of which initially appeared to suggest that substituents at C2 and C6 of the pyridine ring were poorly tolerated, whereas those at C4 and C5 were well tolerated.…”