A Convenient Selective N-Alkylation of 4-Oxo-1,4-dihydro-2-quinoline Carboxylic Acid

Abstract

The selective N-alkylation of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid has been achieved from 1,2-dihydro [1,4]oxazino[4,3-a]quinoline-4,6-dione by the 2-morpholinone ring opening. In the same time, we have developed a new methodology to obtain the 1,2-dihydro[1,4]oxazino[4,3-a]quinoline-4,6-dione that involves an intramolecular cyclization of the 2-chloroethyl 6-fluoro-4-oxo-1,4-dihydro-2-quinoline carboxylate.Quinolones, more known for their antibacterial activity, sometimes display hypoglycaemic activity. Indeed, according to Baker and Bramhall 1 in 1972, these molecules act on the glucose metabolic pathway.Recent work 2 has clearly shown the efficacy of some quinolones for inhibiting the activity of the ATP-K + channel of the b cell pancreatic membrane, thereby inducing the production of insulin. These quinolones act according to a mechanism similar to that found with sulfonylureas.Recently, we reported the in vivo activities of some quinolinoylguanidines, 3 and encouraged by these promising results, we therefore decided to investigate the structure / activity relationships of the N-[(2-quinolin)carbonyl]guanidines. We were interested in the selective introduction of a functional group at the nitrogen atom of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid.Historically N-alkyl quinoline-2-carboxylic acids have been obtained from N-alkyl anilines, using the method of Conrad and Limpach, 4 or from 2-amino acetophenones and derivatives, by condensation with diethyl oxalate using ethoxide as the base. 5 Nevertheless, these two methods only provide routes to derivatives with alkyl substituents such as isoamyl, propyl or ethyl because of the chemistry involved in the synthesis of the quinolinic skeleton and moderate yields are often obtained.Previously, by using standard alkylation methodology of the quinoline ring using sodium hydride and iodomethane, Jaen et al. 6 obtained a mixture of N-alkylated and O-alkylated products in 22% and 78% yield, respectively. This reaction revealed that a competitive alkylation takes place due to the prototropic equilibrium shown in Scheme 1.

8‐Fluoro‐4‐hydroxy‐1H‐[1,2,4]triazino[4,5‐a]quinoline‐1,6(2H)‐dione: Synthesis and reactivity

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A simple and versatile methodology to synthesise 4-hydroxy-1H-[1,2,4]triazino[4,5-a]quinoline-1,6(2H)dione from methyl 6-fluoro-4-oxo-1,4-dihydro-2-quinolinecarboxylate has been developed. It involves carbohydrazide formation followed by a condensation with triphosgene to form the fused [1,2,4]triazino ring. In addition, the reactivity of the [1,2,4]triazino ring has been studied.

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“…Recently, we reported the in vivo activities of some quinolinoylguanidines as hypoglycaemic agents [1], and encouraged by these promising results, we therefore decided to investigate the structure/activity relationships of the N-[ (2-quinolin) carbonyl]guanidines [2]. This prompted us to investigate the selective introduction of a functional group at the nitrogen atom of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid.…”

“…We have been particularly interested for some time in the synthesis of novel fused tricyclic quinolones that are non carboxylic at the C3 position, and containing a fouratom bridge connecting the N1 and C2 positions which incorporates a [1,2,4]triazino ring.…”

“…The 8-fluoro-1H- [1,2,4]triazino [1,6-a]quinoline -2,4,6(3H)-trione I (Scheme 1), the first molecule of this class, was obtained from methyl 6-fluoro-4-oxo-1,4-dihydro-2-quinolinecarboxylate by an N-amination followed by a condensation of an aroyl isocyanate to form an alpha semicarbazido-carboxylate that readily cyclizes to give a fused [1,2,4] triazino ring upon treatment with ammonia/ethanol solution as described previously [3].…”

“…In order to perform some structural modifications within the framework of our SAR studies, we have been interested in preparing the 8-fluoro-4-hydroxy-1H- [1,2,4]triazino [4,5-a] quinoline-1,6(2H)-dione II (Scheme 1) and in studying the reactivity of the new [1,2,4]triazino ring.…”