Analogs of biologically active compounds VIII. 1 Synthesis of some derivatives of 6-azalumazine

In this paper the preparations of some N-aryl derivatives of 6-azalumazine are described, by ammonolysis of the corresponding ethyl 1-aryl-N-ethoxycarbonyl-6-azacytosine-5-carboxylates. The latter were obtained in two different ways by multistep reactions from amidinoacetate


Introduction
Attention has been paid previously to derivatives of 6-azapteridine, especially in view of their potential biological activity, 2,3 such as the antiviral activity 4 which was already found before.6-Azalumazine and its derivatives are interesting from this point of view.Syntheses of the above described heterocyclic system are well known, [5][6][7][8][9][10][11][12][13][14] started from convenient derivatives of pyrimidine or 1,2,4-triazine, where the second condensed ring is closed through the synthesis.Up to now all the derivatives of 6-azalumazines 15,16 were prepared by the above-mentioned protocols, but N-aryl derivatives of the 1,2,4-triazine ring had not yet been described; this communication deals with these derivatives.

Results and Discussion
The synthesis is based on the preparation of convenient derivatives of 1-aryl-6-azacytosine-5carboxylic acid on which the condensed pyrimidine ring is subsequently formed.A similar procedure was used to that which used in the synthesis of 1-aryl-6-azauracils 17,18 for the preparation of derivatives of 6-azacytosines.
Ethyl amidinoacetate, 1, 19 was used as a starting material, which was treated with diazonium salts to afford the corresponding hydrazones 3a-d in high yield.The optimal course of these azo-coupling reactions was found in an aqueous solution of sodium acetate and sodium carbonate.These derivatives are sensitive to hydrolysis of the ester group, so the prolonged boiling of the reaction mixture in water solution is accompanied by the formation of the poorly soluble free acid.This fact was considered when the derivatives were crystallized.
The prepared hydrazones 3 were converted into the corresponding ethyl 2-aryl-3-oxo-5ethoxycarbonylamino-2,3-dihydro-1,2,4-triazine-6-carboxylates 5a-d by double acylation with ethyl chloroformate in pyridine.The bis-ethoxycarbonylated hydrazones 4a-d, formed as intermediates by the acylation with ethyl chloroformate have not been isolated yet, because in an alkaline solution of pyridine the spontaneous cyclization takes place to provide the furnished compounds 5.The most easily formed were the derivatives 5a and 5b.In the case of derivatives 5c and 5d, the reaction time was prolonged, and the non-cyclized hydrazones 4c and 4d were detected at shorter reaction time.These, the most probable intermediates, were separated by TLC from the reaction mixture and evidenced by mass spectroscopy (4c: Compounds 5a-d were also prepared by another method, the coupling reaction of diazonium salts with ethyl 3,3-bis[(ethoxycarbonyl)amino]acrylate (2).This compound was provided by the double acylation of ethyl amidinoacetate (1) with ethyl chloroformate.It was supposed that there is formed ethyl 3-[(ethoxycarbonyl)amino]-3-[(ethoxycarbonyl)imino]propanoate (2'), but from NMR spectroscopy it was apparent that the prepared compound is tautomeric form 2. In the 1 H-NMR spectra there are two protons (δ: 10.17 ppm and 11.0 ppm) belonging to an N-H carbamate group and one proton (δ: 5.77 ppm) belongs to methine hydrogen.The presence of the methine hydrogen was also proved by 13

Scheme 2
Compound 2 is likely in an alkaline medium to be in tautomeric equilibrium with tautomer 2', which depends on the basicity of the medium.The coupling reaction does not take place in pyridine solution, but it does take place in aqueous pyridine, sodium acetate, or sodium carbonate.However, the yields of these coupling reactions were relatively low.Neither a longer reaction time nor increased pH (from the presence of sodium hydroxide -where the starting material is hydrolyzed) was accompanied by a higher yield.
C-NMR spectroscopy by the APT method, which unambiguously confirmed structure 2.