Synthesis of 9-Thia-3,7-diazabicyclo[3.3.1]nonane 9,9-Dioxides. -(VLASOVA, L. I.; BAIBULATOVA, N. Z.; LATYPOVA, D. R.; YUNUSOV, M. S.; DOKICHEV*, V. A.; TOMILOV, Y. V.; Russ.

A. N. Lobov, L. V. Spirikhin, and V. A. DokichevUnnatural amino acids containing the 3,7-diazabicyclo [3,3,1]nonane unit were synthesized in one step by the reaction of diethyl 3-oxoglutarate, bis(methoxycarbonylmethyl) sulfone, with formaldehyde and primary amino acids under conditions of the Mannich reaction.Keywords: bis(methoxycarbonylmethyl) sulfone, 3,7-diazabicyclo[3,3,1]nonan-9-ones, diethyl 3-oxoglutarate, unnatural amino acids, 9-thia-3,7-diazabicyclo[3,3,1]nonane 9,9-dioxide, Mannich reaction.An important direction at present in the area of organic and pharmaceutical chemistry is the synthesis of new confomationally rigid analogs of natural amino acids [1]. Showing similarities in a number of parameters with natural analogs, the twenty classical amino acids, these compounds possess a high potential for physiological activity. The limited conformational mobility of the molecules may bring about high activity and selectivity in reactions with receptors.Many conformationally hindered and rigid amino acids, and peptide-mimics and synthetic peptides based on them, have been synthesized [1]. However there are few data on conformationally rigid cyclic amino acids containing the 3,7-diazabicyclo[3,3,1]nonane unit. Most of the publications are concerned with the synthesis of amino acids by functionalization of the natural alkaloid cytisine at the N-12 atom [2-4]. The paper [5] must also be noted in which two examples of unnatural amino acids of the 3,7-diazabicyclo[3,3,1]nonane series were synthesized by the reaction of glycine and L-alanine with paraformaldehyde and dibenzyl ketone.The high physiological activity (anticancer [6], antiarrhythmic [7], insecticidal [8], etc.) of derivatives of 3,7-diazabicyclo[3,3,1]nonane predetermines the development of new methods and principles for the preparation of amino acids of unnatural origin, containing the 3,7-diazabicyclo[3.3.1]nonane unit which are of interest from the point of view of developing pharmaceutical preparations. One of the possible methods for the synthesis of nitrogenous heterocycles is the reaction of CH-acids with aldehydes and primary amines, on the basis of which we developed methods for the preparation of derivatives of 1,5-dihydro-3,7-diaza-bicyclo[3,3,1]nonane [9, 10] and 9-thia-3,7-diazabicylo[3,3,1]nonane 9,9-dioxide [11].

1,3-Dimethyl-5-nitro-5-hexahydropyrimidinyl)propionic acid methyl ester (I) was obtained with a 83% yield using a Mannich type reaction of 4-nitrobutanoic acid methyl ester with excess formalin and methylamine. It was found that compound I possesses low toxicity and shows antiarrhythmic activity on models of arrhythmia induced by intravenous injections of calcium chloride and aconitine in rats.

5 Nitropentan 2 one reacts with methylamine and formaldehyde according to the Mannich reaction pattern to give 5 hexahydropyrimidinylcarbonyl substituted 1 nitro 3,7 diazabi cyclo[3.3.1]nonane in one experimental stage. When methyl 3 R 4 nitrobutanoates are used, the reaction stops after the formation of substituted 5 nitrohexahydropyrimidines in 40-98% yields.

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