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Amino‐mercapto‐pyrimidine (I) bzw. (IV) reagieren mit Bromdimedonen (II) zu Pyrimidobenzothiazinen (III) bzw. (V) und dem Thioether (XIII).

We have previously reported [2, 3] preparative methods and properties for pyrimido [4,5-b][1,4]thiazin-6-one. A study of the biological properties of these compounds has shown that they selectively suppress the growth of tumor cells when compared with the growth of normal cells [4].In a development of this work, we have undertaken the synthesis and study of the reactions of a series of novel pyrimido [4,5-b][1,4]thiazin-6-ones containing a carbethoxy group at position 7. With this in mind, we examined the reaction of 5-amino-6-mercaptopyrimidines Ia-c with diethyl bromomalonate (II). It was found that reaction of 5-amino-4-chloro-6-mercaptopyrimidine (Ia) with compound II in alcohol in the presence of potassium hydroxide gave 5-amino-4-chloro-6-dicarbethoxymethylthiopyrimidine (IIIa). The structure of pyrimidine IIIa was confirmed by the presence in its IR spectrum of absorption bands for the amino group at 3340 and 3440 and two absorption bands for vco from the ester groups at 1735 and 1750 cm ~.It was, however, not possible to convert IIIa to the corresponding pyrimidothiazin-6-one. This is evidently attributable to the lower nucleophilicity of an amino group at position 5 of the pyrimidine ring due to the I-effect of the chlorine atom.Exchange of the chlorine atom in compound Ia for an alkoxy group significantly raises the nucleophilicity of the amino group and leads to closing of the thiazine ring. Hence reaction of the 4-methoxy-and 4-ethoxy-5-amino-6-mercaptopyrimidines (Ib,c) with ester II under the conditions for preparing Ilia leads to the formation of the ethyl esters of 4-alkoxy-6-oxopyrimido [4,5-b][1,4]thiazine-7-carboxylic acids (mb,c). If the same reaction between the named components is carried out at 90-95~ without solvent and in the absence of base, the cyclization process is accompanied by hydrolysis of the alkoxy group in position 4 of the pyrimidine ring. Under these conditions, the reaction of pyrimidines Ib,c with ester II gives the ethyl ester of 4,6-dioxopyrimidothiazine-7-carboxylic acid (IIId). The IR spectra of the pyrimidothiazinones mb-d show the presence of CO and NH absorption bands from the amide group at 1684-1688 and 3210-3325 respectively and an ester carbonyl group at 1733-1738 cm ~, which agrees with their structure. * For communication 49 see [1].

Keywords: pyrimidyl aryl sulfides, pyrimido[4,5-b]-1,4-benzothiazepine, pyrimido [5,4-c]isoquinoline.In previous work [2, 3], we described synthesis of derivatives of 1,4-thiazine tricyclic systems, which include substances with antitumor and psychotropic activity. In continuing these studies, we have developed a method for obtaining 4-alkoxy(amino)-8-nitro derivatives of pyrimido[4,5-b]-1,4-benzothiazepines 1a-d [1]. This work is devoted to study of the properties of compounds 1a-d and synthesis of novel derivatives of this heterocyclic system which are of interest for biological tests.In the first step of this work, we studied reduction of pyrimidobenzothiazepines 1a-c. We established that when these substances are treated with sodium borohydride in ethanol medium at 18-20°C, the dihydropyrimidobenzothiazepines 2a-c are smoothly formed. Their structure has been confirmed by the presence of absorption bands in the IR spectra of compounds 2a,b for the NH group in the 3280 cm -1 and 3380 cm -1 region respectively.For the example of compounds 1b and 2b, we established that their reduction by iron filings in acetic acid leads to 8-amino derivatives 2d and 2e. The compound 2e is also formed when pyrimidobenzothiazepine 2d is treated with sodium borohydride under the conditions for synthesis of derivatives 2a-c. Reactions of compound 2d with phenyl isocyanate and phenyl isothiocyanate yield derivatives 2f,g.