Nitrogen and sulfur containing heterocycles. 50. Synthesis and reactions of 6-oxopyrimido[4,5-b][1,4]thiazine-7-carboxylic acid derivatives

Abstract

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].

Synthesis of Novel Derivatives of (Benz)Imidazo[2,1-b]Pyrimido[4,5-d][1,3]Thiazine

“…[1][2][3][4] Among the 1,3-thiazinecontaining heteroaryl-fused structures, pyrimidothiazine derivatives have attracted wide interest due to their considerable biological activities, such as anti-inflammatory, antitumour, antibacterial, antiallergic and antipyretic activity. [5][6][7][8][9] Examples of synthetic methods to prepare pyrimidothiazine-containing compounds include the reaction of 4-methoxy-and 4-ethoxy-5-amino-6-mercaptopyrimidines with diethyl bromomalonate in the presence of potassium hydroxide, 10 cyclisation of mercaptopyrimidine with benzylidine malononitrile in ethoxide solution, 11 the treatment of ethyl-2-cyano-3,3-bis(methylthio) acrylate and thiourea in the presence of potassium carbonate in dimethylformamide, 12 condensation reaction of thioxopyrimidine derivatives and 3-bromopropionic acid, 13 one-pot multicomponent reaction of aryl isocyanides, dialkyl acetylenedicarboxylates and thiouracils 14 and condensation of 5-amino-4-thiopyrimidines with desyl chloride in the presence of sodium acetate. 15 Moreover, imidazothiazines, as other thiazine-fused structures, have often been used as scaffolds in medicinal chemistry.…”