Blzumin E. Nuchleophilic substitution in chlorо-pyrimidincarboxylic acids derivatives

The nucleophilic substitution reaction in some 5-chloropyrimidines was investigated. The interaction of 2-azahetarylacetonitriles with 2-methylsulfonyl-5-chloro-4-pyrimidincarboxylic acid chloride lead to 2-[5-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-2-oxo-1-(2-hetaryl)-ethyl-cyanides. The latter were shown to react with amines and mercaptanes; and the products of regioselectively substitution of methylsulfonyl group were formed. In the reaction of 2-[5-сhloro-2-(methylsulfonyl)-4-pyrimidinyl]-2-oxo-1-(2-pyridinyl)-ethylcyanid with aliphatic amines 3-amino-5-oxo-5H-pyrimido[4,5-c]quinolizines were formed. 2-[5-сhloro-2-(methylsulfonyl)-4-pyrimidinyl]-2-oxo-1-(2-hetaryl)-ethylcyanides cyclized into fused pyridopyrimidines in the presence of tertiary amines. It was shown that this intramolecular nucleophilic cyclization is influenced by basicity of heterocyclic and also on steric hindrance arising at the heterocyclic nitrogen atom during the cyclization stage. The cyclization of quinazoline-4-one derivatives was found to occur regioselective at N3 of the quinazoline-4-one ring. That demonstrated this intramolecular hetarylation is to be more sensitive toward steric factors. The obtained pyridopyrimidines react with N-, O- and С-nucleophiles to give different derivatives on С-3 position of the ring. The method for preparation of hitherto unknown 2-amino-5-halogenо-4-pyrimidincarboxylic acids via amination of 5-halogenо-2-methylsulfonyl-4-pyrimidine-carboxylic acid was worked out. The interaction of ethyl 2-alkylmercapto-4-chlorо-5-pyrimidincarboxylates with 2-azahetaryl-acetonitriles was investigated. As result, the synthesis of ethyl 4-[(2-hetaryl)-cyanomethyl]-2-alkylmercaptopyrimi-din-5-carboxylates was first carried out. Although the cyclization rate of these carboxylates depends of both the basicity of heterocyclic fragment and steric surrounding of the heterocyclic nitrogen atom, it was shown, that this intramolecular acylation turns out to be more sensitive to basicity factor.