Patent GB-1268916-A (GB)
Title: Novel derivatives of pyrazinylmalonates and pyrazineacetic acids
IPC: C07D241/12
Filed: 1969-11-07
Abstract: 1,268,916. Derivatives of pyrazinyl-malonic and acetic acids. McNEIL LABORATORIES Inc. 7 Nov., 1969 [8 Nov., 1968], No. 54700/69. Heading C2C. The invention comprises compounds of the general formula in which R is a phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, trifluoromethylphenyl, lower alkoxyphenyl, di-lower alkoxyphenyl, lower alkyl phenyl, di-lower alkyl phenyl, cyclohexyl or cyclopentyl group or represents two phenyl groups in the 5- and 6-positions; R 1  is hydrogen or a lower alkyl group; R 2  is hydrogen, a lower alkyl or lower alkyl carboxylate group or a sodium, calcium or ammonium carboxylate group; X is a lower alkyl carboxylate ester, carboxylic acid or carboxamide group, an N-lower alkyl-, N,N-di-lower alkyl-, N-aryl-, N-aralkyl- or N-heterocyclic-substituted carboxamide group or a sodium, calcium or ammonium carboxylate group provided that when R 2  is a lower alkyl carboxylate ester group or a carboxylate salt group, X is also respectively a lower alkyl carboxylate ester group or a carboxylate salt group; and also-compounds of the above formula in which R is X, R 1  is hydrogen or lower alkyl, R 2  is hydrogen, a lower alkyl or lower alkyl carboxylate ester group or a sodium, calcium or ammonium carboxylate salt group; X is a lower alkyl carboxylate ester of a carboxylic acid group, or a sodium, calcium or ammonium carboxylate salt group, provided that where R 2  is a lower alkyl carboxylate ester group or a carboxylate salt group, X is respectively a lower alkyl carboxylate ester group or a carboxylate salt group. The term lower alkyl is restricted to alkyl groups containing 1-7 carbon atoms. Compounds of the above formula in which R 1  is hydrogen or alkyl, R 2  is alkyl carboxylate and X is an alkyl carboxylate group may be prepared by reacting the appropriate 2-chloropyrazine with a dialkyl malonate or dialkyl alkylmalonate in the presence of sodium hydride in a solvent. Compounds in which R 1  and R 2  are both hydrogen or R 1  is hydrogen, R 2  is alkyl and X is an alkylcarboxylate group may be prepared by heating the dialkyl pyrazinyl malonate or dialkyl alkyl pyrazinyl malonate prepared as above in a solvent in the presence of sodium cyanide. Compounds in which R 1  and R 2  are both hydrogen or R 1  is hydrogen and R 2  is alkyl and X is a -COOH group may be prepared by refluxing the pyrazine acetates obtained as above in aqueous sodium hydroxide and acidifying the product. Alternatively these compounds may be obtained by treating the dialkyl pyrazinylmalonates and alkyl malonates with a base and acidifying the product. Compounds in which X is a carboxamide group may be prepared by reacting the pyrazine acetate derivatives with ammonium hydroxide. Compounds in which R r  and R 2  are both alkyl and X is an alkyl carboxylate group may be prepared by reacting an alkyl halide with an alkyl-α-alkyl pyrazine acetate in the presence of sodamide in liquid ammonia. These products may be converted to the corresponding acetamides and acetic acids by the methods described above. The N-substituted acetamides may be prepared by reacting the acetic acid derivatives with thionyl chloride and then with the appropriate amine and the carboxylic acid salts may be obtained by reacting the acid with an aqueous base. Numerous examples of the invention are given and in addition certain starting materials are made as follows:-(a) 5-phenylpyrazin-2-olandp-(chlorophenyl)-pyrazin-2-ol are made by reacting phenyl glyoxal hydrate and p-chlorophenyl glyoxal hydrate respectively with glycinamide hydrochloride; and (b) 2-chloro-5-phenyl pyrazine and 2-chloro-5-(p-chlorophenyl)pyrazine are prepared by reacting phosphorus oxychloride with 5-phenyl pyrazin-2-ol and 5-(p chlorophenyl)-pyrazin-2-ol respectively. The pyrazine derivatives may be used as ultraviolet absorbers in polymers and some may be used as anti-inflammatory agents.