Heterocyclische Verbindungen

摘要

1,227,978. 1,2,4-Oxa- or thiadiazole derivatives. IMPERIAL CHEMICAL INDUSTRIES Ltd. 12 Aug., 1969 [13 Sept., 1968], No. 43628/68. Heading C2C. [Also in Division A5] 1,2,4-Oxa- or thiadiazole derivatives of the general formula wherein Y is a phenyl, monohalogenophenyl or dihalogenophenyl group in which the halogeno substituent(s) is/are fluorine, chlorine or bromine atoms and either (i) R1 is a methyl group, R2 is a hydrogen atom or a methyl, C 2-6 alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group and R3 is a carboxy, C 2-6 alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group and, when R2 is a C 2-6 alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group, R3 is the same group; or (ii) R1 and R2 are both a hydrogen atom and R3 is a carboxymethyl, C 3-7 alkoxycarbonylmethyl, benzyloxycarbonylmethyl or phenoxycarbonyl - methyl group, and A is an oxygen or sulphur atom, and non-toxic, pharmaceutically acceptable salts thereof, which are novel with the exception of #-(3-phenyl-1,2,4-oxadiazol-5-yl) propionic acid and the ethyl ester thereof, are prepared (a) when R3 is a COOR4 group in which R4 is a C 1-5 alkyl, benzyl or phenyl group and R1 and R2 are as defined under (i) above, by reaction of an alkali metal derivative of a compound of the general formula with methyl chloride, bromide or iodide; (b) when the CR1R2R2 group is in the 5-position, R3 is a COOR4 group and R2 is R5 which is a hydrogen atom or a methyl group, by reaction of a compound of the general formula with sodium or potassium or a hydride, amide or C 1-4 alkoxide thereof and a carbonate of the general formula CO(OR4) 2 ; (c) when R3 is a COOH group and R 2 is R 5 , -CR1R5 possibly being by hydrolysis of a compound of the general formula wherein R6 is a cyano, carbamoyl, C 2-6 alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl group; (d) when the CR1R2R3 group is in the 5-position and is a -CH 2 CH 2 COOH group, by dehydration of a compound of the general formula (e) when R1 is a methyl group and R3 is a C 2-6 alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group or R1 and R2 are both a hydrogen atom and R3 is a C 3-7 alkoxy carbonylmethyl, benzyloxycarbonylmethyl or phenoxycarbonylmethyl group, by esterification of the corresponding carboxylic acid or a salt thereof; and (f) when R2 is a hydrogen atom, R3 is a COOH group and either R1 is a methyl group or -CR1R2 is a -CH 2 CH 2 - group, by reaction of a compound of the general formula wherein R1 is a methyl group or -CR1 = is a -CH 2 CH = group, with a strong inorganic base in the presence of water and under the influence of heat; followed optionally, where appropriate, by salification of the product. Methyl 3 - p - chlorophenyl - 1,2,4 - oxadiazol- 5-ylacetate is prepared by reaction of p-chlorobenzamidoxime with dimethyl malonate. Methyl 5 - p - chlorophenyl - 1,2,4 - oxadiazol- 3-ylacetate is prepared by reaction of a-carbamoylacetamidoxime with p-chlorobenzoyl chloride in the presence of aqueous sodium hydroxide, dehydration of the resulting α-carbamoyl - O p - chlorobenzoylacetamidozime and reaction of the resulting 5-p-chlorophenyl-1,2,4- oxadiazol-3-ylacetamide with hydrogen chloride in methanol.