Patent GB-1227978-A (GB)
IPC: C07C259/18
Filed: 1968-09-13
Abstract: 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) R<SP>1</SP> is a methyl group, R<SP>2</SP> is a hydrogen atom or a methyl, C 2-6  alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group and R<SP>3</SP> is a carboxy, C 2-6  alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group and, when R<SP>2</SP> is a C 2-6  alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group, R<SP>3</SP> is the same group; or (ii) R<SP>1</SP> and R<SP>2</SP> are both a hydrogen atom and R<SP>3</SP> 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 R<SP>3</SP> is a COOR<SP>4</SP> group in which R<SP>4</SP> is a C 1-5  alkyl, benzyl or phenyl group and R<SP>1</SP> and R<SP>2</SP> 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 CR<SP>1</SP>R<SP>2</SP>R<SP>2</SP> group is in the 5-position, R<SP>3</SP> is a COOR<SP>4</SP> group and R<SP>2</SP> is R<SP>5</SP> 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(OR<SP>4</SP>) 2 ; (c) when R<SP>3</SP> is a COOH group and R 2  is R 5 , -CR<SP>1</SP>R<SP>5</SP> possibly being by hydrolysis of a compound of the general formula wherein R<SP>6</SP> is a cyano, carbamoyl, C 2-6  alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl group; (d) when the CR<SP>1</SP>R<SP>2</SP>R<SP>3</SP> 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 R<SP>1</SP> is a methyl group and R<SP>3</SP> is a C 2-6  alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group or R<SP>1</SP> and R<SP>2</SP> are both a hydrogen atom and R<SP>3</SP> 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 R<SP>2</SP> is a hydrogen atom, R<SP>3</SP> is a COOH group and either R<SP>1</SP> is a methyl group or -CR<SP>1</SP>R<SP>2</SP> is a -CH 2 CH 2 - group, by reaction of a compound of the general formula wherein R<SP>1</SP> is a methyl group or -CR<SP>1</SP> = 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.