| 摘要 |
A process for preparing 5-methylisoxazole-4-carboxylic-(4'-trifluoromethyl)-anilide comprising: (a) reacting ethylacetoacetate, triethylorthoformate, and acetic anhydride at a temperature of from about 75° C. to about 150° C., to form ethyl ethoxymethyleneacetoacetic ester; (b) combining the ethyl ethoxymethyleneacetoacetic ester with sodium acetate or a salt of trifluoroacetic acid in the presence of hydroxylamine sulfate at a temperature of from about -20° C. to 10° C., to form ethyl-5-methylisoxazole-4-carboxylate; (c) reacting the ethyl-5-methylisoxazole-4-carboxylate with a strong acid to form 5-methylisoxazole-4-carboxylic acid; (d) reacting the crystallized 5-methylisoxazole-4-carboxylic acid with thionyl chloride to form 5-methylisoxazole-4-carbonyl chloride; and (e) reacting the 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline and an amine base at a temperature of from about 0° C. to about 50° C. to form 5-methylisoxazole-4-carboxylic-(4'-trifluoromethyl)-anilide. The process of the invention is especially advantageous for preparing 5-methylisoxazole-4-carboxylic-(4'-trifluoromethyl)-anilide, since the process: (1) eliminates or reduces the formation of the by-product 2-cyanoacetoacetic-1-(4'-trifluoromethyl)-anilide (CATA), generally as low as 0.0006%; (2) eliminates or reduces the formation of isomeric impurity ethyl-3-methyisoxazole-4-carboxylate and its corresponding acid as low as 0.1%, (3) produces a high quality of 5-methylisoxazole-4-carboxylic-(4'-trifluoromethyl)-anilide generally having 99.8-100% HPLC potency; and (4) does not require distillation of the isoxazole ester.
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