Patent GB-595775-A (GB)
Title: Improvements in or relating to isoxazole derivatives and process of making the same
Filed: 1945-05-03
Abstract: Sulphanilamido-isoxazole derivatives are prepared by condensing a benzenesulphonyl halide, substituted in the p-position by a nitro- or acyl-amino group, with a 5-amino-isoxazole derivative of the formula <FORM:0595775/IV/1> (in which R1 and R11 are lower alkyl and/or lower alkoxy-alkyl groups) and treating the product to convert the substituent in the p-position into a free amino group.  The sulphanilamido-isoxazole derivatives form neutral or nearly neutral salts by reaction with compounds of alkali metals, alkaline earth metals or strong organic bases.  The following examples are given: (1) p-acetaminobenzenesulphonyl chloride is condensed with 3,4-dimethyl-5-amino-isoxazole and the product hydrolyzed with acid or alkali to give 5-sulphanilamido - 3,4 - dimethyl - isoxazole; (2) 5 - amino-3,4-dimethyl-isoxazole is condensed with p-nitrobenzenesulphonyl chloride and the product reduced to 5-sulphanilamido-3,4-dimethyl-isoxazole by means of zinc dust and hydrochloric acid; (3) 5-sulphanilamido-3-ethyl-4-methyl-isoxazole is prepared from 3-ethyl-4-methyl-5-amino-isoxazole in a manner similar to that in (1); (4) 5-sulphanilamido-3-ethoxymethyl-4-methyl-isoxazole is p  prepared as in (1) from 3-ethoxymethyl-4-methyl-5-amino-isoxazole; (5) the sodium salt is prepared by heating 5-p-aminobenzenesulphonylamino - 3,4 - dimethyl - isoxazole with aqueous sodium hydroxide; (6) the lithium salt is prepared in a manner analogous to that in (5); (7) a stable sterile solution of pH 7.2 is prepared by shaking the sodium salt of (5) with an excess of 5-sulphanilamido-3,4-dimethyl-isoxazole and heating to 100 DEG  C.  A solution of the lithium salt of pH 7.2 to 7.4 can be prepared in a similar manner, and similar solutions can be prepared using the products of (3) and (4); (8) an aqueous suspension of 5-sulphanilamido-3,4-dimethyl-isoxazole is heated with calcium or magnesium carbonate to give the calcium or magnesium salt; (9) 5-sulphanilamido-3,4-dimethyl-isoxazole or the product of (3) or (4) is heated with diethanolamine, ethanolamine or ethylenediamine to give the corresponding salt. 3,4-Dimethyl-5-amino-isoxazole is prepared by treating acetopropionitrile with a hydroxylamine salt in hot aqueous solution while neutralizing the acid.  3 - Ethoxymethyl - 4 - methyl - 5 - amino - isoxazole is prepared by adding ethoxyethyl acetate and propionitrile to sodium in benzene or ether, and heating the ethoxyacetylpropionitrile so formed with hydroxylamine hydrochloride.  The Specification as open to inspection under Sect. 91 includes also an example in which "5-p-aminobenzene sulphanilamido-3-methyl-4-isopropyl-isoxazole" is prepared by condensing 3-methyl - 4 - isopropyl - 5 - amino - isoxazole with p-acetaminobenzene sulphonylchloride in the presence of pyridine and acetone, and hydrolysing the product. 3-Methyl-4-isopropyl-5-amino-isoxazole is made by condensing methyl isobutyl ketone with ethyl formate in presence of sodium to give the sodium enolate of formyl methyl pentanone, condensing this with hydroxylamine hydrochloride to give 4-isopropyl-5-methyl-isoxazole, treating with caustic potash to give the potassium enolate of 3-cyano-4-methyl-pentanone-2, and condensing with hydroxylamine to give the required product.  This subject-matter does not appear in the Specification as accepted.