Patent GB-997653-A (GB)
Title: N-aryl-isatoic anhydride derivatives
IPC: C07D265/26
Filed: 1963-09-17
Abstract: The invention comprises N-arylisatoic anhydrides of the general formula <FORM:0997653/C2/1> wherein Ar is 3-trifluoromethylphenyl or a substituted phenyl radical of general formula <FORM:0997653/C2/2> wherein R1 is methyl or chloro, R2 is lower alkyl, lower alkoxy or chloro and R3 is hydrogen, methyl or chloro, and the preparation thereof (a) by oxidation of an isatin of general formula <FORM:0997653/C2/3> wherein Ar has the above meaning, preferably with an organic peracid, persulphuric acid or hydrogen peroxide advantageously in a slightly acidic media such as acetic or propionic acid solution; (b) by the action of heat on an N-arylanthranilic acid of general formula <FORM:0997653/C2/4> wherein Ar has the above meaning, in the presence of a tertiary amine and an alkyl chloroformate, if the reaction mixture is allowed to stand it is possible to form a mixed anhydride of the formula <FORM:0997653/C2/5> wherein Ar has the above significance, which is then heated; (c) by ring closure of an N-arylisatoic acid N-alkyl ester of general formula <FORM:0997653/C2/6> wherein Ar has the above meaning, for example by the action of heat with or without solvent or by reaction with an acid organic or inorganic halide, or (d) by oxidation of an N-(o-carboxyphenyl) -N-aryloxamic acid of general formula <FORM:0997653/C2/7> wherein Ar has the above meaning, preferably using potassium permanganate in slight excess. The lower alkyl and alkoxy radicals contain less than 4 carbon atoms.  2,6-Dimethyl - 3 - ethylaniline is prepared by reacting 2,6-dimethylacetanilide and acetyl chloride, treating the resulting 3-acetamido-2, 4-dimethylacetophenone with hydrogen under pressure to form 2,6-dimethyl-3-ethyl-acetanilide and treating this compound with acid.  2,6 - Dimethyl - 3 - ethyl - diphenylamine is prepared by heating N-(2,6-dimethyl-3-ethylphenyl) - anthranilic acid. 2,6-Dichloro-3-methyl-diphenylamine is prepared by a similar method. 2,6 - Dichloro - 3 - methoxydiphenylamine is prepared by reacting 2,4-dichloro-3-nitrophenol with dimethyl sulphate, hydrogenating the resulting 2,4 - dichloro - 3 - nitro - anisole, treating the resulting 2,6-dichloro-3-methoxyaniline with cupric o-bromobenzoate, and heating the resulting N-(2,6-dichloro-3-methoxyphenyl)-anthranilic acid in the presence of copper powder.  The isatins of the third general formula above may be prepared either by reaction of the required diphenylamine oxalyl chloride to to form an N-aryl-N-phenyloxamic acid chloride which is then heated with aluminium chloride in carbon disulphide followed by hydrolysis, or by reaction of a 2-chloro-4-methyl-quinoline with ArONa, conversion of the 2-aryloxy-4-methyl-quinoline product to a N-arylcarbostyril by heating, and oxidation and acidification of the product to give the isatin.  The N-arylanthranilic acids of the fourth general formula above may be prepared by reaction of the potassium salt of o-bromobenzoic acid with the amine ArNH2 in the presence of a base and a copper containing catalyst and treatment of the product with acid.  The N-arylisatoic acid N-allyl esters of the fifth general formula above may be prepared by allowing a mixed anhydride of general formula <FORM:0997653/C2/8> to stand at room temperature but the reaction may be accelerated by heating.  The N - (o - carboxyphenyl) - N - aryloxamic acids of the sixth general formula above may be prepared either by reaction of an N-arylanthranilic acid with oxalyl chloride followed by hydrolysis, or by reaction of 2-chloroquinoline and a phenol of the formula ArOH in the presence of sodium hydride to form a 2-aryloxquinoline, this compound is heated to form an N-arylcarbostyril which is oxidized with potassium permanganate in pyridine and the product is acidified. Pharmaceutical compositions containing an isatoic anhydride of the first general formula above in association with an inert carrier or diluent having anti-inflammatory and, in certain cases, analgesic properties for oral or parental administration.