Patent GB-627297-A (GB)
Title: Method for the preparation of heterocyclic compounds
Filed: 1946-06-05
Abstract: 4-Hydroxy and 4-halo-quinoline compounds are manufactured by heating a substituted acrylate or isomeric anil, of the general formula <FORM:0627297/IV (b)/1> (wherein X represents a monovalent or bivalent substituent, of which one or more may be present, Y represents a carbalkoxy, carbaralkoxy, cyano or substituted carbanilino group and R1 an alkyl or aralkyl radical), hydrolysing the cyclized product, decarboxylating the resulting 4-hydroxyquinoline-3-carboxylic acid, and if desired, replacing the hydroxy group by halogen by the action of an acid halide.  When the starting materials contain a substituent in m-position to the group <FORM:0627297/IV (b)/2> the cyclization step yields predominantly the 7-substituted compound.  Cyclization is effected by heating to about 250 DEG  C., preferably in a solvent, though where Y is carbalkoxy good results can be obtained by heating the starting material alone. The hydrolysis step may be effected with aqueous alkali when Y is carbalkoxy or carbaralkoxy, and with strong (e.g. 75 per cent) aqueous sulphuric acid when Y is cyano or carbanilino, whilst decarboxylation is readily accomplished by fusing the free carboxylic acid until effervescence ceases or by heating it in the solvent used in the cyclization (e.g. diphenyl ether).  Examples describe the preparation of 4-hydroxy-7-chloroquinoline from the appropriate starting materials in which R1 is ethyl and Y is carbethoxy, cyano or carbo-m-chloranilino, and of 7-trifluoromethyl-, 7-fluoro-, 5- and 6-methoxy-7-chloro-and 6-methoxy-4-hydroxyquinoline from starting materials in which R1 is ethyl and Y is carbethoxy, and the conversion of the products to the corresponding 4-chloro compounds by treatment with phosphorus oxychloride or a mixture thereof with phosphorus pentachloride.  Reference is also made to the production of 4 : 41 - dihydroxy - 6 : 61 - diquinolyl ether, 4 - hydroxy - 8 - aminoquinoline, 4 - hydroxy-5 : 6-methylenedioxyquinoline and 4-hydroxy-5 : 6-dimethoxy-8-carboxyquinoline.  Acrylates or anils of the general formul  above are obtainable as follows: (a) when Y is carbalkoxy, by condensing an alkoxymethylenemalonic ester with the appropriate nuclear substituted aniline (e.g. diethyl ethoxymethylenemalonate with m-chloro-, m-trifluoromethyl- or m-fluoro-aniline, 5-chloro-3-amino-or 2-chloro-4-amino-anisole, or p-anisidine); (b) when Y is cyano, similarly from an alkoxy-methylenecyanacetic ester (e.g. from ethyl ethoxymethylenecyanacetate and m-chloraniline); (c) when Y is <FORM:0627297/IV (b)/3> by condensing the appropriate nuclear substituted aniline (e.g. m-chloraniline) with an orthoformic ester to form the corresponding diarylformamidine and condensing this with a malonic ester.  Diethyl ethoxymethylenemalonate is obtainable by condensing ethyl orthoformate with diethyl malonate in the presence of a trace of zinc chloride.  The Specification as open to inspection under Sect. 91 comprises also the use of starting materials of the general formul  above in which Y is any substituted carboxylic amide group, and contains a reference to the production of 4 - hydroxy - 8 - mercaptoquinoline from di(o-aminophenyl) disulphide.  This subject-matter does not appear in the Specification as accepted.