Patent GB-615328-A (GB)
Title: Improvements in or relating to the production of metanilamidodiazines and intermediates thereof
IPC: C07D239/69
Filed: 1946-01-14
Abstract: Metanilamidodiazines of the general formula <FORM:0615328/IV(b)/1> wherein Dz represents a diazine group (i.e. a pyrimidine, pyridazine or pyrazine residue, which may be free from further substituents or may be substituted in one or more of the remaining three possible positions, e.g. by alkyl, alkoxy, alkoxyalkyl, carbalkoxy, carboxy, alkaryl, aryl, amino, nitro or halogen), are manufactured by reducing (e.g. by means of a solution of hydrogen sulphide in aqueous ammonia, or iron and acetic acid) or hydrolysing (e.g. in aqueous alkali) a compound of the formula <FORM:0615328/IV(b)/2> (wherein X represents a nitro, acidylamino, phthalimido or succinimido group); or by reacting a m-aminobenzene sulphonyl fluoride with an aminodiazine (which may contain additional substituents).  The intermediates for the first method are in turn made by one of the following processes: (a) reacting a benzene sulphonyl halide containing X as a m-substituent with an aminodiazine in the presence of a tertiary amine (e.g. pyridine) and, if desired, a non-hydroxylated inert solvent (e.g. benzene, ether, chloroform or dioxane); (b) reacting a benzene sulphenyl halide containing X as a m-substituent with an aminodiazine and oxidizing the sulphur group of the product (e.g. with potassium permanganate at room temperature or with chromic acid anhydride in glacial acetic acid at about 90 DEG  C.); (c) reacting a benzene sulphonyl halide containing X as a m-substituent with an aminodiazine and halogenating the product (in the diazine nucleus); (d) (when X is a nitro group) reacting a benzene sulphonyl halide with an aminodiazine and nitrating the product (in the benzene nucleus).  The products are therapeutically useful, the metanilamidodiazines (into which the intermediates may be converted in the body) being effective as prophylactic and curative agents against protozoal organisms of the type which cause arian malaria. Examples illustrate the various features of the invention, using as diazine starting materials 2-aminopyrimidine and its 5-chloro-, 5 - bromo-, 4 - methyl-, 5 - bromo - 4 - methyl-, 4 : 6-dimethyl-, 4-ethoxy-, 4-phenyl-and 5 - carbethoxy - derivatives, 2 : 4 - diamino - pyrimidine and its 5-bromo-derivative, 4- and 5 - aminopyrimidine, 3 - aminopyridazine, 5-amino-2-chloropyrimidine and 2-aminoquinoxaline.  2-Amino-5-chloropyrimidine is obtainable by the chlorination of aminopyrimidine in acid solution.  2 : 4-Diamino-5-bromopyrimidine is obtainable by the bromination of 2 : 4-diaminopyrimidine in acid solution.  2-Amino-5-carbethoxypyrimidine is obtainable by the reaction of guanidine with carbethoxymalondialdehyde acetal.  The Specification as open to inspection under Sect. 91 comprises also: the replacement of the hydrogen atom of the sulphonamide group by a cationic salt-forming radical or an alkyl group (as described in Specification 614,926, as open to inspection under Sect. 91); the manufacture of intermediates of the general formula given above in which X is -N=N-, CH3NH-, C2H5NH-, R1CH=N- (where R1 is CH3-, C2H5- or HOCH2(CHOH)4-), H2NCO-, N3-, (CH3CO)2N- or an amine salt group such as -A+H3N; the following further methods of making the intermediates: (a) reacting a benzene sulphonyl halide containing X as a m-substituent with guanidine and treating the product with a halomalondialdehyde, and (b) reacting a benzene sulphonyl halide containing X as a m-substituent with an aminodiazine to form a bis-(m-X-benzenesulphonyl)-aminodiazine and further treating this product with the aminodiazine or with an acid or alkaline hydrolysing agent; and many additional examples, in which, inter alia: (i) 2-metanilamidopyrimidine and its 5 - chloroderivative are refluxed with acetic anhydride to produce their N3-acetyl derivatives; (ii) 2 - metanilamido - 5 - carbethoxypyrimidine is hydrolysed to the free carboxylic acid; (iii) metanilylguanidine is heated with acetylacetone to yield 2-metanilamido-4 : 6-dimethylpyrimidine; (iv) 2-(m-bromobenzenesulphonamido)-5-chloropyrimidine is heated under pressure with aqueous ammonia in the presence of cuprous oxide to replace the bromine atom by an amino group.  This subject-matter does not appear in the Specification as accepted.