Patent GB-623809-A (GB)
Title: Improvements relating to the preparation of n-(pyrimido[4,5-b]-pyrazylmethyl)aminophenyl compounds and intermediates thereof
Filed: 1946-05-03
Abstract: Pyrimido [4, 5-b] pyrazylmethyl compounds ("Ring Index" nomenclature) of the general formula <FORM:0623809/IV (b)/1> (wherein Y represents the residue of a tertiary amine or quaternary ammonium and may be of the form -NRR1 or -NRR1R11X, where R, R1 and R11 may be aliphatic or aromatic radicals or may jointly form with the nitrogen atom a saturated or unsaturated ring structure such as that of piperidine or pyridine, and X is a monovalent anion such as -OH, -HSO3, or preferably halogen) are manufactured by admixing 2 : 4 : 5 - triamino - 6 - hydroxypyrimidine with a halogenated aldehyde of the formula <FORM:0623809/IV (b)/2> preferably in the presence of a mild oxidizing agent.  The pyrimidine compound is advantageously employed in the form of an acid salt thereof, alkali being added to reduce the resulting acidity.  The halogenated aldehydes may be prepared (if desired in situ) by the interaction of a 2 : 3-dihalopropionaldehyde with a secondary or tertiary amine (e.g. diethylamine, di-isopropylamine, dioctylamine, morpholine, piperidine, methylaniline, pyridine, dimethylaniline, trimethylamine or quinoline).  When Y is a quaternary ammonium group, the products are useful as surface active agents, germisides, fungicides or insecticides.  In examples: (1) 2 : 3 - dibromopropionaldehyde is treated with pyridine in ether in the cold, the product is extracted into water, the aqueous solution is added to a solution of 2 : 4 : 5-triamino - 6 - hydroxypyrimidine dihydrochloride and the mixture is treated with sodium hydroxide solution and then with iodine-potassium iodide solution, producing N-(2-amino-4-hydroxy-6-pyrimido [4, 5-b] pyrazyl)-methylpyridinium iodide; the product yields 2 - amino - 4 - hydroxy - 6 - carboxypyrimido [4, 5-b] pyrazine on oxidation with alkaline permanganate solution; (2) the iodine-potassium iodide solution in (1) is replaced by potassium iodide alone; (3) the 2 : 3-dibromopropionaldehyde in (1) is replaced by the dichloro compound; (4) 2 : 3-dibromopropionaldehyde is reacted with 2 : 4 : 5-triamino-6-hydroxypyrimidine dihydrochloride and pyridine in aqueous acetone and the reaction mixture is treated with hydrochloric acid and iodine-potassium iodide solution to give the product of (1); (5) the pyridine in (1) is replaced by diethylamine, yielding 2-amino-4-hydroxy-6-(diethylaminomethyl)-pyrimido [4, 5-b] pyrazine hydriodide, and, by treatment with sodium hydroxide, the free base, which forms 2 - amino - 4 - hydroxy - 6 - carboxypyrimido [4, 5-b] pyrazine on oxidation with alkaline permanganate.  N - (Pyrimido - [4, 5 - b] - pyrazylmethyl)-aminophenyl compounds of the general formula <FORM:0623809/IV (b)/3> (wherein R1 represents hydrogen or a substituent which is non-functional in the reaction for the production of the compounds) are manufactured by heating a pyrimido [4, 5-b] pyrazylmethyl compound of the general formula given above in the presence of alkali with a compound of the formula <FORM:0623809/IV (b)/4> especially such a compound in which R1 represents an amide group, e.g. o-, m- or p-aminobenzamide or other amides obtainable by the reaction of an aminobenzoyl halide (preferably the p-isomer) with an aliphatic or aromatic amine, e.g. ethylamine, ethanolamine, dodecylamine, ethylhexylamine, benzylamine, morpholine or aniline or particularly with a natural or synthetic, opically active or inactive amino acid, e.g. glutamic acid, or polypeptides thereof such as glutamylglutamic, glutamylglutamic or glutamylglycylglutamic acid, or glycine, aspartic acid, lencine, alamine, isovaline or cysteine, or the salts or esters of these amino acids.  The reaction is usually carried out at 100-200 DEG  C. (preferably at 140-180 DEG  C.), advantageously in a moderately strong alkaline medium (pH at least 8), e.g. in the presence of alkali metal alcoholates, e.g. sodium methylate or ethylate or potassium methylate, alkali metal hydroxides, carborates, acetates or phosphates, or pyridine, and may be effected in the presence of water, though better yields are obtained under anhydrous conditions, e.g. by simply heating the reactants together or in a non-aqueous solvent (e.g. alcohols, ethers, hydrocarbons, pyridine or preferably ethylene glycol).  In examples: (6) and (7) N-(p-aminobenzoyl)-l-glutamic acid is heated with (2-amino - 4 - hydroxy - 6 - pyrimido [4, 5-b] pyrazyl)-methylpyridinium iodide in ethylene glycol in the presence of sodium methylate; (8) part of the sodium methylate is replaced by sodium acetate; (9) N-(p-aminobenzoyl)-aspartic acid is treated as in (6); (10) the N-(p-aminobenzoyl)-glutamic acid in (6) or (7) may be replaced by aniline, N-(m-aminobenzoyl)-glutamic acid, m- or p-aminobenzoic acid, N-(p-aminobenzoyl)-leucine, metanilamide or N-metanilylglutamic acid, the amount of sodium methylate being decreased where the starting materials contain fewer carboxylic acid groups; ((1) diethyl N-(4-aminobenzoyl)-glutamate is treated as in (7); (12) 2-amino-4-hydroxy- 6 (diethylaminomethyl)-pyrimido [4, 5-b] pyrazine is reacted with N-(p-aminobenzoyl)-glutamic acid as in (6).  The Specification as open to inspection under Sect. 91 comprises also the manufacture of similar compounds in which the pyrimidine ring may be unsubstituted or substituted otherwise than as shown (e.g. by alkyl groups), or which may contain, instead of the pyrimidine ring, another aromatic ring, which may be isocyclic (e.g. benzene) or heterocyclic (e.g. pyridine or pyrazine).  In a further example, g -oxo-b -bromopropylpyridinium bromide is condensed with o-phenylenediamine to produce 2-quinoxalylmethylpyridinium bromide hydrobromide hydrate. Additional starting materials specified are 1 : 2 - diamino - 4 - methylbenzene, 2 : 3-diaminopyrazine, 4 : 5 - diaminopyrimidine, 2 : 3 : 6 - triaminopyridine, 2 : 3 - diamino - 5-chloropyridine, and 2 - methyl- and 2 - undecyl-4 : 5-diamino-6-hydroxypyrimidine.  This subject-matter does not appear in the Specification as accepted.