GB657903A - Improvements in or relating to the production of substituted pteridine compounds - Google Patents

Abstract

Substituted pteridines having in at least one tautomeric form the formula <FORM:0657903/IV (b)/1> wherein R is an aromatic radical, are prepared by mixing the following: (i) 2 : 4 : 5 : 6-tetraaminopyrimidine or a tautomer thereof or an acid salt thereof; (ii) an alpha, beta-dihalopropionaldehyde or an acetal thereof, or a 1 : 1 : 3-trichloroacetone; (iii) a primary aromatic amine. Reactant (i) and (ii) may first be mixed and the reaction product thereof mixed with reactant (iii), or reactants (ii) and (iii) may be mixed and the reaction product thereof mixed with reactant (i). The process may be carried out at a temperature from about 0 DEG to 100 DEG C. and/or at a pH between about 1.5 to 6. The reaction may be effected in the presence of water or other inert solvent, a number of which are given. Dihalopropionaldehydes that may be used are alpha, beta-dichloro and dibromo propionaldehydes, and trihaloacetones that may be used are the 1,1,3-trichloro and tribromo acetones. The primary aromatic amines mentioned are the o, m and p-aminobenzoic acid and the salts, esters and amides thereof. Preferred aromatic amines are the amino acid amides of p-aminobenzoic acid, e.g. p-aminobenzoyl glutamic acid and polypeptides thereof, e.g. p-aminobenzoyl-glutamylglutamic acid 3,5-dibromo-4-aminobenzoylglutamic acid and p-aminobenzoyldiglutamyl glutamic acid and others move up of one or more of the various amino acids, e.g. p - aminobenzoylglutamylglycylglutamic acid. Other amino acids mentioned from which the amides of p-aminobenzoic acid may be derived are glycine, aspartic acid, leucine, serine, sarcosine, phenylalanine, alanine, isovaline and cysteine. The amino acids may be natural or synthetic and may be in any of the d, l or d-l forms, while free carboxyl groups may be esterified, neutralized or converted into an amide, e.g. ethyl-p-aminobenzoylgamma-glutamyl gamma-glutamyl glutamate may be used. Other amides mentioned are p-amino-benzamide and amides formed by the reaction of aminobenzoic acid and ethylamine, ethanolamine, dodecylamine, ethylhexylamine, benzylamine, morpholine, aniline and 2-aminopyrimidine. Oxidizing agents may be added to the reaction mixture to prevent the formation of the corresponding dihydropteridines, e.g. those having an oxidation-reduction potential of about -0.49 to 1.42 volts, e.g. iodine, chlorine, potassium bromate, benzoquinone, manganese dioxide, sodium dichromate and ferric chloride. A number of detailed examples are given. N-(p-aminobenzoyl)-alanine is prepared by hydrogenating N-(p-nitrobenzoyl)-alanine in alcohol in the presence of palladium on activated charcoal. The corresponding N-(p-aminobenzoyl) substituted phenylalanine, valine and serine are prepared by a similar method.