Patent GB-638411-A (GB)
Title: Improvements relating to the preparation of substituted pteridines
Filed: 1946-04-24
Abstract: Substituted pteridines of the general formula <FORM:0638411/IV (b)/1> wherein R is OR1 or NR2R3, R1 being hydrogen or an alkyl group and R2 and R3 being hydrogen atoms or aromatic or aliphatic groups, are prepared by mixing: (i) 2 : 4 : 5 - triamino - 6 - hydroxypyrimidine or a tautomer thereof; (ii) an alpha, beta-dihalogenopropion-aldehyde or an acetal thereof or a monohalogenopyruvicaldehyde or an acetal thereof; (iii) para-aminobenzoic acid or a salt, aliphatic ester or an amide thereof.  Reactants (i) and (ii) may be mixed and the reaction product thereof mixed with reactant (iii), or reactants (ii) and (iii) may be mixed and the reaction thereof mixed with reactant (i).  The reaction may be carried out in an inert solvent, e.g. water, ethyl alcohol, acetone, benzene, carbon tetrachloride and chloroform, or mixtures thereof, or in an aqueous medium at a pH between 3 and 5.  Reactant (ii) may be alpha-, beta-, dibromo- or dichloro-propionaldehyde or bromo- or chloropyruvic aldehyde. Reactant (iii) may be the methyl, ethyl, butyl or benzyl ester of paraaminobenzoic acid, aliphatic and aromatic amides of para-aminobenzoic acid derived from ethylamine, ethanolamine, dodecylamine, ethylhexylamine, benzylamine, morpholine and aniline, aminoacids such as glutamic acid, glutamylglutamic acid, glutamylglutamylglutamic acid and others containing peptide linkages such as glutamylglycylglutamic acid. There may also be used glycine, aspartic acid, leucine, alanine, isovaline or cysteine, and the amino acids may be natural or synthetic and may be in any of the d, l or dl forms.  Salts and esters of these aminoacids may be employed.  Acid salts of the substituted pteridines may be obtained by the addition of mineral acids such as hydrochloric or sulphuric acid, or salts with cations may also be obtained by treatment with alkali such as alkali metal hydroxide, ammonia or an amine, and by double decomposition methods to introduce cations such as zinc, silver, nickel, copper, magnesium or barium.  A number of examples are given. Diethylglutamate is prepared by esterifying glutamic acid in absolute alcohol.  p-Nitrobenzoyl-dl-aspartic acid is prepared by reacting dl-aspartic acid and p-nitrobenzoyl chloride. p-Aminobenzoyl-dl-aspartic acid is prepared by reducing the above compound with ferrous sulphate and ammonium hydroxide. p-Nitrobenzoylglutamic anhydride is prepared by treating the corresponding acid with acetic anhydride. p-Nitrobenzoylglutamylglutamic acid is prepared by reacting the above anhydride and diethylglutamate.  p-Aminobenzoylglutamylglutamic acid is prepared by reducing the above compound with ferrous sulphate and ammonium hydroxide and has the formula <FORM:0638411/IV (b)/2> The compound of the formula <FORM:0638411/IV (b)/3> is prepared by reacting the anhydride of p-nitrobenzoylglutamic acid with alcohol to form the alpha ester, which is converted to the acid chloride with phosphorus pentachloride, and reacted with glutamic acid to yield the polypeptide linkage, the alpha ester group is then hydrolysed and the nitro group reduced.  Pyruvic aldehyde acetal is prepared by refluxing g ,g -diethoxy aceto acetate with aqueous potassium hydroxide.  Monobromopyruvic aldehyde is prepared by reacting the above acetal and bromine in carbon disulphide.  The Specification as open to inspection under Sect. 91 refers to the preparation of substituted of the general formula <FORM:0638411/IV (b)/4> and intermediates thereof, wherein OR is OR1 or NR1R11, R1 and R11 being hydrogen, aromatic or aliphatic radicals, by mixing any two of the following three reactants to produce intermediates or admixing all three reactants simultaneously or in any desired sequence to produce the final product: (i) 2 : 4 : 5-triamino-6-hydroxypyrimidine or a tautomer thereof; (ii) a substituted propane having at least two, preferably three carbon atoms thereof substituted with one or more oxo or halo radicals or radicals convertible thereto; (iii) aminobenzoic acid or a salt, ester or amide thereof.  Suitable reactants (ii) are alpha, beta-dihalo-propionaldehydes, alpha, alpha, beta-trihalo-propionaldehydes, halopyruvic aldehydes, esters of 2-oxo-2-halo-propionic acids, esters of haloacetols of the formula <FORM:0638411/IV (b)/5> where X is halogen and Y is an aceto or propiono radical, and compounds of the formula <FORM:0638411/IV (b)/6> wherein R and R1 are hydrogen, alkyl or carbalkoxy radicals and Z is oxygen or two alkoxy radicals.  If the corresponding dihydropteridine of the formula <FORM:0638411/IV (b)/7> is obtained, it can be oxidized to the aromatic form with oxidizing agents, e.g. air or iodine.  In examples, the following compounds are prepared: 2 - amino - 4 - hydroxy - 6 - carboxypyrimido - [4,5-6] - pyrazine, which may be converted to the corresponding 6-carbomethoxy compound, 2 - amino - 4 - hydroxy - 6 - methyl-pyrimido-[4,5-6]-pyrazine which may also be prepared by heating 2-amino-4-hydroxy-6-carboxymethyl pyrimido-[4,5-6]-acetic acid, 2 - amino - 4 - hydroxy - 6 - pyrimido -[4,5-6]-pyrazine acetic acid which may be heated to give the corresponding 6-methyl compound and 2 - amino - 4 - hydroxy - 6:7 - dimethyl - pyrimido-[4,5-6]-pyrazine.  The Specification as open to inspection under Sect. 91 included the subject-matter of Specification 638,480.  This subject-matter does not appear in the Specification as accepted.