Patent GB-730085-A (GB)
Title: Improvements in or relating to the preparation of halogenated substituted pteridines
IPC: C07D475/04
Filed: 1951-03-07
Abstract: The invention comprises halogenated pteridines having in one tautomeric form the general formula <FORM:0730085/IV (b)/1> wherein R1 represents an amino or hydroxy radical, R2 represents a hydroxy radical or -COR2 is an amide radical derived from an aliphatic amino acid, Hal represents one or two like halogen atoms, and X and Y represent hydrogen atoms or alkyl radicals, at least one being an alkyl radical, the preparation thereof by mixing: (i) 2,4,5,6-tetra-aminopyrimidine, 2,4,5 - triamino - 6 - hydroxypyrimidine, or a tautomer of either compound, or an acid salt of either compound; (ii) an a ,b -dihalogenopropionaldehyde, a ,a ,b - trihalogenobutyraldehyde, a ,a ,b  - trihalogeno - g  - alkylbutyraldehyde, or an acetal thereof, or a 1,1,3-trihalogenoacetone; and (iii) a halo substituted benzoic acid of the general formula <FORM:0730085/IV (b)/2> wherein R2, X and Hal have the significance indicated above, and a method for preparing hydrohalide salts of 31,51-dihalogenated substituted pteridines of the above general formula by treating the corresponding non-halogen substituted pteridines with substantially two molecular proportions of halogen.  The first method may be modified by mixing reactants (i) and (ii) and then treating the resultant product with reactant (iii), or by mixing reactants (ii) and (iii) and treating the reaction product with reactant (i).  The preferred reaction solvent for this process is water, but other inert solvents may be used, e.g. ethyl alcohol, acetone, benzene, carbon tetrachloride, chloroform or acetic acid, or mixtures of organic liquids, or mixtures of organic liquids with water.  The reaction temperature is preferably within the range of 0 DEG  to 100 DEG  C., and the reaction may be carried out at a pH range of 1.5 to 6. The reactant (ii) may be a ,b -dibromo-or dichloro-propionaldehyde, 2,2,3-trichlorobutanal, 2,2,3-trichloropentanal, or 1,1,3-tribromo- or trichloro-acetone. Reactant (iii) may be a 2-chloro-, 2,6-dichloro-, 2,3-dichloro-or 3 - fluoro - 4 - aminobenzoic acid, 4 - methylamino-3,5-dichlorobenzoic acid, or an amide of 4-aminobenzoic acid derived from glutamic or aspartic acid, or glycine, leucine, serine, phenylalanine, cysteine or isovaline. The alternative process for preparing the hydrohalide salts of the 31,51 - dihalogeno compounds is preferably carried out in a solvent, e.g. an aqueous solution of a mineral acid, to which the halogen may be added as a gas or in a suitable solvent such as acetic acid.  The hydrohalide salt thus produced may be neutralized to the free acid.  The halogen may also be formed in situ with the aid of hydrogen peroxide.  A suitable temperature for carrying out the halogenation reaction is within the range of -10 DEG  to 35 DEG C.  In the examples the following compounds are prepared: 31,51 - dichloro -, 31,51 - dibromo -, 31 - chloro-and 21,51-dichloro-9-methylpteroylglutamic acid, 31,51-dibromo-, 31-chloro- and 21,51-dichloro - 4 - amino - 9 - methylpteroylglutamic acid, 21 - chloro - 9 - methylpteroic acid, 21 - chloro - 4 - amino - 9 - methylpteroic acid, 31,51 - dichloro - 10 - methylpteroic acid, 31,51 - dichloro - 9,10 - dimethylpteroic acid, 31,51 - dichloro - 4 - amino - 9,10 - dimethylpteroic acid, 31,51 - dichloro - 4 - amino - 9,10 - dimethylpteroic acid, 31,51 - dichloro - 9,10 - dimethylpteroylglutamic acid and 31,51 - dichloro - 4 - amino - 9,10 - dimethylpteroylglutamic acid, and salts thereof. 2,5-Dichloro-4-nitrobenzoic acid is prepared by oxidizing 2,5-dichloro-4-nitrotoluene with potassium dichromate and sulphuric acid.  2,5-Dichloro-4-nitrobenzoyl chloride is prepared by treating the above free acid with thionyl chloride. 2,5-Dichloro-4-nitrobenzoyl glutamic acid is prepared by reacting the above acid chloride with glutamic acid in the presence of sodium hydroxide.  2,5-Dichloro-4-aminobenzoyl glutamic acid is prepared by reducing the corresponding 4-nitro compound with a zinc-copper couple and hydrochloric acid.  4-Methylamino-3,5-dichlorobenzoic acid is prepared by reacting 4-methylaminobenzoic acid and sulphuryl chloride.