Patent GB-685860-A (GB)
Title: Improvements in or relating to substituted pteridine compounds
Filed: 1950-05-16
Abstract: The invention comprises substituted pteridines of the general formula <FORM:0685860/IV (b)/1> wherein R1 is a hydrogen atom or an alkyl group having one to four carbon atoms, R2 is a hydrogen atom or an alkyl group having one to four carbon atoms, A is a hydroxyl group or a group of the general formula -NR3R4, where R3 is a hydrogen atom or an alkyl group having one to four carbon atoms, R4 is a hydrogen atom, an alkyl group, or a group having the general formula <FORM:0685860/IV (b)/2> or R3 and R4 together represent a polymethylene group connected at both ends to the nitrogen atom, R5 is a hydrogen atom or an alkyl group having one to four carbon atoms, R6 is a hydrogen atom or an alkyl group having one to four carbon atoms, and X is an hydroxyl group or a carboxylic amino acid group connected to the -CO- group through its nitrogen atom, at least one of the groups -NR1R2 and A being a substituted amino group, and a process for preparing the above compounds by admixing: (i) 4,5-diaminopyrimidine having the general formula <FORM:0685860/IV (b)/3> wherein R1, R2 and A have the above significance, or a salt thereof; (ii) a halogeno aliphatic aldehyde or ketone having the general formula <FORM:0685860/IV (b)/4> wherein Z represents an oxygen atom or two halogen atoms, X is an oxygen atom, two halogen atoms or a hydrogen atom and a halogen atom, and Y is a hydrogen atom or an alkyl group having one to four carbon atoms; (iii) p-aminobenzoic acid, a p-monoalkylaminobenzoic acid having one to four carbon atoms in the alkyl group or a carboxylic amino acid amide of such acids. The preferred reaction temperature is between 0 DEG C. and 100 DEG  C., and the reaction is preferably carried out in the presence of water as a solvent and preferably at a pH between 1.5 and 6.  An oxidizing agent may be added to the reaction mixture, e.g. an oxidizing agent having an oxidation-reduction potential of approximately -0.49 to 1.42 volts such as iodine, potassium bromate, chlorine, benzoquinone, manganese dioxide, sodium dichromate and ferric chloride.  Suitable reactants (ii) referred to are 2,3-dibromo- and dichloro-propionaldehyde, 1,1,3-tribomo and trichloro-acetone and butylchloral.  Suitable reactants (iii) referred to are p-aminobenzoic acid and the amides thereof derived from an aminoacid, e.g. glutamic acid and aminoacids containing peptide linkages such as glutamylglutamic acid, diglutamylglutamic acid and serylglutamic acid, glycine, aspartic acid, leucine, serine, sarcosine, phenylolamine, isovaline and cystine.  The amino acids may be natural or synthetic and may be of the d, l, or dl forms, while the free carboxyl groups in the amide may be esterified, neutralized or converted into an amide.  In the examples the following compounds are prepared: 4-dimethylaminopteroylglutamic acid, 4-dimethylamino-9 - methylpteroylglutamic acid, 4 - dimethylamino - N10 - methylpteroylglutamic acid, 4 - dimethylamino - 9,10 - dimethylpteroylglutamic acid, 4 - dimethylamino - 9 - methylpteroic acid, 4 - dimethylamino - N10 - methylpteroic acid, 4 - dimethylamino - 9,10 - dimethylpteroic acid, 4 - dimethylaminopteroylaspartic acid, 4 - dimethylaminopteroylglutamylglutamylglutamic acid, 4 - dimethylaminopteroylserylglutamic acid, 4 - methylaminopteroylglutamic acid, 4 - (1 - piperidyl) pteroylglutamic acid, N2,N2 - dimethyl - 4 - aminopteroylglutamic acid, N2,N2 - dimethyl - 4 - amino - 9 - methylpteroylglutamic acid, N2,N2-dimethyl-4-aminoN10 - methylpteroylglutamic acid, N2,N2 - dimethylamino - 9,10 - dimethylpteroylglutamic acid, N2,N2 - dimethyl - 4 - aminopteroylaspartic acid, N2,N2 - dimethyl - 4 - aminopteroylglutamylglutamylglutamic acid, N2,N2 - dimethyl - 4 - aminopteroylserylglutamic acid, N2,N2 - dimethylpteroylglutamic acid, N2,N2 - dimethyl - 9 - methylpteroylglutamic acid, N2,N2 - dimethyl - 9,10 - dimethylpteroylglutamic acid, N2,N2-dimethylpteroylaspartic acid, N2,N2 - dimethylpteroylglutamylglutamylglutamic acid, N2,N2-dimethylpteroylserylglutamic acid, and p-[N,N1-(2-amino-6-methylpteridyl-4,9)-bis-amino] benzoylglutamic acid.  2,4-diamino-6-chloropyrimidine is prepared by treating 2,4-diamino-6-hydroxypyrimidine with phosphorus oxychloride and is converted to:-  2,4 - diamino - 6 - dialkylaminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reaction with a dialkylamine (in an example, dimethylamine is used and first forms a double compound of 2,4-diamino-6-dimethylaminopyrimidine and dimethylamine hydrochloride and the desired free base is obtained by treatment with sodium hydroxide and may be in the form of its hydrochloride salt), and is converted into:-  2,4 - Diamino - 5 - nitroso - 6 - dialkylaminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reaction with nitrous acid (2,4 - diamino - 5 - nitroso - 6 - dimethylaminopyrimidine is prepared in an example) and is converted into:-  2,4,5 - Triamino - 6 - dialkylaminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reduction (2,4,5 - triamino - 6 - dimethylaminopyrimidine is prepared in an example using sodium dithionite as the reducing agent, and is converted into the sulphate salt).  2-Dialkylamino-4,6-diaminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) is prepared by reacting the required dialkylguanidine with malononitrile (in an example, 2 - dimethylamino - 4,6 - diaminopyrimidine is prepared and is converted into the sulphate salt) and is converted into:-  2 - Dialkylamino - 4,6 - diamino - 5 - nitrosopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reaction with nitrous acid (in an example, 2-dimethylamino-4,6-diamino-5-nitrosopyrimidine is prepared) and is converted into:-  2 - Dialkylamino - 4,5,6 - triaminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reduction (in an example 2-dimethylamino-4,5,6-triaminopyrimidine is prepared using sodium dithionite as the reducing agent, and is converted to the sulphate salt).  2 - Dialkylamino - 4 - hydroxy - 6 - aminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) is prepared by reacting the required dialkylguanidine and cyanoacetic ester (in an example, 2-dimethylamino-4-hydroxy-6-aminopyrimidine is prepared) and is converted into:-  2 - Dialkylamino - 4 - hydroxy - 5 - nitroso - 6 - aminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reaction with nitrous acid (in an example, 2 - dimethylamino - 4 - hydroxy - 5 - nitroso - 6 - aminopyrimidine is prepared) and is converted into:-  2 - Dialkylamino - 4 - hydroxy - 5,6 - diaminopyrimidine (the alkyl groups having 1 to 4 carbon atoms) by reduction (in an example, 2 - dimethylamino - 4 - hydroxy - 5,6 - diaminopyrimidine sulphite is obtained using sodium dithionite as the reducing agent).  2,4 - Diamino - 6 - methylaminopyrimidine is prepared by reacting 2,4-diamino-6-chloropyrimidine and methylamine and is converted to:-  2,4 - Diamino - 5 - nitroso - 6 - methylaminopyrimidine by reaction with nitrous acid and is converted to:-  2,4,5 - Triamino - 6 - methylaminopyrimidine by reduction with sodium dithionite (the sulphate salt is also mentioned).  2,4 - Diamino - 6 - (1 - piperidyl) - pyrimidine is obtained by the reaction of 2,4-diamino-6-chloropyrimidine and piperidine and is converted to:-  2,4 - Diamino - 5 - nitroso - 6 - (1 - piperidyl) - pyrimidine by reaction with nitrous acid and is converted to:-  2,4,5 - triamino - 6 - (1 - piperidyl) - pyrimidine by reduction with sodium dithionite (the sulphate salt is also mentioned).  p - (2,4 - Diamino - 6 - pyrimidyl) - aminobenzoylglutamic acid is prepared by reacting 2,4-diamino-6-chloropyrimidine and p-aminobenzoylglutamic acid and is converted to:-  p - (2,4 - Diamino - 5 - nitroso - 6 - pyrimidyl) - aminobenzoylglutamic acid by reaction with nitrous acid and is converted to:-  p - (2,4,5 - Triamino - 6 - pyrimidyl) - aminobenzoylglutamic acid by reduction with sodium dithionite (the sulphate salt is also mentioned).