Patent GB-676107-A (GB)
Title: Improvements in or relating to the preparation of pteridines
Filed: 1949-08-11
Abstract: 2-Amino-4-hydroxy-6 or 7-substituted pertidine is prepared by reacting a 2-amino-4-hydroxy-6 or 7-bromomethylpyrimido [4,5-6] pyrazine with p-aminobenzoic acid or a salt, ester, amide or salt of an acid amide thereof in water or a mixture of water and a water-miscible organic solvent, e.g. at a pH between 9 to 11.5 and maintaining the pH within this range throughout the reaction.  The preferred reaction temperature range is between 0 DEG  and 100 DEG C., e.g. between 10 DEG  and 30 DEG  C.  One mol. of said pyrimido-pyrazine reactant may be reacted with 4 to 5 mols. of p-aminobenzoic acid, or salt, ester, amide or salt of acid amide thereof.  Suitable 2-amino-4-hydroxy-6 or 7-bromomethylpyrimido [4,5-6] pyrazines mentioned are 2-amino-4-hydroxy-6-bromomethyl-, 2-amino-4-hydroxy-6-dibromomethyl-, 2-amino-4 - hydroxy - 6 - bromomethyl - 7 - carboxy-, 2 - amino - 4 - hydroxy - 6 - bromomethyl - 7 - methyl-, 2 - amino - 4 - hydroxy - 7 - bromomethylmethyl-, 2 - amino - 4 - hydroxy - 7 - dibromomethyl-, 2 - amino - 4 - hydroxy - 6 - methyl - 7 - bromomethyl-, 2 - amino - 4 hydroxy-6-carboxy-7-bromomethyl-, and 2-amino - 4 - hydroxy - 6,7 - di - (bromohethyl) pteridine. Suitable amides of p-aminobenzoic acid mentioned are p-aminobenzoylglutamic acid and other amides derived from aminoacids, e.g. p-aminobenzoylaspartic acid, p-aminobenzoyl-beta-alanine or p-aminobenzoylglycine, or amides of amino acids having one or more peptide linkages, e.g. p-aminobenzoyldiglutamylglutamic acid.  In the examples the following compounds are prepared:-pteroylglutamic acid, N - [4 - {[(2 - amino - 4 - hydroxy - 7 - methyl - 6 - pyrimido [4,5-6] pyrazyl) methyl] amino} benzoyl]-glutamic acid and the corresponding 7 - carboxy substituted compound, N - [4 - {[(2 - amino - 4 - hydroxy - 7 - pteridyl) methyl] amino}-benzoyl] glutamic acid, N - [4 - {[(2 - amino - 4 - hydroxy - 6 - methyl-7-pyrimido [4,5-6] pyrazyl) methyl] amino} benzoyl] glutamic acid and the corresponding 6-carboxy compound, N,N1[4-{[(2-amino - 4 - hydroxy - 6,7 - pyrimido [4,5-6] - pyrazyl) methyl] amino} benzoyl]-glutamic acid, pteroyl-alpha-glutamyl-alpha-glutamyl-glutamic acid and the corresponding gammaglutamyl compound, pteroylglycine, pteroyl-beta - alanine and pteroylmorpholine.  The following compounds are also mentioned: pteramide, pteroylpiperidine, pteroylethanolamine and pteroyldiethanolamine.  p - Aminobenzoyl - alpha - glutamyl - alpha - glutamylglutamic acid is prepared by reducing the corresponding nitro compound with zinc and copper in the presence of ethanol.  2 - Amino - 4 - hydroxy - 6 - methyl - 7 - carboxypteridine is prepared by oxidizing 2-amino-4-hydroxy-6,7-dimethylpteridine with aqueous sodium hydroxide and potassium permanganate.  2 - Amino - 4 - hydroxy - 6 - bromomethylpteridine is prepared from the corresponding 6-methyl compound by the action of bromine in the presence of a photoflood lamp followed by treatment with hydrobromic acid.  2 - Amino - 4 - hydroxy - 7 - bromomethylpteridine is prepared by the action of hydrobromic acid on the corresponding 7-methyl compound.  2 - Amino - 4 - hydroxy - 6,7 - di - (bromomethyl)-pteridine is prepared by reacting 2,4,5-triamino - 6 - hydroxypyrimidine dihydrochloride, hydrobromic acid and dibromodiacetyl.-  2 - Amino - 4 - hydroxy - 6 - bromomethyl - 7 - methylpteridine is prepared from the above 6,7-di-(bromomethyl) pteridine by the reaction of hydrobromic acid, potassium iodide and sodium hydrosulphite.  2 - Amino - 4 - hydroxy - 6 - bromomethyl - 7 - carboxypteridine is prepared by the reaction of bromine and hydrobromic acid on 2-amino-4-hydroxy-6-methyl-7-carboxypteridine.  2 - Amino - 4 - hydroxy - 7 - dibromomethylpteridine is prepared by the bromination of the corresponding 7-methyl compound.  2 - Amino - 4 - hydroxy - 6 - methyl - 7 - bromomethylpteridine is prepared by reacting hydrobromic acid and 2-amino-4-hydroxy-6,7-dimethylpteridine.  2 - Amino - 4 - hydroxy - 6 - carboxy - 7 - bromomethylpteridine is prepared by the reaction of 2,4,5 - triamino - 6 - hydroxypyrimidine, sulphur dioxide and alpha-oximino-beta-keto-gammabromoethyl butyrate. The Specification as open to inspection under Sect. 91 refers to the preparation of the above 2-amino-4-hydroxy-6 or 7-substituted pteridine by the method given above using any 2-amino-4-hydroxy-6 or 7-halomethyl pyrimido [4,5-6] pyrazine.  The preparation of pteroylbenzene from p-aminobenzophenone by the method given above is also referred to.  This subject-matter does not appear in the Specification as accepted.