Abstract: Process for the production of methotrexate, which is N[p-([(2,4-diamino-6-pteridyl)-methyl]-N.sup.10 -methylamino)-benzoyl]-L-glutamic acid. The process includes converting 1,1-dichloroacetone with 2,4,5,6-tetraaminopyrimidine in the presence of sodium bisulfite at a constant pH between 3.5 and 5 and at a temperature between 10.degree. and 100.degree. C. The resultant 2,4-diamino-6-methylpteridine is converted in a reaction medium with bromide. 0.3 to 1.0 ml of bromine is used per 1.0 g of the 2,4-diamino-6-methylpteridine. The 2,4-diamino-6-bromo methyl pteridine is converted with p-(N-methyl)-aminobenzoyl-L-glutamic acid or a salt thereof in a polar reaction medium into methoxtrexate.

Abstract: Process for the production of p-(N-methyl)-amino-benzoyl-L-glutamic acid. The process includes introducing a formyl group into p-(N-methyl)-amino-benzoic acid, with p-(N-methyl-N-formyl)-aminobenzoic acid being formed. The p-(N-methyl-N-formyl)-aminobenzoic acid is chlorinated with a chloridizing agent, such as, sulfonyl chloride or thionyl chloride, with p-(N-methyl-N-formyl)-aminobenzoic acid chloride forming. The p-(N-methyl-N-formyl)-aminobenzoic acid chloride is reacted with L-glutamic acid in the presence of a base as an acid acceptor, with p-(N-methyl-N-formyl)-amino benzoyl-L-glutamic acid forming. The p-(N-methyl-N-formyl)-amino benzoyl-L-glutamic acid is converted into p-(N-methyl)-amino benzoyl-L-glutamic acid by alkaline hydrolysis in a 2.5 to 3.5 normal caustic soda solution at 30.degree. to 70.degree. C. Intermediates which are obtained include: p-(N-methyl-N-formyl)-aminobenzoic acid; p-(N-methyl-N-formyl)-aminobenzoic acid chloride; and p-(N-methyl-N-formyl)-amino benzoyl-L-glutamic acid.

Abstract: The process for the production of 2-amino-4-hydroxy-6-methylpteridine from 2,4,5-triamine-6-hydroxypyrimidine and 1,1-dichloroacetone which is characterized in that the 2,4,5-triamino-6-hydroxypyrimidine in the form of one of its stable salts is converted with 1,1-dichloroacetone. The 1,1-dichloroacetone is present in a 1 to 2 equivalents ratio, based upon the 2,4,5-tiramino-6-hydroxypyrimidine, to 2-amino-4-hydroxy-6-methylpteridine. The conversion is conducted in a solvent at a pH of 3.5 to 4.5 in the presence of sodium bisulfite. From 1.2 mole of the sodium bisulfite per mole of the stable salt of 2,4,5-triamino-6-hydroxypyrimidine at 5 liters of reaction solution up to 3 moles of sodium bisulfite per mole of the stable salt of 2,4,5-triamino-6-hydroxypyrimide at 50 liters of reaction solution is used.

Abstract: In the process for the production of the ethyl ester of aminocyanoacetic acid by reduction of the ethyl ester of nitrosocyanoacetic acid, the improvement of hydrogenating the ethyl ester of nitrosocyanoacetic acid in a low-boiling polar solvent in the presence of Raney nickel at an excess pressure with hydrogen of 1 to 10 atms. and at a temperature of 10.degree. C. for 40 hours to 60.degree. C. for 8 hours.