Process for the preparation of high purity methotrexate and derivatives thereof
AssigneeAmerican Cyanamid Company
InventorsBalwant Singh, Frederic C. Schaefer
Life of this patent
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Abstract
An improved process for the preparation and purification of N-{p-([2,4-diamino-6-pteridinyl)-methyl]methylamino)benzoyl} glutamic acid, also known as methotrexate, using the alkali metal, calcium and zinc salts of N-methyl-p-aminobenzoylglutamate, tetraaminopyrimidine sulfate, 1,1,3-tribromoacetone and the alkali metal and zinc salts of methotrexate.
Claims2
A process for preparing a compound of the formula ##STR4## wherein R is hydrogen or C.sub.1 to C.sub.4 alkyl which comprises simultaneously reacting 2,4,5,6-tetraaminopyrimidine sulfate and 1,1,3-tribromoacetone with a salt of the formula ##EQU1## in water at a temperature of about 30.degree. to about 60.degree. C. and a pH of about 1.5 to about 3.5;
- adjusting the pH of the reaction mixture with ammonium hydroxide to a pH of from about 9 to about 10;
- lowering the pH of the filtrate to about pH 6.0 with hydrochloric acid to precipitate the zinc salt;
- filtering and water-washing the resultant precipitate;
- reslurrying said precipitate in water and adjusting the pH of the slurry to about pH 1.5 with hydrochloric acid, filtering and water-washing the resultant precipitate;
- dispersing the filtered and water-washed precipitate in water and adjusting the pH of the solution of pH of about 10 with sodium hydroxide;
- acidifying the solution to a pH of about 1.5 with hydrochloric acid;
- water-washing the resultant precipitate;
- redissolving said precipitate in water and adjusting the pH of the solution to about pH 10 with sodium hydroxide;
- diluting the solution with acetone and dissolving the precipitate in water;
- and acidifying to a pH of about pH 4.0 with sulfuric acid.
A process for preparing a compound of the formula:
- ##STR5## which comprises simultaneously reacting 2,4,5,6-tetraaminopyrimidine sulfate and 1,1,3-tribromoacetone with a salt of the formula ##STR6## at a temperature of about 50.degree. C. and a pH of about 2.0;
- adjusting the pH of the reaction mixture with ammonium hydroxide to a pH of from about 9 to about 10;
- lowering the pH of the filtrate to about pH 6.0 with hydrochloric acid to precipitate the zinc salt of methotrexate;
- filtering and water-washing the resultant precipitate;
- reslurrying said precipitate in water and adjusting the pH of the slurry to about pH 1.5 with hydrochloric acid;
- filtering and water-washing the resultant precipitate;
- dispersing the filtered and water-washed precipitate in water and adjusting the pH of the solution to pH of about 10 with sodium hydroxide;
- acidifying the solution to a pH of about pH 1.5 with hydrochloric acid;
- water-washing the resultant precipitate;
- redissolving said precipitate in water and adjusting the pH of the solution to about pH 10 with sodium hydroxide;
- diluting the solution with acetone and dissolving the precipitate in water;
- and acidifying to a pH of about pH 4.0 with sulfuric acid.
Dependencies are inferred from the claim text.