US4374987A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Process for the preparation of high purity methotrexate and derivatives thereof
Assignee: Wyeth Holdings LLC
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Filing: 1980-08-14
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Granted: 1983-02-22
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Expires: 2000-08-14
Abstract
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.
Inventors
- 👤 Balwant Singh
- 👤 Frederic C. Schaefer
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 11:58
CPC Classifications
C; C07; C07D; C07D475/00; C07D475/06; C07D475/08
Claims Analysis
Total Claims: 4
Claim 1
Independent Claim
207 words
A process for preparing a compound of the formula ##STR4## wherein R is hydrogen or C 1 to C 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° to about 60° 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.
Claim 2
Dependent Claim
207 words
A process for preparing a compound of the formula ##STR4## wherein R is hydrogen or C 1 to C 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° to about 60° 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.
Claim 3
Dependent Claim
191 words
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° 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.
Claim 4
Dependent Claim
191 words
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° 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.
References Cited (Backward Citations)
US2570391A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1986-02-21 | 1986-08-23 | 1987-02-22 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-02-21 | 1990-08-23 | 1991-02-22 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-02-21 | 1994-08-23 | 1995-02-22 | $7700.00 | Window Closed / Lapsed |