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US 12,503,441 B2Granted
Process for preparing diphenylureido-dihalokynurenic acids and tosylate addition salts thereof
AssigneeLohocla Research Corporation
InventorsAnanya Sengupta, Sergiy Krasutsky, Scott Tweedie, Gurusankar Ramamoorthy
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Abstract
A method of preparing 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylic acid tosylate addition salts is provided, which involves direct conversion of esters of Formula V as described herein to acids of Formula VIII as described herein. Tosylate addition salts of Formula IX as described herein are then prepared from the acids of Formula VIII.
Claims24
A method of preparing a diphenylureido-dihalokynurenic acid tosylate addition salt comprises the sequential steps of:
- (a) adding an excess of solid sodium hydroxide to a stirring solution of diphenyl carbamoyl chloride and a 4-amino-5,7-dihalo-quinoline-2-carboxylic ester of Formula V in a polar aprotic solvent, and stirring the resulting mixture until carbamylation of the amino group of the 4-amino-5,7-dihalo-quinoline-2-carboxylic ester is complete, thereby forming a solution of a diphenylureido-dihalokynurenic ester of Formula VI;
- (b) adding water to the solution of the diphenylureido-dihalokynurenic ester from step (a), and stirring the resulting solution until hydrolysis of the ester group thereof is complete, thereby forming a diphenylureido-dihalokynurenic acid sodium salt of Formula VII;
- and adjusting the pH of the reaction mixture to about 6 with an acid;
- (c) filtering the pH adjusted precipitate of step (b), and washing the filter cake comprising sodium salt of Formula VII with water;
- (d) adding a sufficient amount of an aqueous carboxylic acid to the filter cake of step (c) to achieve a pH in the range of about 6 to about 7 and stirring the resulting slurry of a diphenylureido-dihalokynurenic acid of Formula VIII until conversion of the sodium salt to the diphenylureido-dihalokynurenic acid is complete;
- (e) filtering the slurry from step (d), and washing the filter cake comprising the diphenylureido-dihalokynurenic acid of Formula VIII with water to remove water soluble impurities therefrom;
- (f) dissolving the washed filter cake from step (d) in an organic solvent, adding a molar excess of an aqueous solution of p-toluenesulfonic acid thereto, and stirring the resulting slurry of a diphenylureido-dihalokynurenic acid tosylate addition salt of Formula IX until precipitation of the tosylate addition salt is complete;
- and
- (g) isolating the diphenylureido-dihalokynurenic acid addition salt of Formula IX;
- wherein:
- X is halogen;
- M is Na, and
- R is C1 to C4 alkyl.
10 more elements
A method of preparing diphenylureido-dihalokynurenic acid comprises the sequential steps of:
- (a) adding an excess of solid sodium hydroxide to a stirring solution of diphenyl carbamoyl chloride and a 4-amino-5,7-dihalo-quinoline-2-carboxylic ester of Formula V in a polar aprotic solvent, and stirring the resulting mixture until carbamylation of the amino group of the 4-amino-5,7-dihalo-quinoline-2-carboxylic ester is complete, thereby forming a solution of a diphenylureido-dihalokynurenic ester of Formula VI;
- (b) adding water to the solution of the diphenylureido-dihalokynurenic ester from step (a), and stirring the resulting solution until hydrolysis of the ester group thereof is complete, thereby forming a diphenylureido-dihalokynurenic acid sodium salt of Formula VII;
- and adjusting the pH of the reaction mixture to about 6 with an acid;
- (c) filtering the pH adjusted precipitate of step (b), and washing the filter cake comprising sodium salt of Formula VII with water;
- (d) adding a sufficient amount of an aqueous carboxylic acid to the filter cake of step (c) to achieve a pH in the range of about 6 to about 7 and stirring the resulting slurry of a diphenylureido-dihalokynurenic acid of Formula VIII until conversion of the sodium salt to the diphenylurcido-dihalokynurenic acid is complete;
- (e) filtering the slurry from step (d), and washing the filter cake comprising the diphenylureido-dihalokynurenic acid of Formula VIII with water to remove water soluble impurities therefrom;
- and
- (f) isolating the diphenylureido-dihalokynurenic acid;
- wherein:
- X is halogen;
- M is Na, and
- R is C1 to C4 alkyl.
9 more elements
Dependencies are inferred from the claim text.