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US 6,441,176 B1Granted
Method for preparing sodium-hydrogen exchanger type 1 inhibitor
AssigneePfizer Inc.
InventorNorma J. Tom
Life of this patent
Estimating the term…
Abstract
Methods of preparing NHE-1 disclosed. The NHE-1 inhibitors are useful for the reduction of tissue damage resulting from tissue ischemia.
Claims5
A process for making N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine comprising:
- a. combining quinolin-5-yl-hydrazine and methyl-3-cyclopropyl-2-dimethylenamino-3-oxopropanoate in a reaction-inert solvent in the presence of an amine base to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester;
- b. hydrolyzing the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid;
- c. combining the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid and thionyl chloride in toluene to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid chloride;
- and
- d. combining guanidine hydrochloride and sodium hydroxide to a suspension of the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid chloride in tetrahydrofuran at a temperature of about −10° C. to about 10° C. for about 1 hour to about 3 hours.
2 more elements
A process for making N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate salt comprising:
- a. combining methyl-3-cyclopropyl-3-oxopropanoate and N,N-dimethylformamide dimethylacetal at a temperature of about 50° C. to about 110° C. for about one to about five hours under neat conditions;
- b. combining quinolin-5-yl-hydrazine and methyl-3-cyclopropyl-2-dimethylenamino-3-oxopropanoate in a reaction-inert solvent in the presence of an amine base to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid methyl ester;
- c. hydrolyzing the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester in methanol in the presence of sodium hydroxide at reflux to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid;
- d. combining 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid and thionyl chloride to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid chloride;
- e. combining guanidine hydrochloride and sodium hydroxide to a suspension of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid chloride in tetrahydrofuran at a temperature of about −10° C. to about 10° C. for about 1 hour to about 3 hours to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine;
- and
- f. combining N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine with methanesulfonic acid to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate salt.
4 more elements
Dependencies are inferred from the claim text.