Methods for preparing oltipraz

Abstract

The invention provides improved methods of synthesizing oltipraz, which result in higher overall yield and better purity of the desired product.

1 - 20 . (canceled) 
     
     
         21 . A method of making oltipraz, comprising the steps of:
 (i) reacting a quantity of pyrazine-2-carboxylic acid methyl ester with methyl propionate to form methyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate, wherein the reaction is carried out in the presence of a base comprising potassium t-butoxide or sodium pentanoate, and a solvent comprising 1,4-dioxane in tetrahydrofuran (THF), wherein the ratio of 1,4-dioxane in the THF is at least about 1:5;   (ii) adding at least one aqueous liquid to quench the reaction in Step (i);   (iii) adding a nonpolar organic solvent and an ionic salt, thereby forming composition comprising an aqueous component and an organic component, wherein the organic component comprises the nonpolar solvent and methyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate;   (iv) separating the organic component from the aqueous component;   (v) reacting the methyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate ester in the organic component with P 2 S 5  in the presence of a nonpolar organic solvent to form 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione (oltipraz).   
     
     
         22 . The method of  claim 21 , wherein the ratio of 1,4-dioxane to THF in Step (i) is from about 1:5 to about 1:3. 
     
     
         23 . The method of  claim 22 , wherein, and the ratio of 1,4-dioxane to THF is about 4:1. 
     
     
         24 . The method of  claim 21 , wherein the base comprises potassium t-butoxide. 
     
     
         25 . The method of  claim 21 , wherein the mole ratio of the base to methyl propionate is from about 3:1 to about 1:1. 
     
     
         26 . The method of  claim 21 , wherein the nonpolar organic solvent used in Step (iii) comprises toluene. 
     
     
         27 . The method of  claim 21 , wherein the nonpolar organic solvent in Step (v) comprises toluene. 
     
     
         28 . The method of  claim 21 , wherein the nonpolar solvent in Step (iii) is the same nonpolar solvent used in Step (v). 
     
     
         29 . The method of  claim 21 , wherein the yield of oltipraz is greater than 20% based on the amount of pyrazine-2-carboxylic acid methyl ester. 
     
     
         30 . The method of  claim 29 , wherein the oltipraz obtained from Step (v) is subjected to recrystallization to yield oltipraz having a purity of at least 97%.