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 a composition comprising 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 a 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 . A method according to  claim 21 , wherein the ratio of 1,4-dioxane to THF in Step (i) is from about 1:5 to about 1:3. 
     
     
         23 . A method according to  claim 22 , wherein, the ratio of 1,4-dioxane to THF is about 1:4. 
     
     
         24 . A method according to  claim 21 , wherein the base comprises potassium t-butoxide. 
     
     
         25 . A method according to  claim 21 , wherein the mole ratio of the base to methyl propionate is from about 3:1 to about 1:1. 
     
     
         26 . A method according to  claim 21 , wherein the nonpolar organic solvent used in Step (iii) comprises toluene. 
     
     
         27 . A method according to  claim 21 , wherein the nonpolar organic solvent in Step (v) comprises toluene. 
     
     
         28 . A method according to  claim 21 , wherein the nonpolar solvent in Step (iii) is the same nonpolar solvent used in Step (v). 
     
     
         29 . A method according to  claim 21 , wherein the yield of oltipraz is greater than 21% based on the amount of pyrazine-2-carboxylic acid methyl ester. 
     
     
         30 . A composition comprising oltipraz prepared by the process of  claim 21 . 
     
     
         31 . A method of making a purified oltipraz composition, 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 a 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);   (vi) quenching the reaction with an aqueous composition to yield a composition comprising (i) an aqueous component and (ii) an organic component that comprises oltipraz;   (vii) separating the organic component comprising oltipraz to yield an organic composition comprising oltipraz in the nonpolar organic solvent;   (viii) reducing the amount of solvent in the organic composition;   (ix) precipitating the oltipraz in the organic composition to yield a composition comprising oltipraz;   (x) separating the precipitated oltipraz; and   (xi) purifying the separated oltipraz precipitate.   
     
     
         32 . A method according to  claim 31 , wherein the ratio of 1,4-dioxane to THF in Step (i) is from about 1:5 to about 1:3. 
     
     
         33 . A method according to  claim 31 , wherein step (viii) comprises evaporating at least a portion of the solvent in the organic composition, step (ix) comprises adding to the organic composition a solvent that causes the oltipraz to precipitate, and step (x) comprises separating the oltipraz by filtering. 
     
     
         34 . A method according to  claim 31 , wherein the step of purifying comprises recrystallization, and excludes purification that comprises chromatographic separation. 
     
     
         35 . A method of making a composition comprising methyl 2-methyl-3-oxo-3-(pyrazin-2-yl), comprising the step 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.   
     
     
         36 . A method according to  claim 35 , wherein the yield of methyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate is greater than 80% based on the amount of pyrazine-2-carboxylic acid methyl ester. 
     
     
         37 . A method according to  claim 35 , further comprising the step of adding at least one aqueous liquid to quench the reaction in Step (i), thereby forming a composition comprising an organic component and an aqueous component. 
     
     
         38 . A method according to  claim 37 , further comprising the step of separating the organic component from the aqueous component to yield a composition comprising the organic component. 
     
     
         39 . A composition made by the method of  claim 37 . 
     
     
         40 . A composition made by the method of  claim 38 .