Methods for preparing oltipraz
The invention provides improved methods of synthesizing oltipraz, which result in higher overall yield and better purity of the desired product.
1. 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).
2. A method according to claim 1 , wherein the ratio of 1,4-dioxane to THF in Step (i) is from about 1:5 to about 1:3.
3. A method according to claim 2 , wherein, the ratio of 1,4-dioxane to THF is about 1:4.
4. A method according to claim 1 , wherein the base comprises potassium t-butoxide.
5. A method according to claim 1 , wherein the mole ratio of the base to methyl propionate is from about 3:1 to about 1:1.
6. A method according to claim 1 , wherein the nonpolar organic solvent used in Step (iii) comprises toluene.
7. A method according to claim 1 , wherein the nonpolar organic solvent in Step (v) comprises toluene.
8. A method according to claim 1 , wherein the nonpolar solvent in Step (iii) is the same nonpolar solvent used in Step (v).
9. A method according to claim 1 , wherein the yield of oltipraz is greater than 21% based on the amount of pyrazine-2-carboxylic acid methyl ester.