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 . A method comprising the steps of:
 a) combining in a first container a first solvent and a first base;   b) stirring the contents of the first container at a temperature of about 0° C. for about 5 minutes;   c) adding to the first container, over a period of time of about 15 minutes, methyl propionate;   d) stirring the contents of the first container at about 0° C. for about 15 minutes;   e) adding to the first container a solution of   
       
         
           
           
               
               
           
         
       
       in a second solvent, wherein the solution is added over a period of time of about 30 minutes while warming the first container to a temperature of about 22° C.; and the second solvent is a mixture of tetrahydrofuran and 1,4-dioxane; and
 f) stirring the contents of the first container at about 22° C. for a first period of time. 
 
     
     
         2 . The method of  claim 1 , wherein the first solvent is tetrahydrofuran. 
     
     
         3 . The method of  claim 1 , wherein the first solvent is a mixture of tetrahydrofuran and 1,4-dioxane. 
     
     
         4 . The method of  claim 1 , wherein the first solvent is about a 5:1, about a 4:1, or about a 3:1 mixture by volume of tetrahydrofuran and 1,4-dioxane. 
     
     
         5 . The method of  claim 1 , wherein the first base is sodium pentanoate or potassium t-butoxide. 
     
     
         6 . The method of  claim 1 , wherein the concentration of the first base in the first solvent is about 1.0 M, about 1.2 M, about 1.4 M, about 1.6 M, or about 1.8 M. 
     
     
         7 . The method of  claim 1 , wherein the mole ratio of first base to methyl propionate is about 3:1, about 2:1, or about 1:1. 
     
     
         8 . The method of  claim 1 , wherein the concentration of 
       
         
           
           
               
               
           
         
       
       in the second solvent is about 1.6 M, about 1.8 M, or about 2.0 M. 
     
     
         9 . The method of  claim 1 , wherein the mole ratio of methyl propionate to 
       
         
           
           
               
               
           
         
       
       is about 2:1, about 1.8:1, or about 1.6:1. 
     
     
         10 . The method of  claim 1 , wherein the second solvent is about a 1.2:1, about a 1:1, or about a 0.8:1 mixture by volume of tetrahydrofuran and 1,4-dioxane. 
     
     
         11 . The method of  claim 1 , wherein the method is a method of synthesizing 
       
         
           
           
               
               
           
         
       
       in a yield greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. 
     
     
         12 . The method of  claim 1 , wherein the method is a method of synthesizing 
       
         
           
           
               
               
           
         
       
       in a yield greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% without purification other than isolation. 
     
     
         13 . A method comprising the steps of:
 i) combining in a second container P 2 S 5  and a first quantity of toluene;   ii) heating the second container at a temperature of about 100° C.;   iii) adding to the second container a solution of   
       
         
           
           
               
               
           
         
       
       in a second quantity of toluene; and
 iv) heating the contents of the second container to reflux for a second period of time, wherein no xylene is added or included at any step; and 
 further comprising synthesizing 
 
       
         
           
           
               
               
           
         
       
       according to steps a-f:
 a) combining in a first container a first solvent and a first base; 
 b) stirring the contents of the first container at a temperature of about 0° C. for about 5 minutes; 
 c) adding to the first container, over a period of time of about 15 minutes, methyl propionate; 
 d) stirring the contents of the first container at about 0° C. for about 15 minutes; 
 e) adding to the first container a solution of 
 
       
         
           
           
               
               
           
         
       
       in a second solvent, wherein the solution is added over a period of time of about 30 minutes while warming the first container to a temperature of about 22° C.; and the second solvent is a mixture of tetrahydrofuran and 1,4-dioxane; and
 f) stirring the contents of the first container at about 22° C. for a first period of time. 
 
     
     
         14 . The method of  claim 13 , wherein the concentration of P 2 S 5  in the first quantity of toluene is about 0.2 M, about 0.25 M, about 0.3 M, about 0.35 M, about 0.4 M, about 0.45 M, or about 0.5 M. 
     
     
         15 . The method of  claim 13 , wherein P 2 S 5  and the first quantity of toluene are combined in the second container under an inert atmosphere. 
     
     
         16 . The method of  claim 13 , wherein the method is a method of synthesizing oltipraz; and the purity of the oltipraz produced by the claimed method is greater than 97%, greater than 98%, or greater than 99%, as determined by gas chromatography. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 13 , wherein the mole ratio of 
       
         
           
           
               
               
           
         
       
       to P 2 S 5  is about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, or about 1.8:1. 
     
     
         19 . The method of  claim 13 , wherein the method is a method of synthesizing oltipraz; and the overall yield of oltipraz from 
       
         
           
           
               
               
           
         
       
       is greater than 21%, greater than 22%, greater than 23%, greater than 24%, greater than 25%, greater than 26%, greater than 27%, greater than 28%, greater than 29%, or greater than 30%. 
     
     
         20 . The method of  claim 13 , wherein the method is a method of synthesizing oltipraz; and the overall yield of oltipraz from 
       
         
           
           
               
               
           
         
       
       is greater than 21%, and the purity of the resulting oltipraz is greater than 97%, as determined by gas chromatography.