Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles

Abstract

Improved processes for preparing substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are disclosed.

1 . A process for preparing a thioester compound of formula A:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 4  are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R 3  is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising reacting a thioether compound of formula B:  
       
         
           
           
               
               
           
         
       
       wherein R 1  through R 4  are as in formula A, with an oxidizing agent selected from the group consisting of OXONE® and potassium peroxymonosulfate to produce selective oxidation of the thioether compound of formula B to form the thioester compound of formula A.  
     
     
         2 . The process according to  claim 1 , wherein the oxidation is performed at a temperature from about −10° C. to about 30° C.  
     
     
         3 . The process according to  claim 1 , wherein the oxidation is performed for about 2 hours to about 10 hours.  
     
     
         4 . The process of  claim 1 , wherein R 1  is methyl, R 2  is methoxy; R 3  is methyl; and R 4  is methoxy.  
     
     
         5 . The process of  claim 1 , wherein R 1  is methyl; R 2  is 2-trifluoroethoxy; R 3  is hydrogen; and R 4  is hydrogen.  
     
     
         6 . The process of  claim 1 , wherein R 1  is methoxy; R 2  is methoxy; R 3  is hydrogen; and R 4  is difluoromethoxy.  
     
     
         7 . The process of  claim 1 , wherein R 1  is methyl; R 2  is MeOCH 2 CH 2 CH 2 O; R 3  is hydrogen; and R 4  is hydrogen.  
     
     
         8 . The process of  claim 1 , wherein the oxidizing agent is OXONE®.  
     
     
         9 . The process of  claim 8 , wherein the molar ratio of OXONE® and the compound of formula B is about 1.25-1.6 to about 1.  
     
     
         10 . The process of  claim 8 , wherein the molar ratio of OXONE® and the compound of formula B is about 1.4-1.6 to about 1.  
     
     
         11 . The process of  claim 8 , wherein the oxidation is performed in an aqueous organic solvent.  
     
     
         12 . The process of  claim 8 , wherein the oxidation is performed in the presence of at least one solvent wherein the solvent is selected from the group consisting of acetone, methanol and a mixture thereof.  
     
     
         13 . The process of  claim 8 , wherein the oxidation is performed in about 5% aqueous methanol.  
     
     
         14 . The process of  claim 8 , wherein the oxidation is performed in a two-phase system selected from CH 2 Cl 2 /H 2 O and ethyl acetate/H 2 O.  
     
     
         15 . The process of  claim 14 , wherein the oxidation is performed in the presence of a phase-transfer catalyst.  
     
     
         16 . The process of  claim 15 , wherein the phase-transfer catalyst is tert-butyl ammonium bromide.  
     
     
         17 . The process according to  claim 1 , wherein the oxidizing agent is potassium peroxymonosulfate.  
     
     
         18 . The process according to  claim 17 , wherein the molar ratio between potassium peroxymonosulfate and the compound of formula B is about 1.25-1.6 to about 1.  
     
     
         19 . The process according to  claim 17 , wherein the molar ratio between potassium peroxymonosulfate and the compound of formula B is about 1.4-1.6 to about 1.  
     
     
         20 . The process according to  claim 17 , wherein the oxidation is performed in an aqueous solution.  
     
     
         21 . The process according to  claim 17 , wherein the oxidation is performed in the presence of at least one solvent wherein the solvent is selected from the group consisting of acetone, methanol and a mixture thereof.  
     
     
         22 . The process according to  claim 17 , wherein the oxidation is performed in about 5% aqueous methanol.  
     
     
         23 . The process according to  claim 17 , wherein the oxidation is performed in a two-phase system selected from CH 2 Cl 2 /H 2 O and ethyl acetate/H 2 O.  
     
     
         24 . The process according to  claim 17 , wherein the oxidation is performed in the presence of a phase-transfer catalyst.  
     
     
         25 . The process according to  claim 24 , wherein the phase-transfer catalyst is tert-butyl ammonium bromide.  
     
     
         26 . The process according to  claim 17 , wherein the oxidation is performed at a temperature between about −10° C. to about 30° C.  
     
     
         27 . The process according to  claim 17 , wherein the oxidation is performed over a time period of about 2 to about 10 hours.  
     
     
         28 . The process according to  claim 8 , wherein the oxidation is performed at a temperature between about −10° C. to about 30° C.  
     
     
         29 . The process according to  claim 8 , wherein the oxidation is performed over a time period of about 2 to about 10 hours.  
     
     
         30 . The process according to  claim 1 , wherein the produced thioester compound of formula A has less than about 0.5% of a sulfone by-product.  
     
     
         31 . The process according to  claim 1 , wherein the produced thioester compound of formula A has less than about 0.2% of a sulfone by-product.