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.  
   
   
       32 . 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 tert-butyl hydroperoxide in the presence of a catalyst and an organic solvent to produce selective oxidation of the thioether compound of formula B to form the thioester compound of formula A, wherein the molar ratio of tert-butyl hydroperoxide to the compound of formula B is in the range of about 1.24:1 to about 4.5:1, and wherein 
 (a) the organic solvent is toluene;  
 (b) the organic solvent is isopropanol;  
 (c) the oxidation is performed at a temperature between about − 10 ° C. to about 30° C.;  
 (d) the oxidation is performed over a period of about 2 to about 10 hours;  
 (e) the tert-butyl hydroperoxide is dry;  
 (f) the tert-butyl hydroperoxide is aqueous; or  
 (g) the thioester compound of formula A produced has less than about 4.5% of a sulfone by-product.  
 
   
   
       33 . The process of  claim 32 , wherein the organic solvent is toluene or isopropanol.  
   
   
       34 . The process of  claim 32 , wherein the oxidation is performed at a temperature between about −10° C. to about 30° C., and/or the oxidation is performed over a period of about 2 to about 10 hours.  
   
   
       35 . The process of  claim 32 , wherein the tert-butyl hydroperoxide is dry.  
   
   
       36 . The process of  claim 32 , wherein the tert-butyl hydroperoxide is aqueous.  
   
   
       37 . The process of  claim 32 , wherein the thioester compound of formula A produced has less than about 4.5% of a sulfone by-product.  
   
   
       38 . A process for preparing a thioester compound of formula A:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is methyl, R 2  is methoxy; R 3  is methyl; and R 4  is methoxy, comprising reacting a thioether compound of formula B:  
     
       
         
         
             
             
         
       
     
     wherein R 1  through R 4  are as in formula A, with an oxidizing agent to produce selective oxidation of the thioether compound of formula B to form the thioester compound of formula A.