Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation

Abstract

The present invention relates to an improved method for the synthesis of the (S)- or (R)-enantiomer of omeprazole, characterized in that 2-[[(4-X-3,5-dimethylpyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole or 2-[[(4-X-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole, wherein X is a leaving group, is oxidized into the corresponding sulphoxide which is obtained as a crystalline compound. Recrystallisation of the thus obtained sulphoxide results in a compound of enhanced chemical and optical purity, which is subsequently transformed into the (S)- or (R)-enantiomer of omeprazole.

1 . A compound of formula I in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound,  
       
         
           
           
               
               
           
         
       
       wherein Het is  
       
         
           
           
               
               
           
         
       
       and X is a leaving group.  
     
     
         2 . The compound 2-[[(4-chloro-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.  
     
     
         3 . The compound 2-[[(4-nitro-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.  
     
     
         4 . The compound 2-[[(4-chloro-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.  
     
     
         5 . The compound 2-[[(4-nitro-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.  
     
     
         6 . A process for enantioselective synthesis of a sulphoxide of formula I in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the entiomerically enriched form of the compound,  
       
         
           
           
               
               
           
         
       
       wherein Het is  
       
         
           
           
               
               
           
         
       
       and X is a leaving group, wherein the process comprises oxidizing a pro-chiral sulphide of the formula II,  
       
         
           
           
               
               
           
         
       
       wherein Het is defined above, in an organic solvent with an oxidising agent and in the presence of a chiral titanium complex and optionally a base.  
     
     
         7 . A process for synthesizing S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, wherein the process comprises replacing a leaving group of a compound according to Formula I with methoxide,  
       
         
           
           
               
               
           
         
       
       wherein Het is  
       
         
           
           
               
               
           
         
       
       and X is the leaving group.  
     
     
         8 . The compound S-5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole prepared according to the process of  claim 6  or  7 .  
     
     
         9 . A pharmaceutical formulation comprising S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole and a pharmaceutically acceptable carrier or diluent, wherein the S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole is prepared according to  claim 6  or  7 .  
     
     
         10 . The compound according to  claim 1 , wherein the leaving group X is selected from the group consisting of halogen, NO 2 , N 2   + , and OSO 2 R, wherein R is CH 3 , CF 3 , p-toluene, m-chlorobenzene, or p-chlorobenzene.  
     
     
         11 . The process according to  claim 6 , wherein the leaving group X is selected from the group consisting of halogen, NO 2 , N 2   + , and OSO 2 R, wherein R is CH 3 , CF 3 , p-toluene, m-chlorobenzene, or p-chlorobenzene.  
     
     
         12 . The process according to  claim 6 , wherein the process is carried out in the presence of a base.  
     
     
         13 . The process according to  claim 6 , wherein the titanium complex is prepared in the presence of the pro-chiral sulphide.  
     
     
         14 . The process according to  claim 6 , wherein the titanium complex is prepared at an elevated temperature and/or during a prolonged preparation time.  
     
     
         15 . The process according to  claim 6 , wherein the titanium complex is prepared in the presence of the pro-chiral sulphide and at an elevated temperature and/or during a prolonged preparation time.  
     
     
         16 . The process according to  claim 7 , wherein the leaving group X is selected from the group consisting of halogen, NO 2 , N 2   + , and OSO 2 R, wherein R is CH 3 , CF 3 , p-toluene, m-chlorobenzene, or p-chlorobenzene.  
     
     
         17 . The process according to  claim 7 , wherein the leaving group X is replaced prior to or after a reduction step during which the oxidopyridine is reduced to pyridine.