Transition metal mediated oxidation of hetero atoms in organic molecules coordinated to transition metals: oxidation of coordinated benzimidazole to omeprazole

Abstract

The present invention is directed to a process for the catalytic oxidation of the thioether 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylthio)-1H-benzimidazole to its sulfoxide: 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl) methylsulfinyl)-1H-benzimidazole comprising: reacting the thioether with: 1) a transition metal catalyst; and, 2) an oxygen source; wherein the thioether is oxidized to the sulfoxide commonly known as omeprazole and wherein one of either the R and S enantiomers is formed to an enantiomeric excess.

Having described the invention, we claim: 
     
         1 . A composition of matter comprising a sulfoxide, 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole, said sulfoxide having R and S enantiomers and further comprising a compound selected from the group consisting of a transition metal catalyst and an oxygen source wherein said transition metal catalyst is a transition metal complex comprising said sulfoxide and wherein said oxygen source is selected from the group consisting of peracids, hydrogen peroxide, dimethyldioxirane and molecular oxygen and has one of either the R and S enantiomers in an enantiomeric excess. 
     
     
         2 . A composition according to  claim 1 , wherein the S enantiomer of the sulfoxide is present in a amount of from about 55% to about 99% of the combined weight of the enantiomers. 
     
     
         3 . A composition according to  claim 1 , wherein the S enantiomer of the sulfoxide is present in a amount of from about 55% to about 95% of the combined weight of the enantiomers. 
     
     
         4 . A composition according to  claim 1 , wherein the S enantiomer of the sulfoxide is present in a amount of from about 55% to about 90% of the combined weight of the enantiomers. 
     
     
         5 . A composition according to  claim 1 , wherein the S enantiomer of the sulfoxide is present in an amount of from about 55% to about 85% of the combined weight of the enantiomers. 
     
     
         6 . The composition of  claim 1  wherein said transition metal complex comprises a ligand selected from the group consisting of monodentate, bidentate tridentate or polydentate ammines, di-ammines, polyamines, phosphines, di-phosphines and polyphosphines. 
     
     
         7 . The composition of  claim 1  wherein said transition metal complex is a non-symmetric coordination complex of said transition metal. 
     
     
         8 . The composition of  claim 1  wherein said transition metal complex additionally comprises cyclopentadienyl. 
     
     
         9 . The composition of  claim 6  wherein said transition metal complex is a non-symmetric coordination complex of said transition metal. 
     
     
         10 . The composition of  claim 9  wherein said transition metal complex additionally comprises cyclopentadienyl. 
     
     
         11 . The composition of  claim 1  comprising an amount of a racemic mixture of 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole wherein the S-enantiomer is present in an amount of from about 50% to about 80% of the combined weight of the enantiomers. 
     
     
         12 . A stable pharmaceutical preparation suitable for oral administration containing the acid labile benzimidazole compound 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole which preparation comprises:
 (a) a nucleus formed by an inert core, the acid labile benzimidazole compound, a non-alkaline inert water soluble polymer and non-alkaline reacting pharmaceutical acceptable exicipients;   (b) an inert non-alkaline coating disposed on said nucleus, formed by a non-alkaline water soluble polymer and non-alkaline pharmaceutical excipients,   (c) an outer layer disposed on the previous coating comprising an enteric coating and wherein the acid labile benzimidazole compound is made according to a process wherein the thioether 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylthio)-1H-benzimidazole is catalytically coverted to its sulfoxide: 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole by:
 a. reacting the thioether with: 1) a transition metal catalyst; and, 2) an oxygen source; wherein the thioether is oxidized to a sulfoxide and wherein one of either the R and S enantiomers is formed to an enantiomeric excess. 
   
     
     
         13 . The preparation of  claim 12  consisting essentially of a capsule and more than one pellet wherein the pellet consists of:
 (a) an inert core; 
 (b) a drug layer surrounding the inert core consisting of 20-70 wt % of 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole, 0.1-5 wt % of a surface active agent, 20-70 wt % of a filler, 1-20 wt % of a pharmaceutically acceptable alkaline agent and 0.1-5 wt % of a binder; and 
 (c) a coating layer surrounding the drug layer that consists essentially of an enteric coating agent and an inert processing aid wherein the coating layer is applied directly to the 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole containing drug layer without a separating layer between the 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole containing drug layer and the coating layer and wherein the benzimidazole compound is made according to a process wherein the sulfoxide: 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylsulfinyl)-1H-benzimidazole is catalytically converted from the thioether 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylthio)-1H-benzimidazole by:
 b. reacting the thioether with: 1) a transition metal catalyst; and, 2) an oxygen source; wherein the thioether is oxidized to a sulfoxide and wherein one of either the R and S enantiomers is formed to an enantiomeric excess. 
 
 
     
     
         14 . A composition comprising:
 a) a transition metal;   b) a chiral ligand selected from the group consisting of bidentate, tridentate or polydentate ammines, di-ammines, polyamines, phosphines, di-phosphines and polyphosphines; and   c) 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)methylthio)-1H-benzimidazole   
     
     
         18 . The composition of claim  17  comprising a sulfoxide compound obtained by the oxidation of the thioether. 
     
     
         19 . The composition of  claim 14  wherein said transition metal is selected from the group consisting of Cr, W, Ru, Rh, Pd, Ir and Pt. 
     
     
         20 . The composition of  claim 19  comprising a sulfoxide compound obtained by the oxidation of the thioether.