Preparation of (S)-clopidogrel and related compounds

Abstract

A process for producing enantiomerically enriched (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5 (4H)-acetic acid hydrocarbyl ester, represented by the formula: Is provided, wherein R 1 and R 2 are hydrogens and R 3 is methyl (i.e., (S)-Clopidogrel). The process includes the steps of: (a) contacting N-2-chlorobenz-aldehyde-ylidene-1-ethylamine-2 (2-thiophenyl)imine and an HCN source, in the presence of a non-metallic asymmetric Strecker catalyst to form enantiomerically enriched (S)-α,α-(2-thiophenylethylamino) (2-chlorophenyl) acetonitrile; (b) contacting the enantiomerically enriched (s)-α,α-(2-thiophenylethylamino) (2-chlorophenyl) acetonitrile and a formaldehyde equivalent, in the presence of an acid catalyst to form enantiomerically enriched α-5 (4,5,6,7-tetrahydro[3,2-c] thienopyridyl) (2-chlorobenzyl)-nitrile; and (c) contacting the enantiomerically enriched α-5(4,5,6,7-tetrahydro[3,2-c] thienopyridyl) (2-chlorobenzyl)-nitrile and a reagent capable of converting a cyano group into an ester group to form enantiomerically enriched hydrocarbyl ester of (S)-α-(2-chlorophenyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)-acetic acid.

1 . A process comprising the step of: 
 contacting a derivative of N-2-chlorobenzaldehydeylidene-1-ethylamine-2 (2-thiophenyl) imine represented by the formula:                          and an HCN source, optionally in the presence of a catalyst represented by the formula:                          wherein R 1  is a substituent at the 3, 4, 5 or 6 position of the chlorophenyl ring and R 2  is a substituent at the 4 or 5 position of the thiophene ring; wherein each R 1  and R 2  is independently selected from the group consisting of: H, linear, branched or cyclic alkyl of 1 to 22 carbon atoms, aryl of 6 to 22 carbon atoms, aralkyl of 7 to 22 carbon atoms, alkylaryl of 7 to 22 carbon atoms, halogen, cyano, nitro, amido, carbamato, imido, alkoxy, aryloxy, acyl, alkoxycarbonyl and trifluoromethyl;    wherein R 3  is a hydrocarbyl group; and    wherein R is selected from the group consisting of: phenyl, tolyl, xylyl, naphthyl, heteroaryl, amido, imido, carbamato, polystyrene beads, and a mixture thereof; said contacting being at a temperature and length of time sufficient to form said enantiomerically enriched derivative of (S)-α,α-(2-thiophenylethylamino) (2-chlorophenyl) acetonitrile.    
     
     
         2 . The process of  claim 1 , wherein said derivative of N-2-chlorobenzaldehydeylidene-1-ethylamine-2-(2-thiophenyl)-imine is prepared by a process comprising the step of contacting an R 1  substituted derivative of 2-chlorobenzaldehyde and an R 2  substituted derivative of 2-(2-aminoethyl)-thiophene, optionally in the presence of a catalyst, at a temperature and length of time sufficient to produce said derivative of N-2-chlorobenzaldehydeylidene-1-ethylamine-2-(2-thiophenyl)-imine.  
     
     
         3 . The process of  claim 2 , wherein said catalyst is selected from the group consisting of: an acid, molecular sieves, and a combination thereof.  
     
     
         4 . The process of  claim 1 , further comprising the step of contacting said enantiomerically enriched derivative of (S)-α,α-(2-thiophenylethyl-amino)-(2-chlorophenyl)-acetonitrile and an acid HX, wherein X is the counter anion of said acid, at a temperature and length of time sufficient to produce a salt of said enantiomerically enriched derivative of (S)-α,α-(2-thiophenyl-ethylamino)-(2-chlorophenyl)-acetonitrile, said salt being represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         5 . The process of  claim 4 , wherein said acid HX is selected from the group consisting of: mineral acid, organic acid, and a mixture thereof.  
     
     
         6 . The process of  claim 4 , wherein said acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, trichloroacetic acid, trifluoroacetic acid, trichloromethanesulfonic acid, trifluoromethanesulfonic acid and a mixture thereof.  
     
     
         7 . The process of  claim 4 , wherein said acid is selected from the group consisting of: HCl, HOAc, and a mixture thereof.  
     
     
         8 . The process of  claim 4 , further comprising the step of: 
 recrystallizing said salt of said enantiomerically enriched derivative of (S)-α,α-(2-thiophenylethylamino)-(2-chlorophenyl)-acetonitrile from a recrystallizing solvent.    
     
     
         9 . The process of  claim 8 , wherein said solvent is selected from the group consisting of: hexanes, toluene, methanol, ethanol, isopropanol, methylene chloride, tetrahydrofurane, ether, ethyl acetate, acetone and a mixture thereof.  
     
     
         10 . The process of  claim 8 , wherein said recrystallizing solvent is a mixture comprising toluene and isopropanol in a 2:1 ratio by weight.  
     
     
         11 . The process of  claim 4 , further comprising the step of: 
 contacting said enantiomerically enriched derivative of (S)-α,α-(2-thiophenylethylamino) (2-chlorophenyl) acetonitrile, or a salt thereof, and a formaldehyde equivalent, optionally in the presence of a catalyst, at a temperature and length of time sufficient to produce enantiomerically enriched α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorobenzyl)-nitrile represented by the formula:                          
     
     
         12 . The process of  claim 11 , wherein said formaldehyde equivalent is selected from the group consisting of: formaldehyde, paraformaldehyde, formaline, hexamethylenetetraamine, 1,3 dioxolane and a mixture thereof.  
     
     
         13 . The process of  claim 11 , wherein said catalyst is an acid.  
     
     
         14 . The process of  claim 13 , wherein said acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, trichloroacetic acid, trifluoroacetic acid, trichloromethanesulfonic acid, trifluoromethanesulfonic acid and a mixture thereof.  
     
     
         15 . The process of  claim 11 , wherein said enantiomerically enriched (S)-α,α-(2-thiophenylethylamino) (2-chlorophenyl) acetonitrile salt is the hydrochloride salt thereof.  
     
     
         16 . The process of  claim 1 , wherein R 3  is selected from the group consisting of: a linear, branched or cyclic alkyl of 1 to 22 carbon atoms, aryl of 6 to 22 carbon atoms, aralkyl of 7 to 22 carbon atoms, alkylaryl of 7 to 22 carbon atoms and any combination thereof.  
     
     
         17 . The process of  claim 11 , further comprising: 
 contacting said derivative of enantiomerically enriched α-5(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorobenzyl)-nitrile and a reagent capable of converting a cyano group into an ester group at a temperature and length of time sufficient to form a derivative of an enantiomerically enriched hydrocarbyl ester of (S)-α-(2-chlorophenyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)-acetic acid represented by the formula:                          wherein R 1  is a substituent at the 3, 4, 5 or 6 position of the chlorophenyl ring and R 2  is a substituent at the 4 or 5 position of the thiophene ring; wherein each R 1  and R 2  is independently selected from the group consisting of: H, linear, branched or cyclic alkyl of 1 to 22 carbon atoms, aryl of 6 to 22 carbon atoms, aralkyl of 7 to 22 carbon atoms, alkylaryl of 7 to 22 carbon atoms, halogen, cyano, nitro, amido, carbamato, imido, alkoxy, aryloxy, acyl, alkoxycarbonyl and trifluoromethyl;    wherein R 3  is a hydrocarbyl group; and    wherein R is selected from the group consisting of: phenyl, tolyl, xylyl, naphthyl, heteroaryl, amido, imido, carbamato, polystyrene beads, and a mixture thereof.    
     
     
         18 - 20 . (canceled)  
     
     
         21 . A process comprising the step of: 
 contacting N-2-chlorobenzaldehydeylidene-1-ethylamine-2-(2-thiophenyl)-imine represented by the formula:                          and an HCN source in the presence of a catalyst represented by the formula:                          wherein R is selected from the group consisting of: phenyl, tolyl, xylyl, naphthyl, heteroaryl, amido, imido, carbamato, polystyrene beads and a mixture thereof, said contacting being at a temperature and length of time sufficient to form said enantiomerically enriched (S)-α,α-(2-thiophenylethylamino)-(2-chlorophenyl)-acetonitrile.    
     
     
         22 . The process of  claim 21 , wherein said N-2-chlorobenz-aldehydeylidene-1-ethylamine-2-(2-thiophenyl)-imine is prepared by a process comprising the step of contacting 2-chlorobenzaldehyde and 2-(2-aminoethyl)-thiophene, optionally in the presence of a catalyst, at a temperature and length of time sufficient to produce said N-2-chlorobenzaldehydeylidene-1-ethylamine-2-(2-thiophenyl)-imine.  
     
     
         23 . The process of  claim 22 , wherein said catalyst is selected from the group consisting of: an acid, molecular sieves, and a combination thereof.  
     
     
         24 . The process of  claim 21 , further comprising the step of: 
 contacting said enantiomerically enriched (S)-α,α-(2-thiophenylethylamino)-(2-chlorophenyl)-acetonitrile and an acid HX, wherein X is the counter anion of said acid, at a temperature and length of time sufficient to produce a salt of said enantiomerically enriched (S)-α,α-(2-thiophenyl-ethylamino)-(2-chlorophenyl)-acetonitrile, said salt being represented by the formula:                          
     
     
         25 . The process of  claim 24 , wherein said acid HX is selected from the group consisting of: mineral acid, organic acid, and a mixture thereof.  
     
     
         26 . The process of  claim 24 , wherein said acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, trichloroacetic acid, trifluoroacetic acid, trichloromethanesulfonic acid, trifluoromethanesulfonic acid and a mixture thereof.  
     
     
         27 . The process of  claim 24 , wherein said acid is selected from the group consisting of: HCl, HOAc, and a mixture thereof.  
     
     
         28 . The process of  claim 24 , further comprising the step of: 
 recrystallizing said salt of enantiomerically enriched (S)-α,α-(2-thiophenylethylamino)-(2-chlorophenyl)-acetonitrile from a recrystallizing solvent.    
     
     
         29 . The process of  claim 28 , wherein said solvent is selected from the group consisting of: hexanes, toluene, methanol, ethanol, isopropanol, methylene chloride, tetrahydrofurane, ether, ethyl acetate, acetone and a mixture thereof.  
     
     
         30 . The process of  claim 28 , wherein said recrystallizing solvent is a mixture comprising toluene and isopropanol in a 2:1 ratio by weight.  
     
     
         31 . The process of  claim 24 , further comprising the step of: 
 contacting said enantiomerically enriched (S)-α,α-(2-thiophenylethylamino) (2-chlorophenyl) acetonitrile, or a salt thereof, and a formaldehyde equivalent, optionally in the presence of a catalyst, at a temperature and length of time sufficient to produce enantiomerically enriched α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorobenzyl)-nitrile represented by the formula:                          
     
     
         32 . The process of  claim 31 , wherein said formaldehyde equivalent is selected from the group consisting of: formaldehyde, paraformaldehyde, formaline, hexamethylenetetraamine, 1,3 dioxolane and a mixture thereof.  
     
     
         33 . The process of  claim 31 , wherein said catalyst is an acid.  
     
     
         34 . The process of  claim 33 , wherein said acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, trichloroacetic acid, trifluoroacetic acid, trichloromethanesulfonic acid, trifluoromethanesulfonic acid and a mixture thereof.  
     
     
         35 . The process of  claim 31 , further comprising: 
 contacting said enantiomerically enriched α-5(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorobenzyl)-nitrile and a reagent capable of converting a cyano group into an ester group at a temperature and length of time sufficient to form an enantiomerically enriched hydrocarbyl ester of (S)-α-(2-chlorophenyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)-acetic acid represented by the formula:                          wherein R 3  is a hydrocarbyl group.    
     
     
         36 - 38 . (canceled)