Process for the separation of probucol derivatives

Abstract

Provided are methods for the separation of mono-substituted probucol derivatives from a mixture of both mono- and di-substituted probucol derivatives. In particular, methods are provided for the separation of mono-carboxy substituted probucol derivatives from a mixture of mono- and di-carboxy substituted probucol derivatives.

1 . (canceled) 
     
     
         2 . A process for separating a compound of Formula III and/or a salt of a compound of Formula III 
       
         
           
           
               
               
           
         
         wherein R is a bond or —C(O)—, and X is selected from the group consisting of a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; aryl; heteroaryl; heterocycle; alkaryl; arylalkyl; and alkarylkyl, all of which may be optionally substituted, from a mixture is provided, said mixture comprising:
 said compound of Formula III; 
 said salt of a compound of Formula III; 
 a compound of Formula IV and/or a salt of a compound of Formula IV 
 
       
       
         
           
           
               
               
           
         
         wherein R is a bond or —C(O)—, and X is selected from the group consisting of a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; aryl; heteroaryl; heterocycle; alkaryl; arylalkyl; and alkarylkyl, all of which may be optionally substituted;
 an organic phase; and 
 an aqueous phase; 
 
         the process comprising:
 removing from said mixture, said aqueous phase comprising: 
 said compound of Formula IV and/or said salt of a compound of Formula IV, thus leaving the organic phase comprising: 
 said compound of Formula III and/or said salt of a compound of Formula III; isolating said compound of Formula III and/or said salt of a compound of Formula III from said organic phase. 
 
       
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The process of  claim 2 , wherein said organic phase comprises at least a first organic solvent and a second organic solvent. 
     
     
         6 . The process of  claim 5  wherein said first organic solvent is a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated. 
     
     
         7 . The process of  claim 5  wherein said first organic solvent is selected from the group consisting of benzene, toluene, xylene, mesitylene, naphthalene, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, eicosane, cyclohexane, and petroleum ether. 
     
     
         8 . The process of  claim 5  wherein said second organic solvent is selected from the group consisting of an ether, an ester, an alcohol, an amide, a nitrile, or a ketone. 
     
     
         9 . The process of  claim 5  wherein said second organic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl alcohol, ethyl alcohol, isopropyl alcohol, acetonitrile, dimethylformamide, acetone, and 2-butanone. 
     
     
         10 . The process of  claim 5  wherein said first organic solvent is hexane, heptane, or toluene, and said second organic solvent is acetone or 2-butanone. 
     
     
         11 . (canceled) 
     
     
         12 . A process for separating a compound of Formula III and/or a salt of a compound of Formula III, 
       
         
           
           
               
               
           
         
         wherein R is a bond or —C(O)—, and X is selected from the group consisting of a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; aryl; heteroaryl; heterocycle; alkaryl; arylalkyl; and alkarylkyl, all of which may be optionally substituted, from a first mixture, said first mixture comprising:
 said compound of Formula III; 
 a compound of Formula IV, 
 
       
       
         
           
           
               
               
           
         
         
           wherein R is a bond or —C(O)—, and X is selected from the group consisting of a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; aryl; heteroaryl; heterocycle; alkaryl; arylalkyl; and alkarylkyl, all of which may be optionally substituted; and 
           probucol; 
         
         or
 said salt of a compound of Formula III; 
 a salt of a compound of Formula IV; and 
 probucol; 
 
         said process comprising: 
         removing said probucol from said first mixture to afford a second mixture; 
         partially neutralizing said second mixture, optionally adding at least one aqueous solvent, and optionally adding at least one organic solvent, 
         thus affording a partially neutralized third mixture, said partially neutralized third mixture comprising:
 an aqueous phase; 
 an organic phase; 
 said compound of Formula III; 
 said salt of a compound of Formula III; and 
 said compound of Formula IV and/or a salt of a compound of Formula IV; 
 
         removing from said partially neutralized third mixture, said aqueous phase comprising:
 said compound of Formula IV and/or said salt of a compound of Formula IV, 
 
         thus leaving the organic phase comprising:
 said compound of Formula III and/or said salt of a compound of Formula III; 
 
         isolating said compound of Formula III and/or said salt of a compound of Formula III from said organic phase. 
       
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The process of  claim 12 , wherein said organic phase comprises at least a first organic solvent and a second organic solvent. 
     
     
         16 . The process of  claim 15  wherein said first organic solvent is a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated. 
     
     
         17 . The process of  claim 15  wherein said first organic solvent is selected from the group consisting of benzene, toluene, xylene, mesitylene, naphthalene, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, eicosane, cyclohexane, and petroleum ether. 
     
     
         18 . The process of  claim 15  wherein said second organic solvent is selected from the group consisting of an ether, an ester, an alcohol, an amide, a nitrile, or a ketone. 
     
     
         19 . The process of  claim 15  wherein said second organic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl alcohol, ethyl alcohol, isopropyl alcohol, acetonitrile, dimethylformamide, acetone, and 2-butanone. 
     
     
         20 . The process of  claim 15  wherein said first organic solvent is hexane, heptane, or toluene, and said second organic solvent is acetone or 2-butanone. 
     
     
         21 - 31 . (canceled) 
     
     
         32 . A process of separating a compound of Formula III and/or a salt of a compound of Formula III, 
       
         
           
           
               
               
           
         
         wherein R is a bond or —C(O)—, and X is selected from the group consisting of a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; aryl; heteroaryl; heterocycle; alkaryl; arylalkyl; and alkarylkyl, all of which may be optionally substituted, from a first mixture, said first mixture comprising:
 said compound of Formula III; 
 a compound of Formula IV, 
 
       
       
         
           
           
               
               
           
         
         
           wherein R is a bond or —C(O)—, and X is selected from the group consisting of a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; aryl; heteroaryl; heterocycle; alkaryl; arylalkyl; and alkarylkyl, all of which may be optionally substituted; and 
           probucol; 
         
         or
 said salt of compound of Formula III; 
 a salt of compound of Formula IV; and 
 probucol; 
 
         said process comprising: 
         partially neutralizing said first mixture, optionally adding at least one aqueous solvent, and optionally adding at least one organic solvent, 
         thus affording a partially neutralized second mixture, said partially neutralized second mixture comprising:
 an aqueous phase; 
 an organic phase; 
 said compound of Formula III; 
 said salt of a compound of Formula III; 
 said compound of Formula IV and/or a salt of a compound of Formula IV; and 
 probucol; 
 
         removing from said partially neutralized second mixture the aqueous phase comprising:
 said compound of Formula IV and/or said salt of a compound of Formula IV, 
 
         thus leaving the organic phase comprising:
 said compound of Formula III and/or said salt of a compound of Formula III; and probucol; 
 
         isolating said compound of Formula III and/or said salt of a compound of Formula III. 
       
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The process of  claim 32 , wherein said organic phase comprises at least a first organic solvent and a second organic solvent. 
     
     
         36 . The process of  claim 35  wherein said first organic solvent is a straight chain, branched or cyclic hydrocarbon that is saturated, unsaturated or partially unsaturated. 
     
     
         37 . The process of  claim 35  wherein said first organic solvent is selected from the group consisting of benzene, toluene, xylene, mesitylene, naphthalene, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, eicosane, cyclohexane, and petroleum ether. 
     
     
         38 . The process of  claim 35  wherein said second organic solvent is selected from the group consisting of an ether, an ester, an alcohol, an amide, a nitrile, or a ketone. 
     
     
         39 . The process of  claim 35  wherein said second organic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl alcohol, ethyl alcohol, isopropyl alcohol, acetonitrile, dimethylformamide, acetone, and 2-butanone. 
     
     
         40 . The process of  claim 35  wherein said first organic solvent is hexane, heptane, or toluene, and said second organic solvent is acetone or 2-butanone. 
     
     
         41 - 50 . (canceled)