Production of isoflavone derivatives

Abstract

Methods for the hydrogenation of isoflavones are described which provide access to workable quantities of isoflavan-4-ols, isoflav-3-enes, and isoflavans. The isoflavone derivatives can be obtained in high purity and in near quantitative yields whilst employing pharmaceutically acceptable reagents and solvents.

1 . A method for the preparation of a compound of formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , OS(O)R 9 , alkyl, haloalkyl, aryl, arylalkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo, and  
 R 9  is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl,  
 comprising the step of hydrogenating a compound of formula I  
                     
 wherein  
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are as defined above to prepare a compound of formula II.  
 
     
     
         2 . A method of  claim 1 , wherein the hydrogenation step is performed with hydrogen in the presence of a reduction catalyst and a solvent.  
     
     
         3 . A method of  claim 2 , wherein the reduction catalyst comprises palladium, palladium hydroxide, platinum or platinum oxide.  
     
     
         4 . A method of  claim 3 , wherein the reduction catalyst is palladium on activated carbon, palladium on barium sulfate or platinum(IV)oxide.  
     
     
         5 . A method of  claim 4 , wherein the reduction catalyst is palladium on activated carbon (1% Pd to 10% Pd).  
     
     
         6 . A method of  claim 5 , wherein the reduction catalyst is about 5% palladium on activated carbon.  
     
     
         7 . A method of  claim 2 , wherein the solvent is a C 1 -C 8  alcohol, an alkyl acetate or a C 1 -C 3  carboxylic acid.  
     
     
         8 . A method of  claim 7 , wherein the solvent is a methanol, ethanol or C 1 -C 6  alkyl acetate.  
     
     
         9 . A method of  claim 8 , wherein the solvent is absolute methanol or absolute ethanol.  
     
     
         10 . A method of  claim 1  which further comprises the step of dehydrating and optionally deprotecting or transforming a compound of formula II to prepare a compound of formula III  
       
         
           
           
               
               
           
         
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , OS(O)R 9 , alkyl, haloalkyl, aryl, arylalkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo, and  
         R 9  is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl.  
       
     
     
         11 . A method of any one of  claims 1  to  10 , wherein the compounds of formula I, II or III have the following substituents 
 R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or arylalkyl,    R 8  is hydrogen, and    R 9  is methyl, ethyl, propyl, isopropyl or trifluoromethyl.    
     
     
         12 . A method of  claim 11 , wherein the compounds of formula I, II or III have the following substituents 
 R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2 , R 3 , R 4 , R 5  and R 7  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or arylalkyl,    R 6  and R 8  are hydrogen, and    R 9  is methyl.    
     
     
         13 . A method of any one of  claims 1  to  12 , wherein the compound of formula I is 4′,7-diacetoxyisoflavone (daidzein diacetate) or 7-acetoxy-4′-methoxyisoflavone.  
     
     
         14 . A method of any one of  claims 1  to  13 , wherein the compound of formula II is 4′,7-diacetoxyisoflavan-4-ol (tetrahydrodaidzein diacetate) or 7-acetoxy4′-methoxyisoflavan-4-ol.  
     
     
         15 . A method of any one of  claims 10  to  14 , wherein and the compound of formula III is 4′,7-diacetoxyisoflav-3-ene (dehydroequol diacetate), 4′,7-dihydroxyisoflav-3-ene (dehydroequol), 7-acetoxy-4′-methoxyisoflav-3-ene or 7-hydroxy-4′-methoxyisoflav-3-ene.  
     
     
         16 . A method for the preparation of a compound of formula IV  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , OS(O)R 9 , alkyl, haloalkyl, aryl, arylalkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo, and  
 R 9  is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl,  
 comprising the step of hydrogenating a compound of formula I  
                     
 wherein  
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are as defined above to prepare a compound of formula IV.  
 
     
     
         17 . A method of  claim 16 , wherein the hydrogenation step is performed with hydrogen in the presence of a reduction catalyst and a solvent.  
     
     
         18 . A method of  claim 17 , wherein the reduction catalyst comprises palladium, palladium hydroxide, platinum or platinum(IV)oxide.  
     
     
         19 . A method of  claim 18 , wherein the reduction catalyst is palladium on activated carbon (1% Pd to 10% Pd).  
     
     
         20 . A method of  claim 19 , wherein the reduction catalyst is about 5% palladium on activated carbon.  
     
     
         21 . A method of  claim 17 , wherein the solvent is a C 1 -C 8  alcohol, a C 1 -C 6  alkyl acetate or a C 1 -C 3  carboxylic acid.  
     
     
         22 . A method of  claim 21 , wherein the solvent is absolute methanol, ethanol or ethyl acetate.  
     
     
         23 . A method of any one of  claims 16  to  22 , wherein the compound of formula I is 4′,7-diacetoxyisoflavone (daidzein diacetate) or 7-acetoxy-4′-methoxyisoflavone.  
     
     
         24 . A method of any one of  claims 16  to  22 , wherein the compound of formula IV has the following substituents 
 R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2 , R 3 , R 4 , R 5 , R 6 l and R   7  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or arylalkyl,    R 8  is hydrogen, and    R 9  is methyl, ethyl, propyl, isopropyl or trifluoromethyl.    
     
     
         25 . A method of  claim 24 , wherein the compound of formula IV has the following substituents 
 R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2 , R 3 , R 4 , R 5  and R 7  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or arylalkyl,    R 6  and R 8  are hydrogen, and    R 9  is methyl.    
     
     
         26 . A method of  claim 25 , wherein the compound of formula IV is 4′,7-diacetoxyisoflavan-4-one (diacetoxydihydrodaidzein) or 4′,7-dihydroxyisoflavan-4-one (dihydrodaidzein).  
     
     
         27 . A method for the preparation of a compound of formula V  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , OS(O)R 9 , alkyl, haloalkyl, aryl, arylalkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo, and  
 R 9  is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl,  
 comprising the step of hydrogenating a compound of formula III  
                     
 wherein  
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are as defined above to prepare a compound of formula V.  
 
     
     
         28 . A method of  claim 27 , wherein the hydrogenation step is performed with hydrogen in the presence of a reduction catalyst and a solvent.  
     
     
         29 . A method of  claim 28 , wherein the reduction catalyst comprises palladium, palladium hydroxide, platinum or platinum(IV)oxide.  
     
     
         30 . A method of  claim 29 , wherein the reduction catalyst is palladium on activated carbon (1% Pd to 10% Pd).  
     
     
         31 . A method of  claim 30 , wherein the reduction catalyst is about 5% palladium on activated carbon.  
     
     
         32 . A method of  claim 28 , wherein the solvent is a C 1 -C 8  alcohol, a C 1 -C 6  alkyl acetate or a C 1 -C 3  carboxylic acid.  
     
     
         33 . A method of  claim 32 , wherein the solvent is a methanol, ethanol or ethyl acetate.  
     
     
         34 . A method of  claim 33 , wherein the solvent is ethyl acetate.  
     
     
         35 . A method of any one of  claims 27  to  34 , wherein and the compound of formula III is 4′,7-diacetoxyisoflav-3-ene (dehydroequol diacetate), 4′,7-dihydroxyisoflav-3-ene (dehydroequol), 7-acetoxy4′-methoxyisoflav-3-ene or 7-hydroxy-4′-methoxyisoflav-3-ene.  
     
     
         36 . A method of any one of  claims 27  to  34 , wherein the compound of formula V has the following substituents 
 R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or arylalkyl,    R 8  is hydrogen, and    R 9  is methyl, ethyl, propyl, isopropyl or trifluoromethyl.    
     
     
         37 . A method of  claim 36 , wherein the compound of formula V has the following substituents 
 R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2 , R 3 , R 4 , R 5  and R 7  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or arylalkyl,    R 6  and R 8  are hydrogen, and    R 9  is methyl.    
     
     
         38 . A method of  claim 37 , wherein the compound of formula V is 4′,7-diacetoxyisoflavan (equol diacetate) or 4′,7-dihydroxyisoflavan (equol).  
     
     
         39 . Methods substantially as hereinbefore described especially with reference to the Examples.  
     
     
         40 . Compounds of formula II or formula III or formula IV or formula V when prepared by a method of any preceding claim.  
     
     
         41 . A compound of the formulae II, III, IV or V, 
 wherein    R 1  is hydroxy, OR 9 , OC(O)R 9 , thio, alkylthio, or halo, R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently hydrogen, hydroxy, OR 9 , OC(O)R 9 , OS(O)R 9 , alkyl, aryl, thio, alkylthio or halo, and    R 9  is alkyl, fluoroalkyl or arylalkyl    with the proviso that    at least one of R 5 , R 6  and R 7  is not hydrogen, or    when R 5 , R 6  and R 7  are all hydrogen, then R 3  is hydroxy, OR 9 , OC(O)R 9 , OS(O)R 9 , alkyl aryl, thio, alkylthio or halo,    provided that compounds of the formula                          wherein    R 1  is hydroxy or acetoxy,    R 2  is hydrogen, hydroxy, acetoxy, methoxy, methyl, isopropyl or halo,    R 3  is hydrogen, methoxy, methyl, halo or trifluoromethyl,    R 6  is hydrogen, hydroxy or acetoxy, and    R 7  is hydrogen, hydroxy, methyl or methoxy are specifically excluded,    provided that compounds of the formula                          wherein    R 3  is hydroxy or methoxy, and    R 4  is hydrogen or methoxy are specifically excluded,    provided that compounds of the formulae                          wherein    R 1  is hydroxy, methoxy, ethoxy, methylthio or halogen, and    R 2 , R 3  R 4 , R 5 , R 6 , and R 7  are independently hydrogen, hydroxy, methoxy, ethoxy, methylthio or halogen, are specifically excluded, and    provided that the compounds    4′,7-Dihydroxy-3 ′,5′-dimethoxyisoflavan-4-one    4′,5-Dimethoxy-7-hydroxy-8-methylisoflavan-4-one    2′,7-Dihydroxy-4′,8-dimethoxyisoflavan-3 -ene are specifically excluded.    
     
     
         42 . A compound of  claim 41 , 
 wherein    R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2  and R 3  are independently hydrogen, hydroxy, OR 9  or OC(O)R 9 ,    R 4 , R 5 , R 6 , and R 8  are hydrogen,    R 7  is hydroxy, OR 9 , OC(O)R 9 , alkyl, aryl or halo, and    R 9  is methyl, ethyl, propyl, isopropyl, trifluoromethyl or benzyl.    
     
     
         43 . A compound of  claim 41 , 
 wherein    R 1  is hydroxy, OR 9  or OC(O)R 9 ,    R 2  and R 3  are independently hydrogen, hydroxy, OR 9  or OC(O)R 9 ,    R 5  is OR 9 , OC(O)R 9 , alkyl, aryl or halo,    R 4 , R 6 , R 7 , and R 8  are hydrogen, and    R 9  is methyl, ethyl, propyl, isopropyl, trifluoromethyl or benzyl.    
     
     
         44 . A compound of formula I selected from the group consisting of: 
 4′,7,8-Triacetoxyisoflavone    7,8-Diacetoxy-4′-methoxyisoflavone    4′,7-Diacetoxy-8-methylisoflavone    3′,7-Diacetoxy-8-methylisoflavone    7-Acetoxy-4′-methoxy-8-methylisoflavone    4′,7-Diacetoxy-3 ′-methoxy-8-methylisoflavone    4′,5,7-Triacetoxyisoflavone    
     
     
         45 . A compound of formula II selected from the group consisting of: 
 4′,7,8-Triacetoxyisoflavan-4-ol    7,8-Diacetoxy-4-methoxyisoflavan-4-ol    4′,7-Diacetoxy-8-methylisoflavan-4-ol    3′,7-Diacetoxy-8-methylisoflavan-4-ol    7-Acetoxy-4′-methoxy-8-methylisoflavan-4-ol    4′,7-Diacetoxy-3′-methoxy-8-methylisoflavan-4-ol    4′,5,7-Triacetoxyisoflavan-4-ol    4′,7,8-Trihydroxyisoflavan-4-ol    7,8-Dihydroxy-4-methoxyisoflavan-4-ol    4′,7-Dihydroxy-8-methylisoflavan-4-ol    3′,7-Dihydroxy-8-methylisoflavan-4-ol    7-Hydroxy-4′-methoxy-8-methylisoflavan-4-ol    4′,7-Dihydroxy-3 ′-methoxy-8-methylisoflavan-4-ol    4′,5,7-Trihydroxyisoflavan-4-ol    
     
     
         46 . A compound of formula III selected from the group consisting of: 
 4′,7,8-Triacetoxydehydroequol (4′,7,8-Triaceioxyisoflav-3-ene)    7,8-Di acetoxy-4-methoxydehydroequol (7,8-Diacetoxy-4-methoxyisoflav-3-ene)    4′,7-Diacetoxy-g-methylisoflav-3 -ene    3′,7-Diacetoxy-8-methylisoflav-3-ene    7-Acetoxy-4′-methoxy-8-methylisoflav-3-ene    4′,7-Diacetoxy-3′-methoxy-8-methylisoflav-3-ene    4′,5,7-Triacetoxyisoflav-3-ene    Isoflav-3-ene-4′,7,8-triol    4′-Methoxyisoflav-3-ene-7,8-diol    8-Methylisoflav-3-ene-4′,7-diol    8-Methylisoflav-3-ene-3′,7-diol    4′-Methoxy-8-methylisoflav-3 -ene-7-ol    3′-Methoxy-8-methylisoflav-3 -ene-4′,7-diol    Isoflav-3-ene-4′,5,7-triol