Methods of producing c-aryl glucoside sglt2 inhibitors

Abstract

Method for the production of C-aryl glucoside SGLT2 inhibitors useful for the treatment of diabetes and related diseases. and intermediates thereof. The C-aryl glucosides may be complexed with amino acid complex forming reagents.

What is claimed is: 
     
         1 . A method of forming C-aryl glucoside compounds comprising reacting a compound of Formula (IV) 
       
         
           
           
               
               
           
         
         wherein ALG is an acid labile protecting group, with a glycosidation reagent to form the compound of Formula (V) 
       
       
         
           
           
               
               
           
         
         
           reacting the compound of Formula (V) with an acylating reagent to form a compound of Formula (VI) 
         
       
       
         
           
           
               
               
           
         
       
       and
 reacting the compound of Formula (VI) with a reducing reagent to form a compound of Formula (VII) 
 
       
         
           
           
               
               
           
         
         wherein
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is an integer from 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is an integer from 1 to 5; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is an integer from 1 to 3, 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine; 
 
 R 3  is selected from the group consisting of alkoxy, alkenyloxy, alkylthio and alkenylthio; and 
 AC is an acyl protecting group. 
 
       
     
     
         2 . The method of  claim 1  wherein the acid labile protecting group is selected from the group consisting of methoxymethyl ether, methylthiomethyl ether, 2-methoxyethoxymethyl ether, bis(2-chloroethoxy)methyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, 4-methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, 1-ethoxyethyl ether, 1-methyl-1-methoxyethyl ether, 2-(phenylselenyl)ethyl ether, t-butyl ether, allyl ether, triphenylmethyl ether, α-naphthyldiphenylmethyl ether, p-methoxyphenyldiphenyl methyl ether, trialkylsilyl ether, trimethylsilyl ether, triethylsilyl ether, isopropyldimethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether and combinations thereof. 
     
     
         3 . The method of  claim 2  wherein the acid labile protecting group is selected from the group consisting of methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, trimethylsilyl ether, isopropyldimethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, and combinations thereof. 
     
     
         4 . The method of  claim 1  further comprising reacting a compound of Formula (II) 
       
         
           
           
               
               
           
         
         with a compound of Formula (III) 
       
       
         
           
           
               
               
           
         
         wherein Y is a metal, to form the compound of Formula (IV). 
       
     
     
         5 . The method of  claim 4  wherein Y is selected from the group consisting of alkali metals, and alkaline earth metals. 
     
     
         6 . The method of  claim 4  further comprising reacting D-glucono-1,5-lactone with an acid labile protecting group providing reagent to form the compound of Formula (II). 
     
     
         7 . The method of  claim 6  wherein the acid labile protecting group providing reagent is selected from the group consisting of trimethylsilylchloride, trimethylsilyl trifluoromethanesulfonic acid, methyoxymethylchloride, dihydrofuran, benzyloxymethylchloride, triethylsilylchloride and tetrahydropyran. 
     
     
         8 . A method of preparing an intermediate compound of Formula (IV) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, a hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is 1 to 5; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is 1 to 3, 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine; and 
 
 ALG is an acid labile protecting group, 
 
         the method comprising reacting a compound of Formula (II) 
       
       
         
           
           
               
               
           
         
         with a compound of Formula (III) 
       
       
         
           
           
               
               
           
         
         wherein Y is a metal, to form the compound of Formula (IV). 
       
     
     
         9 . A method of preparing an intermediate compound of Formula (V) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is 1 to 5; 
 R 3  is selected from the group consisting of alkoxy, alkenyloxy, alkylthio and alkenylthio; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is 1 to 3, and 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine, said method comprising: 
 
 
         reacting a compound of Formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein ALG is an acid labile protecting group, with a glycosidation reagent to form the compound of Formula (V). 
       
     
     
         10 . The method of  claim 9  further comprising isolating the compound of Formula (V) from the reaction mixture. 
     
     
         11 . A method of preparing an intermediate compound of Formula (VI) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is 1 to 5; 
 R 3  is selected from the group consisting of alkoxy, alkenyloxy, alkylthio and alkenylthio; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is 1 to 3, and 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine; and 
 
 AC is an acyl protecting group, said method comprising: 
 
         reacting a compound of Formula (V) 
       
       
         
           
           
               
               
           
         
         with an acylating reagent to form the compound of Formula (VI). 
       
     
     
         12 . A compound of Formula (IV) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is 1 to 5; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is 1 to 3, 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine; and 
 
 ALG is an acid labile protecting group. 
 
       
     
     
         13 . A compound of Formula (V) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is 1 to 5; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is 1 to 3, 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine. 
 
 
       
     
     
         14 . A compound of Formula (VI) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of hydrogen, hydroxy, bromine, chlorine, fluorine, alkyl, alkoxy, alkylthio, and arylthio, where p is 1 to 4, and with the proviso that bromine, chlorine and fluorine, when present, are only present in at least one of the 3-, 4- and 5-positions; 
 R 2  is selected from the group consisting of hydrogen, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio, where q is 1 to 5; and 
 A is selected from the group consisting of a covalent bond, O, S, NH, and (CH 2 ) n  where n is 1 to 3, 
 with the proviso that when A is in the 4-position, R 1  is not bromine; 
 with the proviso that when one of R 1  is bromine; and
 if A is in the 3- or 6-position, then bromine is in the 5-position, 
 if A is in the 2- or 5-position, then bromine is in the 3-position, and 
 when bromine is in the 3-position, and A is in the 2- or 5-position, then R 1  groups in the 4- and 6-positions are the same and are not bromine, chlorine or fluorine, and 
 when bromine is in the 5-position, and A is in the 3- or 6-position, then R 1  groups in the 2- and 4-positions are the same and are not bromine, chlorine or fluorine; and 
 
 AC is an acyl protecting group.