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.

1 - 16 . (canceled) 
     
     
         17 . A method of forming C-aryl glucoside compounds comprising reacting a compound of Formula (V) 
       
         
           
           
               
               
           
         
         with an acylating reagent to form a compound of Formula (VI) 
       
       
         
           
           
               
               
           
         
         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; 
 
     
     
         18 . The method of  claim 17  wherein the reducing reagent is a silyl hydride. 
     
     
         19 . The method of  claim 18  wherein the reducing reagent is an alkylsilyl hydride. 
     
     
         20 . The method of  claim 17  further comprising the addition of an activating group. 
     
     
         21 . The method of  claim 20  wherein the activating group is a Lewis acid. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 17  wherein the acylating reagent is selected from the group consisting of acyl derivatives, acyl halides, acetyl chloride, acid anhydrides, acetic anhydride, propionic anhydride and combinations thereof. 
     
     
         24 . The method of  claim 17  further 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). 
     
     
         25 . The method of  claim 24  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. 
     
     
         26 . The method of  claim 25  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. 
     
     
         27 . The method of  claim 24  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). 
       
     
     
         28 . The method of  claim 27  wherein Y is selected from the group consisting of alkali metals, and alkaline earth metals. 
     
     
         29 . The method of  claim 27  further comprising reacting D-glucono-1,5-lactone with an acid labile protecting group providing reagent to form the compound of Formula (II). 
     
     
         30 . The method of  claim 29  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. 
     
     
         31 . 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, hydroxy, chlorine, fluorine, alkyl, alkoxy, and alkylthio group, 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). 
       
     
     
         32 . 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). 
       
     
     
         33 . The method of  claim 32  further comprising isolating the compound of Formula (V) from the reaction mixture. 
     
     
         34 . 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). 
     
     
         35 . (canceled) 
     
     
         36 . 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 group, 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. 
 
     
     
         37 . 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 group, 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. 
 
     
     
         38 . 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 group, 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. 
 
     
     
         39 . 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 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 group, 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. 
 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 17  wherein the compound of Formula (V) is a compound of Formula (VA): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from hydrogen, an alkyl group, and chlorine; and 
 R 2  is selected from hydrogen, an alkyl group, an alkoxy group, and an alkylthio group. 
 
     
     
         42 . The method of  claim 41  wherein R 1  is hydrogen and R 2  is ethyl. 
     
     
         43 . The method of  claim 41  wherein R 1  is chlorine and R 2  is ethoxy. 
     
     
         44 . The method of  claim 41  wherein R 1  is methyl and R 2  is methylthio.