Methods of producing C-aryl glucoside SGLT2 inhibitors
View Patent ↗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. A method of forming a C-aryl glucoside of Formula VII
comprising reacting a compound of Formula (VI)
with a reducing reagent; 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;
to form a compound of Formula (VII)
2. The method of claim 1 wherein the reducing reagent is a silyl hydride.
3. The method of claim 2 wherein the reducing reagent is an alkylsilyl hydride.
4. The method of claim 1 further comprising the addition of an activating group.
5. The method of claim 4 wherein the activating group is a Lewis acid.
6. The method of claim 1 wherein p is 1 to 2 and q is 1 to 2.
7. The method of claim 1 wherein p is 1 and R 1 is in the 4-position and is selected from the group consisting of hydrogen, alkyl, chlorine, and fluorine.
8. The method of claim 7 wherein R 1 is chlorine and R 2 is ethyl.
9. The method of claim 7 wherein R 1 is chlorine and R 2 is ethoxy.
10. The method of claim 1 wherein R 2 is in the 4-position and is selected from the group consisting of hydrogen, alkyl, alkoxy, and alkylthio.
11. The method of claim 10 wherein q is 1 and R 2 is selected from the group consisting of ethyl, ethoxy and methylthio.
12. The method of claim 1 wherein A is (CH 2 ) located at the 3-position.
13. A method of preparing an intermediate compound of Formula (VII)
wherein:
R 1 is selected from the group consisting of hydrogen, a hydroxy group, bromine, chlorine, fluorine, an alkyl group, an alkoxy group, an alkylthio group, and an arylthio group, 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 group, chlorine, fluorine, an alkyl group, an alkoxy group, and an alkylthio group, where q is 1 to 5;
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 (VI)
wherein R 3 is OCH 3 and R 1 , R 2 , A, AC, p and q are as defined hereinabove, with a reducing agent which is an alkyl silyl hydride in the presence of an activating group which is BF 3 .Et 2 O, to form the compound of Formula (VII).