Methods of producing C-aryl glucoside SGLT2 inhibitors

1. A method of preparing a compound of Formula (I) or a pharmaceutically acceptable complex thereof

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; 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:

a) forming a compound of Formula (IV) from a lactone protected with an acid-labile protecting group

 wherein ALG is an acid labile protecting group,

b) glycosidating of the compound of Formula (IV) in the presence of a nucleophilic compound which has an R 3 group, with simultaneous removal of the acid-labile protecting group to form a compound of Formula (V);

 wherein R 3 is selected from the group consisting of an alkoxy group, an alkenyloxy group, an alkylthio group and an alkenylthio group;

c) reacting the compound of Formula (V) with an acylating agent to form a compound of Formula (VI);

d) reducing the compound of Formula (VI) to provide a compound of Formula (VII); and

e) removing acyl protecting group from the compound of Formula (VII) to provide a compound of Formula (I);

wherein R 1 , R 2 , A, p and q are as defined hereinabove, and AC is an acyl protecting group.

2. The method of claim 1 wherein p is 1 to 2.

3. The method of claim 1 wherein q is 1 to 2.

4. The method of claim 1 wherein R 1 is selected from the group consisting of hydrogen, alkyl, chlorine, and fluorine.

5. The method of claim 4 wherein p is 1, and R 1 is selected from the group consisting of hydrogen, chlorine, and methyl.

6. The method of claim 5 wherein R 1 is at the 4-position.

7. The method of claim 1 wherein R 2 is selected from the group consisting of hydrogen, an alkyl group, an alkoxy group and an alkylthio group.

8. The method of claim 7 wherein q is 1, and R 2 is selected from the group consisting of ethyl, ethoxy and methylthio.

9. The method of claim 8 wherein R 2 is at the 4-position.

10. The method of claim 1 wherein A is (CH 2 ) located at the 3-position.

11. The method of claim 1 wherein the compound of Formula (I) is a compound of Formula (IA):

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.

12. The method of claim 11 wherein R 1 is hydrogen and R 2 is ethyl.

13. The method of claim 11 wherein R 1 is chlorine and R 2 is ethoxy.

14. The method of claim 11 wherein R 1 is methyl and R 2 is methylthio.

15. The method of claim 1 further comprising reacting the compound of Formula (I) with at least one amino acid complex forming reagent to yield the pharmaceutically acceptable complex of the compound of Formula (I).

16. The method of claim 15 wherein the amino acid is L-phenylalanine.

17. The method as defined in claim 16 wherein the compound prepared is 1-C-(4’-ethyldiphenylmethane-3-yl)-β-D-glucopyranose-L-phenylalanine complex.

18. The method as defined in claim 15 wherein the compound prepared is a complex of a compound of Formula (I):

with an amino acid selected from L-phenylalanine or L-proline.

19. The method of claim 1 wherein steps (a) through (e) are performed in situ.

20. A method of preparing a compound of Formula (I) or a pharmaceutically acceptable complex thereof

wherein:

R 1 is 4-chloro;

p is 1;

q is 1;

A is (CH 2 ) n where n is 1 , and

a) forming a compound of Formula (IV) from a lactone protected with an acid-labile protecting group

wherein ALG is an acid labile protecting group,

b) glycosidating the compound of Formula (IV) in the presence of a nucleophilic compound which has an R 3 group, which compound is methanol, with simultaneous removal of the acid-labile protecting group to form a compound of Formula (V);

wherein R 3 is methoxy;

c) reacting the compound of Formula (V) with an acylating agent to form a compound of Formula (VI);

d) reducing the compound of Formula (VI) to provide a compound of Formula (VII); and

e) removing acyl protecting group from the compound of Formula (VII) to provide a compound of Formula (I);

wherein R 1 , R 2 , A, p and q are as defined hereinabove, and AC is an acyl protecting group.

21. A method of preparing a compound of Formula (I) or a pharmaceutically acceptable complex thereof

wherein

R 1 is 4-chloro;

p is 1;

R 2 is 10-ethyl;

q is 1;

A is (CH 2 ) n where n is 1, and

a 0 forming a compound of Formula (IV) from a lactone protected with an acid-labile protecting group

wherein ALG is an acid labile protecting group and A, R 1 , p, R 2 and q are as defined above;

b) glycosidating the compound of Formula (IV) in the presence of a nucleophilic compound which has an R 3 group, which compound is methanol, with simultaneous removal of the acid-labile protecting group to form a compound of Formula (V);

wherein R 3 is methoxy;

c) reacting the compound of Formula (V) with an acylating agent to form a compound of Formula (VI);

d) reducing the compound of Formula (VI) to provide a compound of Formula (VII); and

e) removing acyl protecting group from the compound of Formula (VII) to provide a compound of Formula (I);

wherein R 1 , R 2 , A, p and q are defined hereinabove, and AC is an acyl protecting group.