Methods for preparation of bile acids and derivatives thereof

1. A method of preparing a compound of Formula (A):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 1 is α-OH or an oxo group;

R 2 is H, F, α-C 1 -C 3 alkyl optionally substituted with F or OH, α-C 1 -C 3 alkoxy, α-C 2 -C 3 alkenyl or alkynyl, cycloalkylmethylene, or cycloalkyl;

R 3 and R 7 are each independently H, F, or C 1 -C 4 alkyl optionally substituted with F or OH, or R 3 or R 7 taken together with another R 3 or R 7 on an adjacent carbon atom forms a substituted or unsubstituted C 1 -C 6 carbocyclic or heterocyclic ring;

R 4 , R 5 and R 8 are each independently H, α-OH, or β-OH;

R 6 is CO 2 H, OSO 3 H, NH 2 , NHCO 2 (CH 2 CHCH)phenyl, NHCO 2 CH 2 CH 3 , C(O)NHOH, C(O)NH(CH 2 ) 2 OH, CONH(CH 2 ) 2 OSO 3 H, or an optionally substituted 5-member heterocycle comprising 1-4 heteroatoms selected from N, S and O; and

n is 0, 1, 2 or 3;

comprising the steps of:

(1) converting Compound 1 to Compound 7

wherein “ ” indicates that the OH at the C3-position or C7-position is in an α- or β-stereochemistry; and

(2) converting Compound 7 to a compound of Formula (A),

2. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 3 is H or C 1 -C 4 alkyl.

3. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 3 is H or C 1 -C 4 alkyl.

4. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (Ib):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is α-C 1 -C 3 alkyl; and

R 3 is H or C 1 -C 4 alkyl.

5. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (II):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is α-C 1 -C 3 alkyl;

R 3 is H or C 1 -C 4 alkyl; and

R 4 is α-OH or β-OH.

6. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (III):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is α-OH or an oxo group;

R 2 is H, α-C 1 -C 3 alkyl, cycloalkylmethylene or cycloalkyl; and

R 3 is H or C 1 -C 4 alkyl.

7. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (IV):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is α-C 1 -C 3 alkyl;

R 3 is H or C 1 -C 4 alkyl; and

R 5 is α-OH or β-OH.

8. The method of claim 1 , wherein the compound of Formula (A) is a compound of Formula (V):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is H or α-C 1 -C 3 alkyl;

R 3 is H or C 1 -C 4 alkyl;

R 4 and R 5 are each independently H, α-OH or β-OH; and

R 6 is an optionally substituted 5-member heterocycle comprising 1-4 heteroatoms selected from N, S and O.

9. A method of preparing a compound of Formula (A):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 1 is α-OH or an oxo group;

R 2 is H, F, α-C 1 -C 3 alkyl optionally substituted with F or OH, α-C 1 -C 3 alkoxy, α-C 2 -C 3 alkenyl or alkynyl, cycloalkylmethylene, or cycloalkyl;

R 3 and R 7 are each independently H, F, or C 1 -C 4 alkyl optionally substituted with F or OH, or R 3 or R 7 taken together with another R 3 or R 7 on an adjacent carbon atom forms a substituted or unsubstituted C 1 -C 6 carbocyclic or heterocyclic ring;

R 4 , R 5 and R 8 are each independently H, α-OH, or β-OH;

R 6 is CO 2 H, OSO 3 H, NH 2 , NHCO 2 (CH 2 CHCH)phenyl, NHCO 2 CH 2 CH 3 , C(O)NHOH, C(O)NH(CH 2 ) 2 OH, CONH(CH 2 ) 2 OSO 3 H, or an optionally substituted 5-member heterocycle comprising 1-4 heteroatoms selected from N, S and O; and

n is 0, 1, 2 or 3;

comprising the steps of:

(1) converting Compound 1 to Compound 2

wherein “ ” indicates that the OH at the C3-position or C7-position is in an α- or β-stereochemistry;

(2) converting Compound 2 to Compound 5

wherein:

X is a leaving group; and

P 1 and P 2 are each independently a protecting group;

(3) converting Compound 5 to Compound 7

 and

(4) converting Compound 7 to a compound of Formula (A)

10. The method of claim 9 , wherein the compound of Formula (A) is a compound Formula (I):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 3 is H or C 1 -C 4 alkyl.

11. The method of claim 9 , wherein the compound of Formula (A) is a compound Formula (Ia):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 3 is H or C 1 -C 4 alkyl.

12. The method of claim 9 , wherein the compound of Formula (A) is a compound Formula (Ib):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is α-C 1 -C 3 alkyl; and

R 3 is H or C 1 -C 4 alkyl.

13. The method of claim 9 , wherein the compound of Formula (A) is a compound of Formula (II):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is α-C 1 -C 3 alkyl;

R 3 is H or C 1 -C 4 alkyl; and

R 4 is α-OH or β-OH.

14. The method of claim 9 , wherein the compound of Formula (A) is a compound Formula (III):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is α-OH or an oxo group;

R 2 is H, α-C 1 -C 3 alkyl, cycloalkylmethylene, or cycloalkyl; and

R 3 is H or C 1 -C 4 alkyl.

15. The method of claim 9 , wherein the compound of Formula (A) is a compound of Formula (IV):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is α-C 1 -C 3 alkyl;

R 3 is H or C 1 -C 4 alkyl; and

R 5 is α-OH or β-OH.

16. The method of claim 9 , wherein the compound of Formula (A) is a compound of Formula (V):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:

R 2 is H, or α-C 1 -C 3 alkyl;

R 3 is H or C 1 -C 4 alkyl;

R 4 and R 5 are each independently H, α-OH or β-OH; and

R 6 is an optionally substituted 5-member heterocycle comprising 1-4 heteroatoms selected from N, S and O.

17. The method of claim 1 , wherein R 2 is cycloalkylmethylene or cycloalkyl.

18. The method of claim 17 , wherein R 2 is cyclopropylmethylene.

19. The method of claim 18 , wherein the compound of Formula A is a compound

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof.