Process and intermediates for the synthesis of obeticholic acid and derivatives thereof

1. A process for preparing a compound of formula (I) or a salt thereof

wherein

R 1 is selected from the group consisting of —(CH 2 )n-OR, —(CH 2 )n-COOR, —(CH 2 )nCONR 2 , —(CH 2 )n-CH(COOR) 2 , —(CH 2 )n-CN, —(CH 2 )n-halogen, —(CH 2 )n-OCOR, —(CH 2 )n-OCOOR, —(CH 2 )n-OSO 2 R, —(CH 2 )n-OSO 3 R, and —(CH 2 )n-OSiR 3 ; wherein n is selected from 0, 1, 2, 3 and 4, and each R is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 ) aryl(C 1-6 )alkyl;

which comprises:

(a) hydrogenation of the double bond and reductive opening of the epoxide of a compound of formula (II) or a salt thereof

wherein R 1 is as defined above, to obtain a compound of formula (Ma) and/or a compound of formula (IIIb), or a salt or solvate thereof

wherein R 1 is as defined above, and

(b) conversion of a compound of formula (Ma) and/or a compound of formula (IIIb), or a salt thereof, into a compound of formula (I), or a salt thereof.

2. Process according to claim 1 , which comprises:

(a) hydrogenation of the double bond and reductive opening of the epoxide of a compound of formula (II), or a salt thereof, to obtain a compound of formula (Ma), or a salt thereof; and

(b) reduction of a compound of formula (Ma), or a salt thereof, to obtain a compound of formula (I), or a salt thereof.

3. Process according to claim 1 , which comprises:

(a) hydrogenation of the double bond and reductive opening of the epoxide of a compound of formula (II), or a salt thereof, to obtain a compound of formula (IIIb), or a salt thereof;

(b) conversion of a compound of formula (Mb), or a salt thereof, into a compound of formula (I), or a salt thereof, by a process comprising:

oxidation of a compound of formula (IIIb), or a salt thereof, to obtain a compound of formula (IV) or a salt thereof

wherein R 1 is as defined in claim 1 ,

epimerization of a compound of formula (IV), or a salt thereof, to obtain a compound of formula (V) or a salt thereof

wherein R 1 is as defined in claim 1 , and

reduction of a compound of formula (V), or a salt thereof.

4. Process according to claim 1 , wherein step (a) is carried out in the presence of Pd/C, Pt/C or PtO 2 , and a base.

5. Process according to claim 1 , wherein step (a) is carried out in the presence of Pd/CaCO 3 , Pd/Al 2 O 3 , Pd/BaCO 3 , Pd/C, Pd 2 (dba) 3 or Pd(PPh 3 ) 4 .

6. Process according to claim 1 , which further comprises converting R 1 into a different R 1 group after step (a) and/or after step (b).

7. Process according to claim 1 , wherein the compound of formula (II), or a salt thereof, is obtained by a process comprising epoxidation of a compound (VI) or a salt thereof

wherein R 1 is as defined in claim 1 .

8. Process according to claim 7 , wherein the compound of formula (VI), or a salt thereof, is obtained by a process comprising isomerization of a compound (VII) or a salt thereof

wherein R 1 is selected from the group consisting of —(CH 2 )n-OR, —(CH 2 )n-COOR, —(CH 2 )nCONR 2 , —(CH 2 )n-CH(COOR) 2 , —(CH 2 )n-CN, —(CH 2 )n-halogen, —(CH 2 )n-OCOR, —(CH 2 )n-OCOOR, —(CH 2 )n-OSO 2 R, —(CH 2 )n-OSO 3 R, and —(CH 2 )n-OSiR 3 ;

wherein n is selected from 0, 1, 2, 3 and 4, and each R is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl.

9. Process according to claim 8 , wherein the compound of formula (VII), or a salt or solvate thereof, is obtained by a process comprising:

converting a compound of formula (X) or a salt or solvate thereof

wherein R 1 is selected from the group consisting of —(CH 2 )n-OR, —(CH 2 )n-COOR, —(CH 2 )nCONR 2 , —(CH 2 )n-CH(COOR) 2 , —(CH 2 )n-CN, —(CH 2 )n-halogen, —(CH 2 )n-OCOR, —(CH 2 )n-OCOOR, —(CH 2 )n-OSO 2 R, —(CH 2 )n-OSO 3 R, and —(CH 2 )n-OSiR 3 ; wherein n is selected from 0, 1, 2, 3 and 4, and each R is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl into an enol ether of formula (IX) or a salt thereof

wherein R 1 is selected from the group consisting of —(CH 2 )n-OR, —(CH 2 )n-COOR, —(CH 2 )nCONR 2 , —(CH 2 )n-CH(COOR) 2 , —(CH 2 )n-CN, —(CH 2 )n-halogen, —(CH 2 )n-OCOR, —(CH 2 )n-OCOOR, —(CH 2 )n-OSO 2 R, —(CH 2 )n-OSO 3 R, and —(CH 2 )n-OSiR 3 ;

wherein n is selected from 0, 1, 2, 3 and 4, and each R is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl;

and R 2 is selected from C 1-6 alkyl, C 6-10 aryl, (C 6-10 )aryl(C 1-6 )alkyl and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 6-10 aryl and C 1-6 alkoxy,

converting a compound of formula (IX), or a salt thereof, into a compound of formula (VII), or a salt thereof.

10. Process according to claim 9 , wherein the compound of formula (IX), or a salt thereof, is converted into a compound of formula (VII), or a salt thereof, by a process comprising either:

(A) formylation of a compound of formula (IX), or a salt thereof, to provide a compound of formula (VIII) or a salt thereof

wherein R 1 and R 2 are as defined in claim 9 , and

methylation followed by dehydration of a compound of formula (VIII), or a salt thereof, to provide a compound of formula (VII), or a salt thereof; or

(B) Mannich reaction of a compound of formula (IX), or a salt thereof, followed by elimination of the resulting amine to provide a compound of formula (VII), or a salt thereof.

11. Process according to claim 1 , wherein the compound of formula (I) is selected from obeticholic acid, INT-767 and ECDCOH, or a salt thereof

12. Process according to claim 1 , for the preparation of obeticholic acid, or a salt thereof, which comprises:

(a) hydrogenation of the double bond and reductive opening of the epoxide of a compound of formula (II′) or a salt thereof

wherein R h , is selected from the group consisting of —OH, halogen, —OCOR, —OSO 2 R, —CH(COOH) 2 , —CH(COOR) 2 , —CH 2 —COOH and —CH 2 —COOR; wherein each R is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl, to obtain a compound of formula (IIIa′) or a salt thereof

wherein R 1 ′ is as defined above, and

(b) conversion of a compound of formula (IIIa′), or a salt thereof, into obeticholic acid, or a salt thereof, by a process comprising either:

(A) if R 1 ′, in the compound of formula (IIIa′), or a salt or solvate thereof, is —CH 2 —COOH or —CH 2 —COOR, wherein R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl:

hydrolysis of the ester groups if R 1 ′ is —CH 2 —COOR, to obtain a compound wherein R 1 ′ is —CH 2 —COOH, and

reduction of the ketone group,

wherein the reduction of the keto group can be performed before hydrolysis of the ester group, or after hydrolysis of the ester group; or

(B) if R 1 ′ in the compound of formula (IIIa′), or a salt thereof, is —CH(COOH) 2 or —CH(COOR) 2 , wherein R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl:

hydrolysis of the ester groups if R 1 ′ is —CH(COOR) 2 , to obtain a compound wherein R 1 ′ is —CH(COOH) 2 ,

decarboxylation reaction, and

reduction of the ketone group,

wherein the reduction of the keto group can be performed before hydrolysis of the ester groups, or before decarboxylation reaction, or after decarboxylation reaction; or

(C) if R 1 ′ in the compound of formula (IIIa′), or a salt thereof, is selected from —OH, halogen, —OCOR, and —OSO 2 R, wherein R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl:

if R 1 ′ is —OH, conversion into a compound wherein R 1 ′ is selected from halogen, —OCOR, and —OSO 2 R, wherein R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl,

reaction with a compound of formula CH 2 (COOR) 2 wherein each R is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl and (C 6-10 )aryl(C 1-6 )alkyl, to obtain a compound wherein R 1 ′ is —CH(COOR) 2 ,

hydrolysis of the ester groups,

decarboxylation reaction, and

reduction of the ketone group,

wherein the reduction of the keto group can be performed before conversion of —OH into halogen, —OCOR, or —OSO 2 R, or before reaction with a compound of formula CH 2 (COOR) 2 , or before hydrolysis of the ester groups, or before decarboxylation reaction, or after decarboxylation reaction.

13. Process according to claim 1 , for the preparation of obeticholic acid, or a salt thereof, which comprises:

(a) hydrogenating the double bond and reductive opening of the epoxide of a compound of formula (II′) or a salt thereof

wherein is selected from the group consisting of —OH, halogen, —OCOR and —OSO 2 R, wherein each R is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl,

to obtain a compound of formula (IIIa′) or a salt thereof

wherein R 1 ′ is as defined above, and

(b) converting a compound of formula (IIIa′), or a salt thereof, into obeticholic acid, or a salt thereof, by a process comprising:

reduction of the ketone group,

reaction with a compound of formula CH 2 (COOR) 2 wherein each R is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl and (C 6-10 ) aryl(C 1-6 )alkyl, to obtain a compound wherein R 1 ′ is —CH(COOR) 2 ,

hydrolysis of the ester groups, and

decarboxylation reaction.

14. A compound of formula (II) or a salt thereof

wherein

R 1 is selected from the group consisting of —(CH 2 )n-OR, —(CH 2 )n-COOR, —(CH 2 )n-CONR 2 , —(CH 2 )n-CH(COOR) 2 , —(CH 2 )n-CN, —(CH 2 )n-halogen, —(CH 2 )n-OCOR, —(CH 2 )n-OCOOR, —(CH 2 )n-OSO 2 R, —(CH 2 )n-OSO 3 R, and —(CH 2 )n-OSiR 3 ; wherein n is selected from 0, 1, 2, 3 and 4, and each R is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl.

15. A compound of formula (IIIa), (VI) or (VII) or a salt thereof

wherein

R 1 is selected from the group consisting of —(CH 2 )n-OR, —(CH 2 )n-COOR, —(CH 2 )n-CONR 2 , —(CH 2 )n-CH(COOR) 2 , —(CH 2 )n-CN, —(CH 2 )n-halogen, —(CH 2 )n-OCOR, —(CH 2 )n-OCOOR, —(CH 2 )n-OSO 2 R, —(CH 2 )n-OSO 3 R, and —(CH 2 )n-OSiR 3 ; wherein n is selected from 0, 1, 2, 3 and 4, and each R is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and (C 6-10 )aryl(C 1-6 )alkyl;

provided that R 1 is not —COOH and —CH 2 —COOMe in the compound of formula (IIIa).

16. A compound according to claim 14 , which is:

wherein

R 1 ″ is selected from the group consisting of —OH, halogen, -OTs, -OTf, -OMs, —OAc, —CH(COOR) 2 and —CH 2 —COOR; wherein each R is independently selected from H and C 1-6 alkyl,

or a salt thereof.

17. A compound according to claim 15 , selected from the group consisting of:

wherein

R 1 ″ is selected from the group consisting of —OH, halogen, -OTs, -OTf, -OMs, —OAc, —CH(COOR) 2 and —CH 2 —COOR; wherein each R is independently selected from H and C 1-6 alkyl, and

R 1 ′″ is selected from the group consisting of —OH, halogen, -OTs, -OTf, -OMs, —OAc, —CH(COOR) 2 and —CH 2 —COOR′; wherein each R is independently selected from H and C 1-6 alkyl, and R′ is selected from Hand C 2-6 alkyl, or a salt thereof.

18. Process according to claim 4 , wherein the base is a pyridine-type base.