Methods and intermediates for the preparation of bile acid derivatives

Patent metadata

Field	Value
Publication number	US-11066437-B2
Application number	US-201816016486-A
Country	US
Kind code	B2
Filing date	Jun 22, 2018
Priority date	Jun 23, 2017
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

The present disclosure relates to methods and novel intermediates useful in the preparation of a compound of formula Ior pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, comprising the step of reacting a compound of formula I-4 with a halogenating reagent to provide a compound of formula I-5a

First claim

The invention claimed is:

1. A method of preparing a compound of formula I

or a pharmaceutically acceptable salt, hydrate, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof,
wherein:
R 1 is OH, alkoxy, or oxo;
R 2 is OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen;
R 3 is H; or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 5 is OH, OR 11 , OSO 3 H, OCOCH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen;
R 6 is H; or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, C(O)NHOH, NH(CH 2 ) 2 SO 3 H, NHCH 2 CO 2 H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl, or 2,4-difluoro-3-hydroxyphenyl;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R 9 and R 10 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
m is 0, 1, or 2;
n is 0 or 1; and
p is 0 or 1;

the method comprising the step of reacting a compound of formula I-4 with a halogenating reagent to provide a compound of formula I-5a

wherein X is —(CHR 8 ) m (CHR 9 ) n (CHR 10 ) p —R 7 , and R 7 , R 8 , R 9 , and R 10 may be protected by R 11 selected from acetyl, benzoyl, C(O)C 1 -C 4 alkyl, C 1 -C 6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzyl, pivaloyl, tetrahydropyranyl ether, tetrahydrofuranyl, 2-methoxyethoxymethyl ether, methoxymethyl ether, ethoxyethyl ether, p-methoxybenzyl ether, methylthiomethyl ether, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl ether.

2. The method of claim 1 , wherein the compound of formula I is a compound of formula I-9

or a pharmaceutically acceptable salt, hydrate, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof.

3. The method of claim 1 , wherein the compound of formula I is a compound of formula II

or a pharmaceutically acceptable salt, hydrate, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof.

4. The method of claim 1 , wherein the compound of formula I is a compound of formula III

or a pharmaceutically acceptable salt, hydrate, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof.

5. The method of claim 1 , wherein the compound of formula I is compound 100

6. The method of claim 1 , wherein the halogenating agent is a brominating agent.

7. The method of claim 1 , wherein the halogenating reagent is an iodinating reagent.

8. The method of claim 1 , further comprising converting a compound of formula I-1 into the compound of formula I-4, comprising the steps of
1) protecting the compound of formula I-1 to provide compound of formula I-2;

2) forming a leaving group at C12 to provide a compound of formula I-3; and
3) eliminating the leaving group at C12 to provide the alkene compound of formula I-4

9. The method of claim 1 , further comprising converting the compound of formula I-5a into a compound of formula I-6a, comprising the step of
5) reacting the compound of formula I-5a with an oxidizing agent to prepare the compound of formula I-6a

10. The method of claim 9 , further comprising converting the compound of formula I-6a into a compound of formula I-7, comprising the step of
6) reacting the compound of formula I-6a with a reducing agent to prepare the compound of formula I-7

11. The method of claim 10 , further comprising converting the compound of formula I-7 into the compound of formula I, comprising the step of
8) reacting the compound of formula I-7 with a reducing agent to provide the compound of formula I.

12. The method of claim 2 , further comprising converting the compound of formula I-5a into the compound of formula I, wherein the compound of formula I-5a is a compound of formula I-5b and the compound of formula I is a compound of formula I-9, comprising the steps of:
1) reacting the compound of formula I-5b with a reducing agent to prepare the compound of formula I-5c

2) reacting the compound of formula I-5c with a reducing agent to provide the compound of formula I-5d

and deprotecting the compound of formula I-5d to provide the compound of formula I-9.

13. The method of claim 10 , further comprising converting the compound of formula I-7 into the compound of formula I, wherein the compound of formula I-7 is a compound of formula I-7a and the compound of formula I is a compound of formula I-9, comprising the steps of:
1) reacting the compound of formula I-7a with a reducing agent to provide a compound of formula I-8a; and
2) deprotecting the compound of formula I-8a to obtain the compound of formula I-9

14. The method of claim 6 , wherein the brominating agent is N-bromosuccinimide.

15. The method of claim 7 , wherein the iodinating agent is N-iodosuccinimide.

16. The method of claim 9 , wherein the oxidizing agent is RuCl 3 .

17. The method of claim 10 , wherein the reducing agent is zinc metal.

18. The method of claim 11 , wherein the reducing agent is sodium borohydride.

19. The method of claim 12 , wherein the compound of formula I-9 is compound 100

20. The method of claim 5 , further comprising converting the compound of formula I-5a into the compound of formula I, wherein the compound of formula I-

Assignees

• Intercept Pharmaceuticals Inc

Inventors

• Pellicciari Roberto
• Gioiello Antimo
• Galvin Gabriel
• Lewis Ii Ronald D
• Yanik Mathew
• Kim Myoung Goo
• Leusink Frederik Ronald
• Koning Bartjan
• Hensel Thomas

Classifications

• C07J31/006

  not covered by C07J31/003 · CPC title

• C07J9/005 Primary

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title