6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal FXR modulators

• US 10,597,423 B2
• Filed: 10/17/2018
• Issued: 03/24/2020
• Est. Priority Date: 11/19/2014
• Status: Active Grant

• Current Assignee: NZP UK Ltd,
• Original Assignee: NZP UK Ltd,
• Inventors: Weymouth-Wilson, Alexander, Komsta, Zofia, Boydell, James, Wallis, Laura, Otter, Carl, Davies, Ieuan, Clarkson, Rob
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US16/163,259
• Publication Number:
  US 20190077827A1
• Time in Patent Office: 524 Days
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07J 71/001 Oxiranes
• CPC Class Codes: C07J 9/005 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Abstract

Disclosed herein is a process for the preparation of a compound of formula (I) and related methods. The compounds of formula (I) are intermediates in the synthesis of synthetic bile acids and its analogues, and the compounds of formula (I) have pharmacological activity. Methods include the synthesizing of these intermediates, and methods of preparing obeticholic acid and obeticholic acid analogues from the prepared compounds.

Claims

1. A process for the preparation of a compound of general formula (I):

2. A process according to claim 1 wherein, in the compound of general formula (I), R¹ is ethyl.

3. A process according to claim 1 wherein, in the compound of general formula (I), Y¹ is an alkylene linker group having from 1 to 8 carbon atoms and optionally substituted with one or more R³ groups.

4. A process according to claim 1 wherein, in the compound of general formula (I), independently or in any combination:

Y¹ is a bond or an alkylene group having 1 to 3 carbon atoms and is optionally substituted with one or two R³ groups;

R⁴ is C(O)OR¹⁰, SO₃R¹⁰, or OSO₃R¹⁰, where R¹⁰ is selected from H, C_1-6 alkyl or benzyl;

R^5b is H or OH.

5. A process according to claim 4 wherein, in the compound of general formula (I), independently or in any combination:

R¹ is ethyl; and

/or

R² is H; and

/or

Y¹ is a bond, —

CH₂—

or —

CH₂CH₂—

; and

/or

R⁴ is C(O)OR¹⁰, where R¹⁰ is H, C_1-6 alkyl or benzyl; and

/or

R^5b is H.

6. A process according to claim 1 wherein the compound of general formula (I) is selected from the group consisting of (6β

, 5β

)-3,7-dioxo-6-ethyl-cholan-24-oic acid and C_1-6 alkyl and benzyl esters thereof and salts thereof.

7. A process according to claim 1 wherein, in the compound of general formula (II), R⁴ is C(O)OR¹⁰, where R¹⁰ is C_1-6 alkyl or benzyl, wherein the base is a strong base, wherein the strong base is selected from sodium or potassium hydroxide, and where epimerization is accompanied by hydrolysis to give a compound of general formula (I) in which R⁴ is C(O)OH.

8. A process according to claim 1 wherein, in the compound of general formula (II), R² and/or R⁵ is a protected OH which is stable in basic conditions and the process optionally comprises and additional step of removing the protecting group to give a compound of general formula (I) in which R² and/or R^5b is OH.

9. A process according to claim 1 for the preparation of a compound of general formula (I) in which R⁴ is C(O)OR¹⁰.

10. A process for the preparation of a compound of general formula (XXI):

11. A process according to claim 10 wherein the reducing agent is a hydride.

12. A process according to claim 10 for the preparation of a compound of formula (XXI) in which R¹ is ethyl, R² and Rya are both H, Y¹ is —

CH₂CH₂—

, and R⁴ is C(O)OH.