5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators

• US 10,131,688 B2
• Filed: 11/19/2015
• Issued: 11/20/2018
• 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, Bartlett, Nathan, Shelbourne, Montserrat
• Primary Examiner(s): Coleman, Brenda L
• Application Number:
  US15/528,220
• Publication Number:
  US 20170320907A1
• Time in Patent Office: 1,097 Days
• 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

The invention relates to compounds of formula (I): wherein R₁, R₂, Y, R₄ and R₅ are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids.

Claims

1. A compound of formula (I):

2. A compound according to claim 1 wherein, independently or in any combination:

Y¹ is an alkylene linker group having from 1 to 8 carbon atoms and optionally substituted with one or more groups R³, wherein R³ is as defined in claim 1;

R⁵ is H or OH.

3. A compound according to claim 1 wherein, 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

R⁵ is H.

4. A compound according to claim 1 which is (6β

,5β

,7α

)-6-ethyl-7-hydroxy-3-oxo-cholan-24-oic acid or the C_1-6 alkyl and benzyl esters thereof and salts thereof.

5. A process for the preparation of a compound of formula (I)

6. A process according to claim 5 wherein the reduction is carried out by catalytic hydrogenation.

7. A process according to claim 6 wherein the catalytic hydrogenation is carried out using a catalyst selected from a palladium/carbon, palladium/calcium carbonate, palladium/aluminium oxide, platinum/palladium or Raney nickel catalyst.

8. A process according to claim 6 wherein the catalyst is a palladium/carbon or palladium/calcium carbonate catalyst.

9. A process according to claim 8 wherein, in the catalyst the palladium is present in an amount of 5-10% by weight with respect to the weight of the matrix, where the matrix is the carbon or calcium carbonate.

10. A process according to claim 6 wherein the hydrogenation is carried out in a solvent selected from alcoholic solvents;

ethyl acetate;

pyridine;

acetic acid;

cyclopentyl methyl ether (CPME) or N,N-dimethylformamide (DMF), any of which may optionally be mixed with a co-solvent and/or a base.

11. A process according to claim 10 wherein the solvent is methanol, ethanol or DMF.

12. A process according to claim 11 wherein the solvent is methanol optionally comprising a substoichiometric amount of a base.

13. A process according to claim 12, wherein the reaction is conducted at a temperature of about −

30 to 25°

C.

14. A process according to claim 11 wherein the solvent is DMF optionally mixed with a co-solvent selected from acetone, TBME, THF, acetonitrile or acetone/water and optionally comprising a substoichiometric amount, of a base.

15. A process according to claim 12 wherein the reaction is conducted at a temperature of −

30 to 0°

C.

16. A process for the preparation of a compound of formula (XIX):

17. A process according to claim 16 wherein, in step (i) the oxidation reaction is carried out using a Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol);

a hypochlorite under acidic conditions;

a Jones reaction using sodium dichromate or chromic trioxide in dilute sulfuric acid;

or TEMPO ((2,2,6,6-Tetramethyl-piperidin-1-yl)oxy) or a derivative thereof.

18. A process according to claim 16 wherein, in the epimerization reaction of step (ii), the compound of formula (XX) is dissolved in an alcoholic solvent, optionally mixed with water and contacted with a base selected from sodium or potassium hydroxide or a sodium or potassium alkoxide.

19. A process according to claim 18 wherein,

in the compound of formula (XX), R⁴ is C(O)OR¹⁰, and in step (ii) the base is sodium or potassium hydroxide and the epimerization is accompanied by hydrolysis to give a compound of formula (XXI) in which R⁴ is C(O)OH;

and/or

in the compound of formula (XX), R² and/or R⁵ is a group OC(O)OR¹⁴, where R¹⁴ is C_1-6 alkyl or benzyl; and

wherein the epimerisation step yields a compound of formula (XXI) in which R² and/or R^5b is OH;

or

in the compound of formula (XX), R² and/or R⁵ is a protected OH which is stable under basic conditions and the process further comprises the step of removing the protecting group before or after step (iii).

20. A process according to claim 16 wherein, in step (iii), the reducing agent is a hydride.

21. A process according to claim 16 for the preparation of a compound of formula (XIX) wherein R¹ is ethyl, R² and Rya are both H, Y¹ is —

CH₂CH₂—

, and R⁴ is C(O)OH.