6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal FXR modulators

• US 10,301,350 B2
• Filed: 11/19/2015
• Issued: 05/28/2019
• 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, Otter, Carl, Wallis, Laura, Batchelor, Rhys
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US15/528,214
• Publication Number:
  US 20170327528A1
• Time in Patent Office: 1,286 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) and related methods, wherein R¹, R², Y, R⁴ and R⁵ are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids with pharmacological activity. The invention futher provides intermediated in the systhesis of obeticholic acid and its analogues. The invention also provides methods related to the synthesizing of these intermediates and methods of preparing obeticholic acid and obeticholic acid analogues from the compound of the invention.

Claims

1. A compound of general formula (I):

2. A compound according to claim 1 wherein the compound of general formula (I) is a compound of general formula (IA):

3. A compound according to claim 1 wherein R¹ is ethyl.

4. A compound according to claim 1 wherein Y is an alkylene or alkenylene 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.

5. A compound according to claim 1 wherein:

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

/or

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

/or

R⁵ is H or OH.

6. A compound according to claim 5 wherein:

R¹ is ethyl; and

/or

R² is H; and

/or

Y is a bond, —

CH₂—

, —

CH₂CH₂—

, —

CH═

CH—

or —

CH═

C(CH₃)—

; and

/or

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

/or

R⁵ is H.

7. A compound according to claim 6 wherein R¹ is ethyl and/or R¹⁰ is C_1-6 alkyl or benzyl.

8. A compound according to claim 1 selected from:

(6β

, 7α

, 22E)-6-ethyl-7-hydroxy-3-oxo-4,22-choladien-24-oic acid;

(6β

, 7α

)-6-ethyl-7-hydroxy-3-oxo-4-cholen-24-oic acid

and C_1-6 alkyl and benzyl esters thereof and salts thereof.

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

10. A process according to claim 9 wherein, in Step (A), the organometallic reagent is a Gilman reagent formed by reaction of an alkyl lithium compound of formula (XXIV):

R¹—

Li 

 

(XXIV)

wherein R¹ is as defined for general formula (I);

and a copper (I) salt;

or

the organometallic reagent is a Grignard reagent R¹MgX, where R¹ is as defined for general formula (I) and X is a halide and wherein the reaction is conducted in the presence of a zinc (II) salt and a catalytic amount of a copper (I) or copper(II) salt or complex.

11. A process for the preparation of a compound of general formula (XVIII):

12. A process according to claim 11 wherein, in step (i), the reducing agent for the conversion of the compound of general formula (I) to the compound of general formula (XIX) is hydrogen in the presence of a palladium/carbon, palladium/calcium carbonate, palladium/aluminium oxide, platinum/palladium or Raney nickel catalyst.

13. A process according to claim 11 wherein, in step (i), the solvent is an alcoholic solvent;

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 such as acetone or water and/or a base such as triethylamine.

14. A process according to claim 11 wherein, in step (ii), 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, chromic trioxide in dilute sulfuric acid;

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

15. A process according to claim 11 wherein, in the epimerization reaction of step (iii), the compound of general formula (XX) is dissolved in an alcoholic solvent, optionally mixed with water and contacted with sodium or potassium hydroxide or a sodium or potassium alkoxide.

16. A process according to claim 15 wherein:

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

/or

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

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

or

in the compound of general 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 (iv).

17. A process according to claim 11 wherein, in step (iv), the reducing agent is a hydride.

18. A process according to claim 11 for the preparation of a compound of general formula (XVIII) wherein R¹ is ethyl, R² and R^5a are both H, Y¹ is —

CH₂CH_2—

, and R⁴ is C(O)OH.