Method for preparing a farnesoid x receptor agonist

Abstract

The invention relates to a process for preparing a compound of formula (I) in particular obeticholic acid and intermediates suitable for its synthesis.

1 . A compound selected from the group consisting of:
 a compound of formula (VII):   
       
         
           
           
               
               
           
         
         a compound of formula (VIIa): 
       
       
         
           
           
               
               
           
         
         a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         a compound of formula (X): 
       
       
         
           
           
               
               
           
         
         a compound of formula (XII): 
       
       
         
           
           
               
               
           
         
         a compound of formula (XIII): 
       
       
         
           
           
               
               
           
         
         a compound of formula (XV): 
       
       
         
           
           
               
               
           
         
         a compound of formula (XVa): 
       
       
         
           
           
               
               
           
         
         a compound of formula (XVI) 
       
       
         
           
           
               
               
           
         
       
       and 
       a compound of formula (XVIa) 
       
         
           
           
               
               
           
         
       
       wherein
 R a  is hydrogen or an optionally substituted linear or branched C 1 -C 6  alkyl group, or an optionally substituted aryl; 
 R b  is hydrogen and R c  is OH or O-PG, wherein PG is an alcohol protecting group; 
 
       or
 R b  is OR 1  and R c  is OR 2 ; 
 wherein each of R 1  and R 2 , which are the same or different, is a C 1 -C 6  alkyl group or R 1  and R 2  taken together form a —(CH 2 ) n - chain, wherein n is 2 or 3, 
 wherein the symbol   indicates that the absolute configuration of the double bond can be (E) or (Z) or a mixture thereof; and 
 the proton H-5 of the compounds of formula (VII), (IX), (X), (XII), (XIII), (XV), and (XVI) is in configuration 5α or 5β or a mixture thereof. 
 
     
     
         2 . A compound according to  claim 1  selected from the group consisting of:
 3-spiro[1,3]dioxolane-(6E/Z)-ethyliden-5β-cholan-24-oic acid methyl ester; 
 3-spiro[1,3]dioxolane-6-ethyliden-cholan-24-oic acid; 
 3-spiro[1,3]dioxolane-(6Z)-ethylidene-5β-cholan-24-oic acid methyl ester; 
 3-spiro[1,3]dioxolane-6-ethyliden-7α-hydroxy-5β-cholan-24-oic acid methyl ester; 
 3-oxo-6-ethylidene-5β-cholan-24-oic acid methyl ester; 
 3α-hydroxy-(6Z)-ethylidene-5β-cholan-24-oic acid methyl ester; 
 3α-(2,2-dimethylpropanoyI)-(6Z)-ethylidene-5β-cholan-24-oic acid methyl ester; and 
 3α-(2,2-dimethylpropanoyl)-7α-hydroxy-(6E)-ethylidene-5β-cholan-24-oic acid methyl ester. 
 
     
     
         3 . A pharmaceutical composition comprising a compound of formula (Ia), which is 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, also known as 6α-ethyl-chenodeoxycholic acid, obeticholic acid or as 6-ECDCA, 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable carrier, wherein the obeticholic acid of formula (Ia) does not comprise chenodeoxycholic acid of formula 2 
       
         
           
           
               
               
           
         
       
     
     
         4 . The pharmaceutical composition as defined in  claim 3 , wherein obeticholic acid of formula (Ia) is obtained starting from hyodeoxycholic acid having the following formula (II)