Preparation of bile acids and intermediates thereof

Abstract

Synthetic methods for preparing deoxycholic acid and intermediates thereof are provided.

1 . A method for preparing deoxycholic acid (DCA) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       said method comprising
 (a) reacting 9α-hydroxyandrost-4-en-3,17-dione 1.0 with H 2  under hydrogenation conditions to form compound 1.1 
 
       
         
           
           
               
               
           
         
         (b) reacting compound 1.1 with acid to form compound 1.2 
       
       
         
           
           
               
               
           
         
         (c) reacting compound 1.2 a reducing agent to form compound 1.3 a mixture of 1.3 and 1.4 
       
       
         
           
           
               
               
           
         
         (d) reacting compound 1.3 with a two carbon olefination reagent under olefin forming conditions to form compound 1.5 
       
       
         
           
           
               
               
           
         
         (e) converting compound 1.5 to a compound of formula 1.6 wherein P is a protecting group 
       
       
         
           
           
               
               
           
         
         (f) reacting a compound of formula 1.6 with an alkylpropiolate CH 2 CH 2 C(O)OR or an alkyl acrylate CH 2 ═CHC(O)OR wherein R is alkyl in the presence of a Lewis acid to form a compound of formula 1.7 wherein P is a protecting group, R is a alkyl, and the dashed line   is a single or double bond; 
       
       
         
           
           
               
               
           
         
         (g) reacting a compound of formula 1.7 with H 2  under hydrogenation conditions to form a compound of formula 1.8 wherein P is a protecting group and R is alkyl 
       
       
         
           
           
               
               
           
         
         (h) reacting compound of formula 1.8 with an oxidizing agent to form a compound of formula 1.9 wherein P is a protecting group and R is alkyl 
       
       
         
           
           
               
               
           
         
         (i) reacting a compound of formula 1.9 with H 2  under hydrogenation conditions to form compound of formula 2.0 wherein P is a protecting group and R is alkyl 
       
       
         
           
           
               
               
           
         
         (j) reacting compound of formula 2.0 with a reducing agent to form a compound of formula 2.1 wherein P is a protecting group and R is alkyl 
       
       
         
           
           
               
               
           
         
       
       and
 (k) exposing compound of formula 2.1 to deprotection and hydrolysis conditions to form deoxycholic acid. 
 
     
     
         2 . The method of  claim 1  wherein the hydrogenation conditions of part (a) comprises a Pd/C catalyst. 
     
     
         3 . The method of  claim 1  wherein the acid of part (b) is a mineral acid. 
     
     
         4 . The method of  claim 3  wherein the mineral acid is H 2 SO 4 . 
     
     
         5 . The method of  claim 1  wherein the reducing agent of part (c) is LiAl (OtBu) 3 H. 
     
     
         6 . The method of  claim 1  wherein the two carbon olefination reagent of part (d) is Ph 3 PCH 2 CH 3   + Br − . 
     
     
         7 . The method of  claim 1  wherein the protecting group P of compound 1.6-2.1 is —C(O)CH 3 . 
     
     
         8 . The method of  claim 1  wherein the Lewis acid of part (f) is EtCl 2 . 
     
     
         9 . The method of  claim 1  wherein the alkylpropiolate or alkylacrylate is methylpropriolate or methylacrylate. 
     
     
         10 . The method of  claim 1  wherein the hydrogenation conditions of part (g) comprises a PtO 2  catalyst. 
     
     
         11 . The method of  claim 1  wherein the oxidizing agent of part (h) is CrO 3 . 
     
     
         12 . The method of  claim 1  wherein the hydrogenation conditions of part (i) comprises a Pd/C catalyst. 
     
     
         13 . The method of  claim 1  wherein the reducing agent of part (j) is LiAl (OtBu) 3 H. 
     
     
         14 . The method of  claim 1  wherein the deprotection and hydrolysis conditions of part (k) when P is —C(O)CH 3  comprises reacting compound 2.1 with an alkali earth hydroxide, alkali earth alkoxide, or a mixture of both. 
     
     
         15 . The method of  claim 14  wherein the alkali earth alkoxide is LiOH. 
     
     
         16 . An intermediate compound selected from the group consisting of
 9α-Hydroxy-5β-andro stan-3,17-dione (1.1);   5β-Androst-9(11)-en-3,17-dione (1.2);   (Z)-3α-Hydroxy-5β-pregna-9(11),17(20)-diene (1.5);   (Z)-3α-Acetoxy-5β-pregna-9(11),17(20)-diene (1.6);   (E)-Methyl 3α-acetoxy-5β-chol-9(11), 16, 22-trien-24-oate (1.7a);   Methyl 3α-acetoxy-5β-chol-9(11), 16-dien-24-oate (1.7b);   Methyl 3α-hydroxy-5β-chol-9(11)-en-12-one-24-oate (1.9a); and   Methyl 3α-acetoxy-5β-cholan-12-one-24-oate (2.0a).