Methods for Preparing Bile Acids

Abstract

The present disclosure provides methods of preparing cholic acid, deoxycholic acid, or chenodeoxycholic acid, an ester thereof, or a pharmaceutically or cosmetically acceptable salt thereof, and novel and useful synthetic intermediates, for example, as described for methods 1, 1A, 1B, 2, 3, 3A, and 4. The method can start with a plant derived steroid as a starting material, such as dehydroepiandrosterone (DHEA) or Acetyl-dehydroepiandrosterone (Ac-DHEA). Also provided are pharmaceutical or cosmetic compositions and uses thereof, which comprise one or more of cholic acid, deoxycholic acid, or chenodeoxycholic acid, an ester thereof, or a pharmaceutically or cosmetically acceptable salt thereof, which is of high purity, for example, free of animal derived impurities.

1 .- 76 . (canceled) 
     
     
         77 . A compound having a structure of 
       
         
           
           
               
               
           
         
         wherein R 31 , R 32  and R 33  are each independently H or a hydroxyl protecting group. 
       
     
     
         78 . The compound of  claim 77 , wherein R 32  is H, and R 31  and R 33  are each independently a hydroxyl protecting group. 
     
     
         79 . The compound of  claim 78 , wherein the hydroxyl protecting group is acetyl. 
     
     
         80 . A method of preparing a compound of Formula III-8 
       
         
           
           
               
               
           
         
         wherein R 31 , R 32  and R 33  are each independently H or a hydroxyl protecting group, 
         the method comprising 
         a) contacting a diketone of Formula III-11a with a ketone reducing agent to form a compound of Formula III-12a 
       
       
         
           
           
               
               
           
         
         b) reacting the compound of Formula III-12a with an amine to form an imine of Formula III-13a 
       
       
         
           
           
               
               
           
         
         wherein n is 0, 1 or 2, and R 34  is C 1-6  alkyl; and, 
         c) oxidizing the imine of Formula III-13a with O 2  in the presence of a copper salt to form the compound of Formula III-8. 
       
     
     
         81 . The method of  claim 80 , wherein the diketone of Formula III-11a is a compound of Formula III-11 
       
         
           
           
               
               
           
         
         and is obtained from the method of preparing the compound of Formula III-11, 
         the method comprising 
         a) reacting the compound of Formula III-9 with an epoxide forming reagent to form an epoxide of Formula III-10 
       
       
         
           
           
               
               
           
         
         b) reducing the epoxide of Formula III-10 under hydrogenation condition to form the compound of Formula III-11. 
       
     
     
         82 . The method of  claim 80 , wherein R 32  is H, and R 31  and R 33  are each independently a hydroxyl protecting group. 
     
     
         83 . The method of  claim 82 , wherein the hydroxyl protecting group is acetyl.