Methods and intermediates for the preparation of bile acid derivatives

Abstract

The present disclosure relates to methods and novel intermediates useful in the preparation of a compound of formula Ior pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof.

1 . A method of preparing a compound of formula I 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, 
         wherein:
 R 1  is OH, alkoxy, or oxo; 
 R 2  and R 3  are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2  and R 3  taken together with the carbon atom to which they are attached form a carbonyl; 
 R 4  is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl; 
 R 5  and R 6  are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen or OH, or R 5  and R 6  taken together with the carbon atom to which they are attached form a carbonyl; 
 R 7  is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, C(O)NHOH, NH(CH 2 ) 2 SO 3 H, NHCH 2 CO 2 H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl; 
 R 8 , R 9 , and R 10  are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8  and R 9  taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R 9  and R 10  taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S; 
 m is 0, 1, or 2; 
 n is 0 or 1; and 
 p is 0 or 1; 
 
         the method comprising the step of reacting a compound of formula I-4 with a halogenating reagent to provide a compound of formula I-5a 
       
       
         
           
           
               
               
           
         
         wherein X is —(CHR 8 ) m   (CHR 9 ) n   (CHR 10 ) p —R 7 , where R 7 , R 8 , R 9 , and R 10  may be protected by R 11  or another protecting group. 
       
     
     
         2 . The method of  claim 1  wherein compound of formula I is compound of formula I-9 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. 
       
     
     
         3 . The method of  claim 1  wherein compound of formula I is compound of formula II 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. 
       
     
     
         4 . The method of  claim 1  wherein compound of formula I is compound of formula III 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, where is R 2  and R 5  and OH. 
       
     
     
         5 . The method of  claim 1  wherein compound of formula I is compound of formula 100 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein halogenating agent is a brominating agent. 
     
     
         7 . The method of  claim 1 , wherein halogenating reagent is an iodinating reagent. 
     
     
         8 . The method of  claim 1  further comprising converting compound of formula I-1 into compound of formula I-4 comprising the steps of
 1) protecting the compound of formula I-1 to provide compound of formula I-2; 
 2) forming a leaving group at C12 to provide compound of formula I-3; and 
 3) eliminating the leaving group at C12 to provide the alkene compound of formula I-4. 
 
     
     
         9 . The method of  claim 1  further comprising converting compound of formula I-5a into compound of formula I-6a comprising the steps of
 5) reacting the compound of formula I-5a with an oxidizing agent to prepare a compound of formula I-6a. 
 
     
     
         10 . The method of  claim 9  further comprising converting compound of formula I-6a into compound of formula I-7 comprising the steps of
 6) reacting the compound of formula I-6a with a reducing agent to prepare the compound of formula I-7. 
 
     
     
         11 . The method of  claim 10  further comprising converting compound of formula I-7 into compound of formula I comprising the steps of
 7) optionally deprotecting the compound of formula I-7 to obtain the compound of formula I-8 and 
 8) reacting the compound of formula I-7 or I-8 with a reducing agent to provide the compound of formula I. 
 
     
     
         12 . The method of  claim 1  further comprising converting compound of formula I-5 or I-5b into compound of formula I comprising the steps of:
 4) reacting compound of formula I-5b with a reducing agent to prepare the compound of formula I-5c; 
 5) reacting the compound of formula I-5c with a reducing agent to provide the compound of formula I-5d; and 
 6) deprotecting the compound of formula I-5d to provide the compound of formula I. 
 
     
     
         13 . The method of  claim 10  further comprising converting compound of formula I-7 or I-7a into compound of formula I comprising the steps of:
 3) reacting the compound of formula I-7a with a reducing agent to provide the compound of formula I-8a; 
 4) deprotecting the compound of formula I-8a to obtain the compound of formula I. 
 
     
     
         14 . The method of  claim 6  wherein the brominating agent is N-bromosuccinimide. 
     
     
         15 . The method of  claim 7  wherein the iodinating agent is N-iodosuccinimide. 
     
     
         16 . The method of  claim 9  wherein the oxidizing agent is RuCl 3 . 
     
     
         17 . The method of  claim 10  wherein the reducing agent is zinc metal. 
     
     
         18 . The method of  claim 11  wherein the reducing agent is sodium borohydride. 
     
     
         19 . The method of preparing a compound of formula D5 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, hydrate, solvate or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein:
 R 7  is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, C(O)NHOH, NH(CH 2 ) 2 SO 3 H, NHCH 2 CO 2 H or optionally substituted tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl; 
 R 8 , R 9 , and R 10  are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8  and R 9  taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R 9  and R 10  taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S; 
 m is 0, 1, or 2; 
 n is 0 or 1; and 
 p is 0 or 1; 
 
         the method comprising the steps of
 a) protecting a compound of formula D to prepare a compound of formula D1; 
 b) reacting the compound of formula D1 with an activating reagent to convert the C-12 alcohol into a leaving group, thus preparing a compound of formula D2; 
 c) reacting the compound of formula D2 with a base to prepare compound of formula D3; 
 d) reacting a compound of formula D3 with a hydrogen source in the presence of a hydrogenation catalyst to generate a compound of formula D4; and 
 e) reacting a compound of formula D4 with deprotecting reagents and a reducing agent to prepare a compound of formula D5, 
 
         wherein R 11  is a protecting group, X is —(CHR 8 ) m   (CHR 9 ) n   (CHR 10 ) p —R 7 , where R 7 , R 8 , R 9 , and R 10  may be protected by R 11  or another protecting group 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 20 , wherein the compound of formula D5 is compound of formula 45