Compounds and synthetic methods for the preparation of retinoid x receptor-specific retinoids

Abstract

Provided herein are compounds useful for the preparation of compounds that have retinoid-like biological activity. Also provided herein are processes for the preparation of compounds that have retinoid-like biological activity.

What is claimed is: 
     
         1 . A method of synthesizing a compound of Formula II 
       
         
           
           
               
               
           
         
         by treating a compound of Formula I 
       
       
         
           
           
               
               
           
         
         wherein R 1  is C 1-20 -alkyl; C 1-20 -alkyl substituted with one or more substituents independently selected from —NH 2 , —NH(C 1-10 -alkyl), —N(C 1-10 -alkyl)(C 1-10 -alkyl), —OH, halogen, —C 1-10 -alkyl, —C 1-10 -haloalkyl, —O—(C 1-10 -alkyl), or —O—(C 1-10 -haloalkyl); C 1-20 -alkenyl; C 1-20 -alkenyl substituted with one or more substituents independently selected from —NH 2 , —NH(C 1-10 -alkyl), —N(C 1-10 -alkyl)(C 1-10 -alkyl), —OH, halogen, —C 1-10 -alkyl, —O—(C 1-10 -alkyl), or —O—(C 1-10 -haloalkyl); C 6-14 -aryl; or C 6-14 -aryl substituted with one or more substituents independently selected from —NH 2 , —NH(C 1-10 -alkyl), —N(C 1-10 -alkyl)(C 1-10 -alkyl), —OH, halogen, —C 1-10 -alkyl, —O—(C 1-10 -alkyl), or —O—(C 1-10 -haloalkyl), 
         or a salt, hydrate, or solvate thereof, 
         with potassium tert-butoxide (KOt-Bu) forming a mixture, and then adding to the mixture a Compound 32, having the structure 
       
       
         
           
           
               
               
           
         
         or a salt, hydrate, or solvate thereof, 
         such that the compound of Formula II, or a salt, hydrate, or solvate thereof, is prepared. 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is C 4-20 -alkyl, C 1-20 -alkenyl, or C 6-16 -aryl. 
     
     
         3 . The method of  claim 1 , wherein the compound of Formula II is a Compound 37, having the structure 
       
         
           
           
               
               
           
         
         and the compound of Formula I is Compound 12, having the structure 
       
       
         
           
           
               
               
           
         
         such that Compound 37 or a salt, hydrate, or solvate thereof, is prepared. 
       
     
     
         4 . The method of  claim 1 , wherein the compound of Formula II is a compound of Formula III 
       
         
           
           
               
               
           
         
         and the Compound 32 is Compound 11, having the structure 
       
       
         
           
           
               
               
           
         
         such that the compound of Formula III, or a salt, hydrate, or solvate thereof, is prepared. 
       
     
     
         5 . The method of  claim 4 , wherein R 1  is C 4-20 -alkyl, C 1-20 -alkenyl, or C 6-16 -aryl. 
     
     
         6 . The method of  claim 4 , wherein the compound of Formula III is Compound 13, having the structure 
       
         
           
           
               
               
           
         
         and the compound of Formula I is Compound 12, having the structure 
       
       
         
           
           
               
               
           
         
         such that Compound 13, or a salt, hydrate, or solvate thereof, is prepared. 
       
     
     
         7 . The method of  claim 1 , wherein treatment of the compound of Formula I with KOt-Bu is carried out under an inert atmosphere. 
     
     
         8 . The method of  claim 1 , wherein the added Compound 32 is in a tetrahydrofuran or ether solvent. 
     
     
         9 . The method of  claim 1 , further comprising quenching the reaction with water. 
     
     
         10 . The method of  claim 9 , further comprising extracting the compound of Formula II with ethyl acetate. 
     
     
         11 . A method of making Compound 38, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       comprising a synthetic process of preparing intermediate compound 37, having the structure 
       
         
           
           
               
               
           
         
         or a salt, hydrate, or solvate thereof, 
       
       by treating compound 12, having the structure 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate, or solvate thereof, 
       with potassium tert-butoxide (KOt-Bu), and then adding to this mixture Compound 32, having the structure 
       
         
           
           
               
               
           
         
       
       such that the intermediate compound 37, or a salt, hydrate, or solvate thereof, is prepared. 
     
     
         12 . The method of  claim 11 , wherein Compound 38 has an enantiomeric excess of Compound A, 
       
         
           
           
               
               
           
         
         of at least about 98.0%. 
       
     
     
         13 . The method of  claim 11 , wherein treatment of compound 12 with KOt-Bu is carried out under an inert atmosphere. 
     
     
         14 . The method of  claim 11 , wherein the added Compound 32 is in a tetrahydrofuran or ether solvent. 
     
     
         15 . The method of  claim 11 , further comprising quenching the reaction with water. 
     
     
         16 . The method of  claim 15 , further comprising extracting Compound 37 with ethyl acetate.