Compounds and methods of making sterols using diols

Abstract

Compounds and methods of synthesizing oxysterols are provided. The compounds and methods provided allow the oxysterol to be safely produced at a high yield. The compounds and methods provided can produce the oxysterol in a stereoselective manner.

1 . A method of making an oxysterol, the method comprising reacting a diol having the formula: 
       
         
           
           
               
               
           
         
       
       with a borane compound to form the oxysterol or a pharmaceutically acceptable salt, hydrate or solvate thereof having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R1 comprises an aliphatic or cyclic substituent having at least one carbon atom, and R2 comprises an aliphatic or cyclic substituent having at least one carbon atom, wherein the oxysterol is in a dihydrate form. 
     
     
         2 . A method of  claim 1 , wherein the borane compound is BH 3  and is reacted with a peroxide. 
     
     
         3 . A method of  claim 2 , wherein the peroxide is hydrogen peroxide. 
     
     
         4 . A method of  claim 3 , wherein the BH 3  and the hydrogen peroxide are reacted in the presence of tetrahydrofuran to form the oxysterol. 
     
     
         5 . A method of  claim 1 , wherein the R1 and R2 comprise a hexyl group and the diol comprises (3S ,8S ,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(S)-2-hydroxyoctan-yl]-2,3,4,7,8,9,11,12,14,15,16,17- dodecahydro-1H-cyclopenta[a]phenanthren-3-ol. 
     
     
         6 . A method of  claim 4 , wherein (i) the oxysterol is hydrated, (ii) the borane is reacted with the diol at a temperature of less than 5° C., (iii) the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C., or (iv) the oxysterol is solidified and separated by filtration. 
     
     
         7 . A method of  claim 1 , wherein the reaction is carried out in a single container to yield the oxysterol having the formula 
       
         
           
           
               
               
           
         
       
       in a dihydrate form. 
     
     
         8 . A method of  claim 1 , wherein the oxysterol is purified by dissolving the oxysterol in an organic solvent. 
     
     
         9 . A method of  claim 8 , wherein the oxysterol is purified by dissolving the oxysterol in an acetone and water to recover purified oxysterol crystals. 
     
     
         10 . A method of  claim 8 , wherein the oxysterol is purified by reflux and recrystallization by dissolving the oxysterol in an acetone and water to recover purified oxysterol crystals. 
     
     
         11 . (canceled) 
     
     
         12 . A method of  claim 10 , wherein the purified oxysterol is hydrated after crystallization. 
     
     
         13 . (canceled) 
     
     
         14 . A method of  claim 1 , wherein the borane compound is reacted with the diol at a temperature of less than 5° C. 
     
     
         15 . A method of  claim 4 , wherein the hydrogen peroxide is reacted with the diol after the borane is reacted and the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C. 
     
     
         16 . A method of  claim 1 , wherein the reaction is carried out in a single container to yield the oxysterol. 
     
     
         17 . A method of making an oxysterol, the method comprising reacting a diol having the formula: 
       
         
           
           
               
               
           
         
       
       with borane, hydrogen peroxide and tetrahydrofuran to form the oxysterol or a pharmaceutically acceptable salt, hydrate or solvate thereof having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R1 comprises an aliphatic or cyclic substituent having at least one carbon atom, and R2 comprises an aliphatic or cyclic substituent having at least one carbon atom, wherein the oxysterol is in a dihydrate form. 
     
     
         18 . A method of  claim 17 , wherein (i) the diol comprises (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(S)-2-hydroxyoctan-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol or (ii) the oxysterol comprises 3S,5S,6S,8R,9S,10R,13S,14S,17S)-17-((S)-2-hydroxyoctan-2-yl)-10,13- dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol. 
     
     
         19 . A method of  claim 17 , wherein R 1  or R 2  comprises a (C 1 -C 20 ) alkyl or heteroalkyl, a (C 2 -C 20 ) aryl or heteroaryl, a (C 6 -C 26 ) arylalkyl or heteroalkyl and a (C 5 -C 20 ) arylalkyl or heteroaryl-heteroalkyl, a (C 4 -C 10 ) alkyldiyl or heteroalkyldiyl, or a (C 4 -C 10 ) alkyleno or heteroalkyleno. 
     
     
         20 . A method of  claim 17  wherein the reaction is carried out in a single container to yield the oxysterol having the formula 
       
         
           
           
               
               
           
         
       
       in a dihydrate form.