Compounds and methods involving sterols

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 - 9 . (canceled) 
     
     
         10 . A method of making a sterol, the method comprising reacting an organometallic compound with pregnenolone or pregnenolone acetate to form the sterol, the sterol having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 1  comprises an aliphatic or cyclic substituent having at least one carbon atom. 
       
     
     
         11 . A method of  claim 10 , wherein R 1  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. 
     
     
         12 . A method of  claim 10 , wherein the sterol 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 and the hydrate is a monohydrate. 
     
     
         13 . A method of  claim 10 , wherein (i) the organometallic compound comprises the formula R 2 MgX, where X is a halide and R 2  comprises an aliphatic or cyclic substituent having at least one carbon atom or (ii) the organometallic compound comprises the formula R 2 Li, where R 2  comprises an aliphatic or cyclic substituent having at least one carbon atom. 
     
     
         14 . A method of  claim 10 , wherein (i) pregnenolone acetate is reacted with the organometallic compound and quenched with aqueous ammonium chloride to produce the sterol in the form of a gel, or (ii) pregnenolone is reacted with the organometallic compound and quenched with acetic acid to produce the sterol in the form of a gel. 
     
     
         15 . A method of  claim 14 , wherein pregnenolone is reacted with the organometallic compound at a temperature of less than 5° C. 
     
     
         16 . A method of  claim 14 , wherein the sterol is reacted with acetic acid in tetrahydrofuran at a temperature of less than 10° C. 
     
     
         17 . A method of making an oxysterol, the method comprising reacting a diol having the formula: 
       
         
           
           
               
               
           
         
       
       with borane and hydrogen peroxide to form the oxysterol or a pharmaceutically acceptable salt, hydrate or solvate thereof having the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  comprises an aliphatic or cyclic substituent having at least one carbon atom, and R 2  comprises an aliphatic or cyclic substituent having at least one carbon atom. 
       
     
     
         18 . A method of  claim 17  wherein R 1  and R 2  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 and the hydrate is a monohydrate. 
     
     
         19 . A method of  claim 17  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., (iv) the oxysterol is solidified and separated by filtration, or (v) 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. 
     
     
         20 . A method of  claim 17  wherein the reaction is carried out in a single container to yield the oxysterol having the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         21 . 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 R 1  is a straight chain alkyl, and R 2  is a straight chain alkyl. 
       
     
     
         22 . A method of  claim 21  wherein R 1  and R 2  comprise a hexyl group and the diol is (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. 
     
     
         23 . A method of  claim 21  wherein (i) the oxysterol is hydrated, (ii) the borane is reacted with the diol at a temperature of less than 5° C., (iii) the oxysterol is solidified and separated by filtration, or (iv) the oxysterol is (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. 
     
     
         24 . A method of  claim 21  wherein the reaction is carried out in a single container to yield the oxysterol having the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         25 . A method of  claim 24 , wherein the reaction is carried out in a reaction vessel that is cooled to less than 10° C. 
     
     
         26 . A method of  claim 24 , wherein the reaction is carried out in a reaction vessel that is cooled to less than 5° C. 
     
     
         27 . A method of  claim 24 , wherein the reaction is carried out in a reaction vessel that is cooled to −5° C. 
     
     
         28 . A method of  claim 24 , wherein the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C.