Preparation of pregabalin and related compounds

Abstract

Materials and methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.

1 . A method of making a compound of Formula 1,  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, in which 
 R 1  and R 2  are different and are each independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, and substituted C 3-12  cycloalkyl,  
 the method comprising:  
 (a) reacting a compound of Formula 2,  
                     
 or a salt thereof, with an acid and water to yield the compound of Formula 1 or a salt thereof; and  
 (b) optionally converting the compound of Formula 1 or a salt thereof into a pharmaceutically acceptable complex, salt, solvate or hydrate, wherein R 1  and R 2  in Formula 2 are as defined in Formula 1.  
 
   
   
       2 . The method of  claim 1 , wherein R 1  is a hydrogen atom and R is isobutyl.  
   
   
       3 . The method of  claim 1 , further comprising reducing a cyano moiety of a compound of Formula 3,  
     
       
         
         
             
             
         
       
     
     or a salt thereof, to yield the compound of Formula 2 or a salt thereof, wherein 
 R 1  and R 2  in Formula 3 are as defined in Formula 1; and  
 R 3  in Formula 3 is C 1-12  alkyl, C 3-12  cycloalkyl, or aryl-C 1-6  alkyl.  
 
   
   
       4 . The method of  claim 3 , wherein R 1  is a hydrogen atom and R 2  is isobutyl.  
   
   
       5 . The method of  claim 3 , further comprising: 
 (a) contacting a compound of Formula 4,                          with an enzyme to yield the compound of Formula 3, or a salt thereof, and a compound of Formula 5,                          wherein the enzyme is adapted to enantioselectively hydrolyze the compound of Formula 4 to the compound of Formula 3 or a salt thereof;    (b) isolating the compound of Formula 3 or a salt thereof; and    (c) optionally racemizing the compound of Formula 5 to yield the compound of Formula 4, wherein    R 1 , R 2 , and R 3  in Formula 4 and Formula 5 are as defined in Formula 3; and    R 4  in Formula 4 and Formula 5 is the same as or different than R 3  and is C 1-2  alkyl, C 3-12  cycloalkyl, or aryl-C 3-12  alkyl.    
   
   
       6 . The method of  claim 5 , wherein R 1  is a hydrogen atom and R is isobutyl.  
   
   
       7 . A method of making a compound of Formula 1,  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, in which 
 R 1  and R 2  are different and are each independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, and substituted C 3-12  cycloalkyl,  
 the method comprising:  
 (a) reducing a cyano moiety of a compound of Formula 6,  
                     
 or a salt thereof, to yield a compound of Formula 7,  
                     
 or a salt thereof;  
 (b) decarboxylating the compound of Formula 7 or a salt thereof to yield the compound of Formula 1 or a salt thereof; and  
 (c) optionally converting the compound of Formula 1 or a salt thereof into a pharmaceutically acceptable complex, salt, solvate or hydrate, wherein R 1  and R 2  in Formula 6 and in Formula 7 are as defined in Formula 1.  
 
   
   
       8 . The method of  claim 7 , wherein R 1  is a hydrogen atom and R 2  is isobutyl.  
   
   
       9 . A method of making a compound of Formula 1,  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, in which 
 R 1  and R 2  are different and are each independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, and substituted C 3-12  cycloalkyl,  
 the method comprising:  
 (a) reducing a cyano moiety of a compound of Formula 8,  
                     
 or a salt thereof, to yield the compound of Formula 1 or a salt thereof; and  
 (b) optionally converting the compound of Formula 1 or a salt thereof into a pharmaceutically acceptable complex, salt, solvate or hydrate, wherein R 1  and R 2  in Formula 8 are as defined in Formula 1, and R 5  in Formula 8 is hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, or aryl-C 1-6  alkyl.  
 
   
   
       10 . The method of  claim 9 , wherein R 1  is a hydrogen atom and R 2  is isobutyl.  
   
   
       11 . A method of making a compound of Formula 3,  
     
       
         
         
             
             
         
       
     
     or a salt thereof, in which 
 R 1  and R 2  are different and are each independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, and substituted C 3-12  cycloalkyl, and  
 R 3  is C 1-12  alkyl, C 3-12  cycloalkyl, or aryl-C 1-6  alkyl,  
 the method comprising:  
 (a) contacting a compound of Formula 4,  
                     
 with an enzyme to yield the compound of Formula 3 and a compound of Formula 5,  
                     
 wherein the enzyme is adapted to enantioselectively hydrolyze the compound of Formula 4 to the compound of Formula 3 or a salt thereof;  
 (b) isolating the compound of Formula 3 or a salt thereof; and  
 (c) optionally racemizing the compound of Formula 5 to yield the compound of Formula 4, wherein  
 R 1 , R 2 , and R 3  in Formula 4 and Formula 5 are as defined above in Formula 3; and  
 R 4  in Formula 4 and Formula 5 is the same as or different than R 3  and is C 1-12  alkyl, C 3-12  cycloalkyl, or aryl-C 1-6  alkyl.  
 
   
   
       12 . The method of  claim 11 , wherein R 1  is a hydrogen atom and R is isobutyl.  
   
   
       13 . A compound of Formula 2,  
     
       
         
         
             
             
         
       
     
     including salts thereof, wherein 
 R 1  and R 2  are different and are each independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, and substituted C 3-12  cycloalkyl, provided that when one of the substituents represented by R 1  or R 2  is hydrogen, the other substituent is not C 1-3  alkyl or C 5  alkyl.  
 
   
   
       14 . A compound of Formula 27,  
     
       
         
         
             
             
         
       
     
     including salts thereof, wherein 
 R 1  and R 2  are different and are each independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, and substituted C 3-12  cycloalkyl, provided that when one of the substituents represented by R 1  or R 2  is a hydrogen atom, the other substituent is not methyl; and  
 R 5  and R 6  are independently selected from hydrogen atom, C 1-12  alkyl, C 3-12  cycloalkyl, or aryl-C 1-6  alkyl, provided that R 5  and R 6  are different if not both hydrogen atoms.  
 
   
   
       15 . A compound selected from: 
 3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid,    (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid,    (2S,3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid,    (2R,3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid,    3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester,    (R)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester,    4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid,    (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid,    3-cyano-2-carboxy-5-methyl-hexanoic acid,    (S)-3-cyano-2-carboxy-5-methyl-hexanoic acid,    3-aminomethyl-2-carboxy-5-methyl-hexanoic acid, and    (S)-3-aminomethyl-2-carboxy-5-methyl-hexanoic acid,    including salts thereof and opposite enantiomers thereof.