Resolution of alpha-(phenoxy) phenylacetic acid derivatives

Abstract

The present invention provides a method for producing an enantiomerically enriched α-(phenoxy)phenylactic acid compound of the formula: from its enantiomeric mixture, where R 1 is alkyl or haloalkyl and X is halide.

1 . A method for resolving an enantiomerically enriched α-(phenoxy)phenylactic acid compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is alkyl or haloalkyl, and  
 X is halide;  
 from an enantiomeric mixture of the α-(phenoxy)phenylactic acid compound comprising a first and a second enantiomers, said method comprising:  
 (a) contacting the enantiomeric mixture of the α-(phenoxy)phenylactic acid compound with less than 0.5 molar equivalents of an enantiomerically enriched chiral amine compound with respect to the α-(phenoxy)phenylactic acid compound and  
 (b) separating the solid acid-base salt of the first enantiomer from the second enantiomer of the α-(phenoxy)phenylactic acid compound.  
 
   
   
       2 . The method of  claim 24 , wherein said step (i) of producing the crystallization solution comprising the solid enantiomerically enriched acid-base salt of the first enantiomer comprises: 
 (i1) heating the solution mixture to a temperature above the nucleation temperature of the first enantiomer; and    (i2) lowering the solution mixture temperature to a temperature at or below the nucleation temperature of the first enantiomer to produce the solid acid-base salt of the first enantiomer.    
   
   
       3 . The method of  claim 2 , wherein said step (ii) of separating the solid acid-base salt of the first enantiomer is conducted at a temperature near or above a saturation temperature of an acid-base salt of the second enantiomer.  
   
   
       4 . The method of  claim 1  further comprising recovering the chiral amine compound by removing the chiral amine compound from the separated solid acid-base salt of the first enantiomer.  
   
   
       5 . The method of  claim 4 , wherein the enantiomerically enriched chiral amine compound used in producing the acid-base salt of said step (a) comprises the recovered chiral amine compound.  
   
   
       6 . The method of  claim 1  further comprising racemizing at least a portion of the second enantiomer in the separated solution mixture by contacting the second enantiomer with a base.  
   
   
       7 . The method of  claim 6 , wherein the enantiomeric mixture of the α-(phenoxy)phenylactic acid compound used in said step (a) comprises a racemized α-(phenoxy)phenylactic acid compound.  
   
   
       8 . The method of  claim 1 , wherein the chiral amine compound is of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 each of R 2  and R 3  is independently hydrogen or alkyl; or R 2  and R 3  together with atoms to which they are attached to form a heterocyclic ring moiety;  
 R 4  is hydrogen or alkyl;  
 each of R 5  and R 6  is independently hydrogen or alkyl, or one of R 5  or R 6  is an amine protecting group; and  
 Ar is aryl.  
 
   
   
       9 . The method of  claim 1 , wherein the α-(phenoxy)phenylactic acid is an enantiomeric mixture of 4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid, said method comprising: 
 (a) producing a crystallization solution mixture comprising an enantiomerically enriched acid-base salt of (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid by contacting the enantiomeric mixture of 4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid with less than 0.5 molar equivalent of an enantiomerically enriched (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol in about 4 grams of an alcoholic solvent per gram of (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid;    (b) separating the enantiomerically enriched acid-base salt from the solution mixture which is enriched with (+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid; and    (c) removing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol from the acid-base salt to produce enantiomerically enriched (−)-4-chloro-α-(3-trifluoromethyl-phenoxy)phenylactic acid.    
   
   
       10 . The method of  claim 9 , wherein the alcoholic solvent is isopropanol.  
   
   
       11 . The method of  claim 10 , wherein about 0.47 molar equivalent or less of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol is used to form the acid-base salt.  
   
   
       12 . The method of  claim 11 , wherein said step (a) of producing a solution comprising an enantiomerically enriched acid-base salt of (−)-4-chloro-α-(3-trifluoromethyl-phenoxy)phenylactic acid comprises heating the solution mixture to a temperature at or above a nucleation temperature of the (−)-acid-base salt.  
   
   
       13 . The method of  claim 12 , wherein said step (b) of separating the enantiomerically enriched acid-base salt is performed at a temperature near or above a saturation temperature of an acid-base salt of the (+)-enantiomer.  
   
   
       14 . The method of  claim 10 , wherein the enantiomerically enriched (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol comprises at least a portion of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol that is removed from the acid-base salt of said step (c).  
   
   
       15 . The method of  claim 10  further comprising racemizing at least a portion of (+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid obtained in said step (b).  
   
   
       16 . The method of  claim 15 , wherein the enantiomeric mixture of 4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid comprises at least a portion of (+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid that is racemized.  
   
   
       17 . An acid-base salt derived from the method of  claim 1 .  
   
   
       18 . The acid-base salt of  claim 17 , wherein the α-(phenoxy)phenylactic acid compound and the chiral amine compound are enantiomerically enriched.  
   
   
       19 . The acid-base salt of  claim 18 , wherein the α-(phenoxy)phenylactic acid compound is (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylactic acid.  
   
   
       20 . The acid-base salt of  claim 18 , wherein the chiral amine compound is (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.  
   
   
       21 . The acid-base salt of  claim 19  having an enantiomeric excess of at least about 95%.  
   
   
       22 . (canceled)  
   
   
       23 . (canceled)  
   
   
       24 . The method of  claim 1 , wherein said step (a) comprises: 
 (i) producing a crystallization solution mixture comprising a solid enantiomerically enriched acid-base salt of a first enantiomer by contacting the enantiomeric mixture of the α-(phenoxy)phenylactic acid compound with the enantiomerically enriched chiral amine compound under conditions sufficient to produce the ratio of the amount of first enantiomer to the amount of the second enantiomer in the salt is at least about 3:1, wherein the total amount of enantiomerically enriched chiral amine compound used is less than 0.5 molar equivalents with respect to the α-(phenoxy)phenylactic acid compound and    (b) separating the solid acid-base salt of the first enantiomer from the solution mixture at a temperature where the concentration of an acid-base salt of the second enantiomer of the α-(phenoxy)phenylactic acid compound is near or below its saturation point.