Resolution of alpha-(phenoxy)phenylacetic acid derivatives with naphthyl-alkylamines

Abstract

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

1 . A method for producing a compound of the formula (I): 
     
       
         
         
             
             
         
       
     
     in an enantiomerically enriched form wherein
 R 1  is alkyl or haloalkyl, and 
 X is halide; 
 
     said method comprising:
 (a) contacting a mixture of a first enantiomer and a second enantiomer of a compound of formula (I) with an enantiomerically enriched naphthylalkylamine under conditions sufficient to form a solid naphthylalkylammonium salt of said first enantiomer and decrease the ratio of the amount of free first enantiomer to the amount of free second enantiomer in the mixture; and 
 (b) separating the naphthylalkylammonium salt of the first enantiomer from the mixture; 
 (c) separating the naphthylalkylamine from the first enantiomer in the naphthylalkylammonium salt to produce enantiomerically enriched compound of formula (I). 
 
   
   
       2 . The method of  claim 1 , wherein said step (a) comprises contacting said mixture with at most about 0.5 molar equivalents of an enantiomerically enriched naphthylalkylamine. 
   
   
       3 . The method of  claim 1 , wherein said step (a) comprises contacting said mixture with at most about 1.0 molar equivalents of a combination of an enantiomerically enriched naphthylalkylamine and a nonchiral base. 
   
   
       4 . The method of  claim 1 , wherein said step (a) comprises contacting a mixture of a first enantiomer and a second enantiomer of a compound of formula (I) with an enantiomerically enriched naphthylalkylamine under conditions sufficient to produce a ratio of the amount of free first enantiomer to the amount of the free second enantiomer in the solution of at least from about 1:20. 
   
   
       5 . The method of  claim 1 , wherein said step (a) comprises:
 (i) heating the mixture in a solvent to a temperature above the nucleation temperature of the first enantiomer; and   (ii) lowering the solution temperature to a temperature about or below the nucleation temperature of the first enantiomer to produce the naphthylalkylammonium salt of the first enantiomer.   
   
   
       6 . The method of  claim 1 , wherein said step (a) comprises:
 (i) heating the mixture in a solvent to a temperature ranging from about 60° C. to about 80° C.; and   (ii) lowering the solution temperature to a temperature ranging from below about 60° C. to produce the naphthylalkylammonium salt of the first enantiomer.   
   
   
       7 . The method of  claim 1 , wherein step (a) is conducted in at most about 4 grams of solvent per gram of compound of formula (I). 
   
   
       8 . The method of  claim 5 , wherein the solvent is a member selected from the group consisting of water, ethanol, t-butyl methyl ether and a combination thereof. 
   
   
       9 . The method of  claim 5 , wherein the solvent is a mixture of water and t-butyl methyl ether. 
   
   
       10 . The method of  claim 1 , wherein said step (b) is conducted about or below the saturation point/temperature of the naphthylalkylammonium salt of the second enantiomer of the compound of formula (I). 
   
   
       11 . The method of  claim 1 , wherein said step (b) is conducted at a temperature ranging from about 60 to about 100. 
   
   
       12 . The method of  claim 1 , wherein said step (c) further comprises recovering naphthylalkylamine. 
   
   
       13 . The method of  claim 12 , wherein the enantiomerically enriched naphthylalkylamine used in step (a) comprises recovered naphthylalkylamine from step (c). 
   
   
       14 . The method of  claim 1 , wherein said step (b) comprises racemizing at least a portion of the second enantiomer in the separated solution by contacting the second enantiomer with a base. 
   
   
       15 . The method of  claim 14 , wherein the mixture of the compound of formula (I) used in said step (a) comprises racemized compound of formula (I). 
   
   
       16 . The method of  claim 1 , wherein the compound of formula (I) is 4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid. 
   
   
       17 . The method of  claim 1 , wherein said first enantiomer has the (−)-configuration. 
   
   
       18 . The method of  claim 1 , wherein the naphthylalkylamine has the formula (II): 
     
       
         
         
             
             
         
       
     
     wherein
 R 2  is alkyl; and 
 each of R 3  and R 4  is independently hydrogen or alkyl, or one of R 3  or R 4  is an amine protecting group. 
 
   
   
       19 . The method of  claim 1 , wherein the naphthylalkylamine is 1-(2-naphthyl)ethylamine. 
   
   
       20 - 32 . (canceled) 
   
   
       33 . A compound of the formula (III): 
     
       
         
         
             
             
         
       
     
     wherein
 R 2  is alkyl; and 
 each of R 3  and R 4  is independently hydrogen or alkyl, or one of R 3  or R 4  is an amine protecting group. 
 
   
   
       34 . The compound of  claim 33 , having the formula (IV): 
     
       
         
         
             
             
         
       
     
   
   
       35 . The compound of  claim 33 , having the formula (V): 
     
       
         
         
             
             
         
       
     
   
   
       36 . The compound of  claim 33 , having the formula (VI): 
     
       
         
         
             
             
         
       
     
   
   
       37 . A method for enantioselectively producing a compound of the formula (VII): 
     
       
         
         
             
             
         
       
     
     said method comprising:
 (a) contacting a mixture of a first enantiomer and a second enantiomer of a compound of formula (I): 
 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is alkyl or haloalkyl, and 
 X is halide; 
 with an enantiomerically enriched naphthylalkylamine under conditions sufficient to form a solid naphthylalkylammonium salt of said first enantiomer and decrease the ratio of the amount of free first enantiomer to the amount of free second enantiomer in the mixture; and 
 (b) separating the naphthylalkylammonium salt of the first enantiomer from the mixture 
 (c) separating the naphthylalkylamine from the first enantiomer in the naphthylalkylammonium salt to produce enantiomerically enriched compound of formula (I); 
 (d) contacting the enantiomerically enriched compound of formula (I) with a carboxylic acid activating reagent; and 
 (e) contacting the product of step (d) with a compound of the formula (R 5 O) w M wherein 
 R 5  is heteroalkyl; 
 M is hydrogen or a metal selected from the group consisting of Na, K, Li, Ca, Mg and Cs; and 
 the subscript w is the oxidation state of M; to produce the compound of formula (VII). 
 
   
   
       38 . The method of  claim 37 , wherein the carboxylic acid activating reagent is selected from the group consisting of thionyl halides, anhydrides and thioester generating reagents. 
   
   
       39 . The method any of the preceding claims, wherein R 1  is trifluoromethyl, X is chloro; and (R 5 O) w M is HOCH 2 CH 2 NHAc. 
   
   
       40 . A method for enantioselectively producing a compound of the formula (VIII): 
     
       
         
         
             
             
         
       
     
     said method comprising:
 (a) contacting a mixture of a first and second enantiomer of 4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid with (S)-(−)-1-(2-naphthyl)ethylamine to form an ammonium salt; and 
 (b) separating the ammonium salt from the solution enriched in (+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid; 
 (c) separating (S)-(−)-1-(2-naphthyl)ethylamine from (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid in the ammonium salt to produce enantiomerically enriched (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid; 
 (d) contacting enantiomerically enriched (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid with a carboxylic acid activating reagent selected from the group consisting of thionyl halides, anhydrides and thioester generating reagents; and 
 (e) contacting the product of step (d) with a HOCH 2 CH 2 NHAc to produce the compound of formula (VIII). 
 
   
   
       41 . The method of  claim 40 , wherein the compound of formula (VIII) is (−)-halofenate.