Process for the preparation of chirally pure nateglinide

Abstract

The invention relates to N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide) in the novel crystalline form “G” and a process for the preparation thereof. A process for the preparation of chirally pure nateglinide by treating a lower alkyl ester thereof with a base to yield an alkali salt and liberating the product from said salt by proper addition of an acid, is also provided. Still another aspect of the invention is a process for the preparation of nateglinide in the crystalline form “H” from other crystalline modifications of nateglinide.

1 - 11 . (canceled) 
     
     
         12 . A process for the preparation of crystalline modification “H” of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide) of the formula (I) 
       
         
           
           
               
               
           
         
       
       which comprises the steps of:
 (a) treating a compound of the formula (II) 
 
       
         
           
           
               
               
           
         
       
       to wherein R is a lower (C 1 -C 4 ) alkyl group or hydrogen, with a base to yield an alkali salt, and
 (b) acidifying the alkali salt with an acid, at a temperature above room temperature, to obtain the desired product. 
 
     
     
         13 . The process for the preparation of crystalline modification “H” of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide) according to  claim 12 , wherein according to step (a), a water-miscible organic solvent is employed. 
     
     
         14 . The process for the preparation of crystalline modification “H” of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide) according to  claim 13 , wherein the water-miscible organic solvent is aqueous methanol. 
     
     
         15 . The process for the preparation of crystalline modification “H” of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide) according to  claim 14  wherein the aqueous methanol is methanol containing 20-50% water by volume. 
     
     
         16 . The process for the preparation of crystalline modification “H” of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide) according to  claim 12 , wherein according to step (b) the acidification temperature is in the temperature range of 65° C. to 70° C. 
     
     
         17 . A process for the preparation of nateglinide in the crystalline modification “H” form, which comprises the step of
 boiling another crystalline modification of nateglinide having a lower melting point or a mixture of such modifications in an alkane, for a time sufficient to provide the nateglinide in the stable “H” crystalline form.   
     
     
         18 . The process for the preparation of nateglinide in the crystalline modification “H” form defined in  claim 17  wherein the alkane is n-hexane or n-heptane. 
     
     
         19 . The process for the preparation of nateglinide in the crystalline modification “H” form defined in  claim 17  wherein, the crystalline modification of nateglinide having a lower melting point is crystalline modification “G” form having the following characteristics:
 (a) a melting point of 100 to 109° C.;   (b) an infra-red spectrum with intensive bands at 1763, 1735, 1614, 1533, 1180, 750, 574 and 491 cm −1 ; and   (c) a Raman spectrum with intensive bands at 1762, 1710, 1182 and 822 cm −1 , is employed as starting material.   
     
     
         20 . A process for the preparation of nateglinide in the crystalline modification “H” form, which comprises the steps of:
 (a) treating a compound of the formula (II)   
       
         
           
           
               
               
           
         
       
       wherein R is a lower (C1-C4) alkyl group or hydrogen, with a base at 20 to 25° C. to yield an alkali salt;
 (b) liberating the product of the Formula (I) from the acid salt with an acid, wherein the acidic liberation of the product is carried out by acidifying the alkali salt in a temperature range of 10 to 15° C. with a first portion of acid to form a suspension, which is then stirred at 13 to 18° C. for 30 minutes, filtered to form a filter cake, washing the filter cake with a methanol/water mixture and then water, dissolving the filter cake in methanol at 25 to 30° C. to form a solution, cooling the solution to 15° C., and again acidifying the solution so that after acidifying the solution again, the pH of the solution is 2 to 3, stirring the solution and adding water at a temperature of 5° C. to the solution to obtain a precipitate, and drying the precipitate at 30 to 35° C. to obtain the crystal modification “G:” form product having the following characteristics: 
 (i) a melting point of 100 to 109° C.; 
 (ii) an infra-red spectrum with intensive bands at 1763, 1735, 1614, 1533, 1180, 750, 574 and 491 cm −1 ; and 
 (iii) a Raman spectrum with intensive bands at 1762, 1710, 1182 and 822 cm −1 ; and 
 (c) boiling the crystal modification “G” Form in an alkane for a time sufficient to provide the nateglinide in the stable “H” crystalline form. 
 
     
     
         21 . The process for the preparation of nateglinide in the crystalline modification “H” form defined in  claim 20  wherein according to step (c) the alkane is n-hexane or n-heptane. 
     
     
         22 . A process for the preparation of chirally pure N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (nateglinide) of the formula (I) 
       
         
           
           
               
               
           
         
       
       from a corresponding compound of the Formula (II) that is less chirally pure, 
       
         
           
           
               
               
           
         
       
       wherein R is a lower (C 1 -C 4 ) alkyl group or hydrogen, which comprises the steps of
 (a) treating the less chirally pure compound of the Formula (II) with a base to yield an alkali salt, 
 (b) liberating the chirally pure compound of the Formula (I) from the salt with a mineral acid, wherein the acidic liberation of the compound of the Formula (I) is accomplished by adding the acid to the alkali salt in two portions in such a way that the first time less than equimolar amount of the acid is added to yield a mixture of nateglinide and an alkali salt thereof, the mixture is isolated and a further amount of mineral acid is added to the mixture; 
 (c) filtering and washing the mixture containing the compound of the Formula (I); and 
 (d) boiling the mixture in an alkane to obtain the chirally pure compound of the Formula (I) having an enantiomeric impurity level of below 0.1%. 
 
     
     
         23 . The process for the preparation of chirally pure N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (nateglinide) of the formula (I) defined in  claim 22  wherein according to step (d) the alkane is n-heptane and the boiling is carried out at 150° C.