Methods for producing nateglinide crystals

Abstract

There is provided methods for producing nateglinide crystals, which comprises the steps of adding an acid(s) to a reaction mixture containing nateglinide to make it acidic, the reaction mixture being obtained by reacting trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent of ketone solvent and water in the presence of an alkali; and then adjusting the temperature of the mixture to 58° C. to 72° C. and the concentration of ketone solvent to more than 8 wt % and less than 22 wt % to conduct precipitation of nateglinide crystals. This producing method is the industrially beneficial methods for crystallization of nateglinide.

1 - 13 . (canceled) 
   
   
       14 . Nateglinide crystals produced by a method comprising:
 (a) mixing one or more acids with a first reaction mixture, said first reaction mixture comprising nateglinide, to obtain a second reaction mixture which is acidic, wherein said first reaction mixture is obtained by reacting trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent comprising a ketone solvent and water in the presence of an alkali; and   (b) adjusting the temperature of said second reaction mixture to 58° C. to 72° C. and the concentration of ketone solvent to more than 8 wt % and less than 22 wt % to effect precipitation of nateglinide crystals.   
   
   
       15 . The nateglinide crystals according to  claim 14 , wherein the crystals have an average long axis of 1 mm or more and an average short axis of 0.1 mm or more. 
   
   
       16 . The nateglinide crystals according to  claim 14 , wherein the crystals are H-type crystals. 
   
   
       17 . H-type crystals of nateglinide, produced by a process comprising:
 (a) mixing one or more acids with a first reaction mixture, said first reaction mixture comprising nateglinide, to obtain a second reaction mixture which is acidic, wherein said first reaction mixture is obtained by reacting trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent comprising acetone and water in the presence of an alkali; and   (b) adjusting the temperature of said second reaction mixture to 58° C. to 72° C. and the concentration of said acetone to more than 8 wt % and less than 22 wt % to effect precipitation of nateglinide crystals.   
   
   
       18 . The nateglinide crystals according to  claim 17 , wherein the crystals have an average long axis of 1 mm or more and an average short axis of 0.1 mm or more.