Method for preparing dipeptidyl peptidase-iv inhibitor and intermediate

Abstract

The present invention relates to an improved method for preparing dipeptidyl peptidase-IV inhibitor and intermediate. The present invention is able to reduce preparation costs by using low cost reagents on reaction and is able to be used in mass production by improving yield.

1 . A method for preparing an intermediate of dipeptidyl peptidase-IV inhibitor represented by Chemical Formula 2, as shown in the following Reaction Formula 1, the method comprising:
 (Step a) preparing a compound represented by Chemical Formula 6 by ring-opening of epoxide ring using Grinard reagent in a compound represented by Chemical Formula 5;   (Step b) preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 with sodium azide;   (Step c) preparing a compound represented by Chemical Formula 8 by reacting the compound represented by Chemical Formula 7 with triphenylphosphine;   (Step d) preparing a compound represented by Chemical Formula 9 by ring-opening of aziridine ring using a cyanogen-based reagent in the compound represented by Chemical Formula 8; and   (Step e) preparing a compound represented by Chemical Formula 2 by hydrolyzing the compound represented by Chemical Formula 9 using a base;   
       
         
           
           
               
               
           
         
         (In the above Reaction Formula 1, X is a halogen and PG is a protecting group.) 
       
     
     
         2 . The method as set forth in  claim 1 , wherein the amine-protecting group is selected from the group consisting of butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl, and tosyl. 
     
     
         3 . A derivative represented by the following Chemical Formula 8, wherein the derivative is produced when producing the compound represented by Chemical Formula 2 as set forth in  claim 1 : 
       
         
           
           
               
               
           
         
         (In the above Chemical Formula 8, PG is a protecting group.) 
       
     
     
         4 . A derivative represented by the following Chemical Formula 9, wherein the derivative is produced when producing the compound represented by Chemical Formula 2 as set forth in  claim 1 : 
       
         
           
           
               
               
           
         
         (In the above Chemical Formula 9, PG is a protecting group.) 
       
     
     
         5 . A method for preparing an intermediate of dipeptidyl peptidase-IV inhibitor represented by Chemical Formula 3, as shown in the following Reaction Formula 2, the method comprising:
 (Step a′) preparing a compound represented by Chemical Formula 11 by introducing t-butoxy group to hydroxyl group of a compound represented by Chemical Formula 10; and   (Step b′) preparing a compound represented by Chemical Formula 3 by inducing a cyclization by reacting the compound represented by Chemical Formula 11 with ethylene diamine;   
       
         
           
           
               
               
           
         
       
     
     
         6 . An improved method for preparing dipeptidyl peptidase-IV inhibitor represented by Chemical Formula 1, as shown in the following Reaction Formula 3, the method comprising:
 (Step 1) preparing a compound represented by Chemical Formula 4 by bonding a compound represented by Chemical Formula 2 and a compound represented by Chemical Formula 3 with peptide bond by reacting them using triphenylphosphine, bis(2,2′-benzothiazolyl)disulfide, and a base in the presence of a reaction solvent; and   (Step 2) preparing a compound represented by Chemical Formula 1 by removing an amine-protecting group of the compound represented by Chemical Formula 4 produced in the above Step 1;   
       
         
           
           
               
               
           
         
         (In the above Reaction Formula 3, PG is a protecting group.) 
       
     
     
         7 . The improved method as set forth in  claim 6 , wherein the reaction solvent is selected from the group consisting of toluene, tetrahydrofuran, methylene chloride, acetonitrile, and N,N-dimethylformamide. 
     
     
         8 . The improved method as set forth in  claim 6 , wherein the base is more than one selected from the group consisting of N-methyl morpholine, isopropylethylamine, triethylamine, and pyridine. 
     
     
         9 . The improved method as set forth in  claim 6 , wherein the reaction of the above Step 1 is performed at −20° C. to 80° C. 
     
     
         10 . The improved method as set forth in  claim 6 , wherein the amine-protecting group is selected from the group consisting of butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl, and tosyl. 
     
     
         11 . The improved method as set forth in  claim 6 , wherein in the Step 2, when the amine-protecting group is butoxycarbonyl (Boc), the amine-protecting group is removed by reacting the compound represented by Chemical Formula 4 with trifluoroacetic acid/dichloromethane, ethyl acetate/hydrogen chloride, diethylether/hydrogen chloride, hydrogen chloride/dichloromethane or methanol/hydrogen chloride. 
     
     
         12 . The improved method as set forth in  claim 6 , wherein in the Step 2, when the amine-protecting group is benzyloxycarbonyl (Cbz), the amine-protecting group is removed by reacting the compound represented by Chemical Formula 4 with hydrogen in the presence of palladium/carbon.