Process for Preparing Ethyl (s)-2-Ethoxy-4-[N-[1-(2-Piperidinophenyl)-3-Methyl-1-Butyl]Aminocarbonyl Methyl]Benzoate and Use Thereof for the Preparation of Repaglinide

Abstract

Described herein is an improved, commercially viable and industrially advantageous process for the preparation of Repaglinide intermediate, ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate. The process provides the Repaglinide intermediate in higher yield and purity compared to the previously disclosed processes, thereby providing for production of Repaglinide and its pharmaceutically acceptable salts in high purity and in high yield.

We claim: 
     
         1 . A method comprising:
 reacting (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine of formula II:   
       
         
           
           
               
               
           
         
         or a salt thereof with a protected carboxylic acid of formula III: 
       
       
         
           
           
               
               
           
         
         in the presence of a dehydrating agent and a suitable solvent to produce substantially pure compound of formula I or a salt thereof; and 
       
       
         
           
           
               
               
           
         
       
       deprotecting the substantially pure compound of formula I or a salt thereof to form repaglinide or a pharmaceutically acceptable salt thereof
 wherein the dehydrating agent is boric acid, a boric acid derivative, or a combination thereof, and 
 wherein R is a protecting group. 
 
     
     
         2 . The method of  claim 1 , wherein the protecting group R is methyl, ethyl, tert-butyl, benzyl, p-nitrobenzyl, or p-methoxybenzyl. 
     
     
         3 . The method of  claim 1 , wherein the protecting group R is ethyl. 
     
     
         4 . The process of  claim 1 , wherein the boric acid derivative is an aryl or a substituted aryl boronic acid. 
     
     
         5 . The process of  claim 4 , wherein the boric acid derivative is selected from the group consisting of phenylboronic acid, 2-chlorophenylboronic acid, 2-nitrophenyl boronic acid, 3-nitrophenylboronic acid, 4-nitrophenylboronic acid, 2-carboxyphenyl boronic acid, 2-chloro-4-carboxyphenylboronic acid, 2-chloro-5-carboxyphenylboronic acid, 3-chloro-4-carboxyphenylboronic acid, 2-chloro-4-fluorophenylboronic acid, 4-chloro-2-fluorophenylboronic acid, 2-chloro-4-methylphenylboronic acid, 2-chloro-5-methylphenylboronic acid, 2-chloro-3-methylpyridine-5-boronic acid, and naphthyl boronic acid. 
     
     
         6 . The process of  claim 1 , wherein the solvent is selected from the group consisting of hydrocarbons, ketone, cyclic ethers, aliphatic ethers, nitriles, alkanes and mixtures thereof. 
     
     
         7 . The process of  claim 1 , wherein the solvent is selected from the group consisting of toluene, benzene, xylene, acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, hexane, heptanes, cyclohexane, methylene chloride, dimethyl formamide and mixtures thereof 
     
     
         8 . The process of  claim 7 , wherein the solvent is toluene, methylene chloride, tetrahydrofuran, acetonitrile or dimethylformamide. 
     
     
         9 . The process of  claim 8 , wherein the solvent is toluene. 
     
     
         10 . The process of  claim 1 , wherein the reaction is carried out at a temperature of- 25° C. to the reflux temperature of the solvent. 
     
     
         11 . The process of  claim 1 , wherein the compound of formula I obtained has a purity greater than 99% as measured by HPLC. 
     
     
         12 . The process of  claim 1 , wherein the compound of formula I obtained has a purity greater than 99.9% as measured by HPLC.