Method For The Preparation Of Cinacalcet And Intermediates And Impurities Thereof

Abstract

A method for the preparation of Cinacalcet is disclosed comprising treating (R)-1-naphthyl ethylamine with an aromatic aldehyde to form (1R)-1-(2-naphthyl)-N-(aryl methylene)ethanamine derivative of Formula (IV), which is further treated with 1-(3-halopropyl)-3-(trifluoromethyl)benzene of Formula (V) to obtain an iminium salt of Formula (VI), followed by hydrolysis to obtain Cinacalcet free base.

What is claimed is: 
     
         1 . A method for the preparation of a compound of Formula (I) or salts thereof, 
       
         
           
           
               
               
           
         
         the method comprising:
 a. reacting a compound of the Formula (II) and a compound of Formula (III) to form a compound of Formula (IV); 
 
       
       
         
           
           
               
               
           
         
         wherein 
         Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, and nitro groups;
 b. treating the compound of Formula (IV) obtained from step (a) with a compound of Formula (V) to form a compound of Formula (VI); 
 
       
       
         
           
           
               
               
           
         
         wherein; 
         Ar is as described above, 
         X is chloro, bromo or iodo; and
 c. treating the compound of Formula (VI) with water and/or acid solution to obtain a compound of Formula (I) or salts thereof. 
 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method according to  claim 1 , wherein the step (a) is carried out at a temperature from about 10° C. to 150° C. 
     
     
         3 . The method according to  claim 2  wherein the step (a) is carried out in the presence of a solvent. 
     
     
         4 . The method according to  claim 3 , wherein the solvent is selected from the group consisting of hydrocarbons, alcohols, C 1 -C 10  ether, C 5 -C 8  cyclic ether, C 2 -C 10  aliphatic ester, C 2 -C 8  aliphatic amides, sulfoxide, C 1 -C 8  chlorinated hydrocarbon, 1-ethyl-3-methyl imidazolium ethylsulfate, and mixtures thereof. 
     
     
         5 . The method according to  claim 1  wherein, the compound of Formula (III) is selected from benzaldehyde, salisaldehyde, p-hydroxyl benzaldehyde, o-chlorobenzaldehyde, p-methoxy benzaldehyde, o-methoxy benzaldehyde, and p-nitrobenzaldehyde. 
     
     
         6 . The method according to  claim 1 , further comprising isolating the compound of Formula (I) or a salt thereof in a crystalline form. 
     
     
         7 . The method according to  claim 1 , wherein the step (b) is carried out at a temperature of 80° C. to 180° C. 
     
     
         8 . The method as according to  claim 7 , wherein the step (b) is carried out in the presence of a solvent. 
     
     
         9 . The method according to  claim 8 , wherein the solvent is selected from the group consisting of hydrocarbons, alcohols, C 1 -C 10  ethers, C 5 -C 8  cyclic ethers, C 2 -C 10  aliphatic esters, C 2 -C 8  aliphatic amides, sulfoxides, C 1 -C 8  chlorinated hydrocarbons, 1-ethyl-3-methyl imidazolium ethyl sulfate, and mixtures thereof. 
     
     
         10 . The method according to  claim 1 , wherein the step (c) is carried out at a temperature of about 20° C. to 60° C. 
     
     
         11 . The method according to  claim 10 , wherein the step (c) is carried out in the presence of a solvent. 
     
     
         12 . The method according to  claim 11 , wherein the solvent is selected from the group consisting of hydrocarbons, alcohols, C 1 -C 10  ethers, C 5 -C 8  cyclic ethers, C 2 -C 10  aliphatic esters, C 2 -C 8  aliphatic amides, sulfoxides, C 1 -C 8  chlorinated hydrocarbons, 1-ethyl-3-methyl imidazolium ethyl sulfate, and mixtures thereof. 
     
     
         13 . The method according to  claim 1 , further comprising isolation of the compound of Formula (I) or salts thereof by:
 I. cooling the reaction mass of step (c) and diluting it with water and a water-immiscible organic solvent;   II. adjusting the pH of the reaction mixture of Step I to a pH of about 10;   III. separating the organic layer comprising the compounds of Formula (I) or salts thereof, Formula (II) and Formula (III), from the aqueous layer comprising the compound of Formula (V);   IV. washing the organic layer separated in Step III with water;   V. further washing the organic layer of Step IV with a solution of sodium meta-bisulphite to remove the compound of Formula (III);   VI. diluting the organic layer of Step V with water and adjusting the pH to about 1 to about 5;   VII. separating the organic layer of Step VI comprising the compound of Formula (I) or salts thereof from the aqueous layer comprising the compound of Formula (II);   VIII. washing the organic layer obtained from Step VII with water and adjusting the pH of the organic layer to about 8 to about 10; and   IX. separating the organic layer mostly comprising the compound of Formula (I) or a salt thereof, and recovering the compound of Formula (I) or salt thereof by removing the solvent from the organic layer.   
     
     
         14 . The method according to  claim 13 , wherein the water-immiscible organic solvent is selected from the group consisting of hydrocarbons, esters, ethers, chlorinated hydrocarbons and mixtures thereof. 
     
     
         15 . The method according to  claim 1 , further comprising isolation of a hydrochloride salt of the compound of Formula (I) by
 I. cooling the reaction mass of step (c) and diluting it with water and a water-immiscible organic solvent;   II. adjusting the pH of the reaction mixture of step I to a pH of around 10;   III. separating the organic layer comprising the compounds of Formula (I) or salts thereof, Formula (II) and Formula (III), from the aqueous layer comprising the compound of Formula (V);   IV. washing the organic layer separated in step III with water;   V. further washing the organic layer of step IV with a solution of sodium metabisulfite to remove the compound of Formula (III);   VI. diluting the organic layer of step V with water and adjusting the pH to about 1 to about 5 by adding hydrochloric acid to obtain a hydrochloride salt of the compound of Formula (I);   VII. separating the organic layer of step VI and further washing it with water; and   VIII. removing the solvent from the organic layer to obtain a hydrochloride salt of the compound of Formula (I).   
     
     
         16 . The method according to  claim 15 , wherein the water-immiscible solvent is selected from the group consisting of hydrocarbons, esters, ethers, chlorinated hydrocarbons, and mixtures thereof. 
     
     
         17 . A method of preparing a compound of Formula (I) or a salt thereof, comprising reacting a compound of Formula (IV) to produce the compound of Formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, and nitro groups. 
       
     
     
         18 . A compound of the Formula (VI), 
       
         
           
           
               
               
           
         
         wherein, 
         Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, or nitro group; and 
         X is chloro, bromo or iodo. 
       
     
     
         19 . A method of preparing the compound of  claim 18 , comprising
 a. reacting a compound of Formula (II) and a compound of Formula (III) to obtain a compound of Formula (IV);   
       
         
           
           
               
               
           
         
       
       wherein 
       Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, and nitro groups; and
 b. treating the compound of Formula (IV) with a compound of Formula (V) to obtain a compound of Formula (VI), 
 
       
         
           
           
               
               
           
         
       
       wherein 
       Ar is as defined above, and 
       X is chloro, bromo, or iodo. 
     
     
         20 . The method according to  claim 19 , wherein the step (a) is carried out at a temperature of 10° C. to 150° C. 
     
     
         21 . The method according to  claim 20 , wherein the step (a) is carried out in the presence of a solvent. 
     
     
         22 . The method according to  claim 21 , wherein the solvent is selected from the group consisting of a hydrocarbons, alcohols, C 1 -C 10  ethers, C 5 -C 8  cyclic ethers, C 2 -C 10  aliphatic esters, C 2 -C 8  aliphatic amides, sulfoxides, C 1 -C 8  chlorinated hydrocarbons, 1-ethyl-3-methyl imidazolium ethylsulfate, and mixtures thereof. 
     
     
         23 . The method according to  claim 19 , wherein the compound of Formula (III) is selected from benzaldehyde, salisaldehyde, p-hydroxy benzaldehyde, o-chlorobenzaldehyde, p-methoxy benzaldehyde, o-methoxy benzaldehyde, and p-nitrobenzaldehyde. 
     
     
         24 . A method of preparing a compound of Formula (I) or a salt thereof, comprising reacting the compound of  claim 18  to produce the compound of Formula (I).