Process for the preparation of candesartan cilexetil

Abstract

The present invention provides an improved synthesis for the manufacture of candesartan and pharmaceutically acceptable salts and esters thereof as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions which comprises the removal of the tetrazolyl protecting group in an organic solvent, and in the presence of a Lewis acid.

1 . Candesartan cilexetil of formula (I) prepared by a process comprising:
 i. deprotection of the triphenylmethane (trityl) of (+/−)-1-[[(cyclohexyloxy) carbony]oxy]-ethyl-2-ethoxy-1-[[2′-(N′-triphenyl-methyltetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (trityl candesartan cilexetil) in an organic solvent and in the presence of a Lewis acid selected from the group consisting of boron trifluoride, aluminum trihalide and zinc dihalide;   ii. adding a second solvent and heating the reaction mixture; and   iii. isolation of the obtained candesartan cilexetil of formula (I), which is substantially free of 2-oxo impurities of structural formula (II):   
       
         
           
           
               
               
           
         
       
       wherein R 1  is: alkyl or alkylaryl, such as methyl, ethyl, benzyl etc.; and R 2  is H or a tetrazolyl protecting group, such as e.g. the triphenylmethyl protection group. 
     
     
         2 . Candesartan cilexetil according to  claim 1 , wherein the protecting group triphenylmethane(trityl) is the triphenylmethyl (triyl) protecting group. 
     
     
         3 . Candesartan cilexetil according to  claim 1 , wherein the organic solvent is a solvent or a solvent mixture selected from the group of alcohols, acetates, ethers, amides, nitriles, halogenated hydrocarbons, ketones, alkanes, cycloalkanes, aromatic hydrocarbons and organic carbonates. 
     
     
         4 . Candesartan cilexetil according to  claim 1 , wherein the solvent mixture consists of a polar solvent and an unpolar solvent. 
     
     
         5 . Candesartan cilexetil according to  claim 1 , wherein the polar solvent is chosen from the group of alcohols, amides, ketones, and nitriles. 
     
     
         6 . Candesartan cilexetil according to  claim 4 , wherein the unpolar solvent is selected from the group consisting of halogenated hydrocarbons, alkanes, cycloalkanes, aromatic hydrocarbons and organic carbonates. 
     
     
         7 . Candesartan cilexetil according to  claim 4 , wherein the polar organic solvent is methanol. 
     
     
         8 . Candesartan cilexetil according to  claim 4 , wherein the unpolar organic solvent is methylene chloride. 
     
     
         9 . Candesartan cilexetil according to  claim 4 , wherein the reaction is carried out at temperature between 20° C. to 100° C. 
     
     
         10 . Candesartan cilexetil according to  claim 1 , wherein the Lewis acid is zinc dichloride. 
     
     
         11 . Candesartan cilexetil according to  claim 1 , wherein the Lewis acid is boron trifluoride. 
     
     
         12 . Candesartan cilexetil according to  claim 1 ,  10  or  11 , wherein the Lewis acid is added in an amount between 0.4 to 1.5 equivalents, preferably in an amount between 0.6 to 1.2 equivalents, most preferably an amount between 0.7 to 1.0 equivalents. 
     
     
         13 . Candesartan cilexetil prepared by the process of:
 i. transesterification or esterification of the trityl candesartan cilexetil-or the trityl candesartan cilexetil in its acid form into trityl candesartan cilexetil;   ii. treating trityl candesartan cilexetil with a Lewis acid selected from the group consisting of boron trifluoride, aluminium trihalide and zinc dihalide in a organic solvent or in a mixture of organic solvents;   iii. adding a second solvent, preferably water, and heating the reaction mixture; and   iv. isolation of the obtained candesartan cilexetil.   
     
     
         14 . Candesartan cilexetil prepared by the process of:
 i. treating (+/−)-1-[[(cyclohexyloxy)carbonyl]oxy]-ethyl-2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)-1, biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (trityl candesartan cilexetil) with a Lewis acid selected from the group consisting of boron trifluoride, aluminum trihalide and zinc dihalide in a organic solvent or in the mixture of the organic solvents;   ii. Adding a second solvent, preferably water, and heating the reaction mixture; and   iv. isolation of the obtained candesartan cilexetil.   
     
     
         15 . The candesartan cilexetil of  claim 13  or  14 , wherein the second solvent of step (iii), preferably water, is added in an amount between 0% (v/v) and 10% (v/v), preferably between 1 and 5%. 
     
     
         16 . Candesartan cilexetil of  claim 13  or  14 , wherein the reaction mixture is heated at a temperature between 0° C. and 120° C., preferably a reflux temperature, for 0.5 hours to 10 hours, preferably for 2 to 5 hours. 
     
     
         17 . The candesartan cilexetil of  claim 1 ,  13  or  14 , wherein alcohols, acetates, ethers, amides, nitriles and mixtures thereof are used as organic reaction solvents. 
     
     
         18 . The candesartan cilexetil of  claim 17 , wherein the methanol is used as the reaction solvent in step (ii). 
     
     
         19 . The candesartan cilexetil of  claim 1 ,  13  or  14 , wherein the isolation of the obtained candesartan cilexetil includes crystallization, precipitation, lyophilization, extraction, including extractions under super-critical conditions or by the used of pressurized gasses, spray-dying or any other procedure known to the person skilled in the art. 
     
     
         20 . The candesartan cilexetil of  claim 1 ,  13  or  14 , wherein the candesartan cilexetil contains less than 5000 ppm residual solvents. 
     
     
         21 . Candesartan cilexetil according to  claim 1  characterized in that it comprises an amount of 2-oxo impurities of structural formula (II) not greater than 0.10%, preferably not greater than 0.05% (w/w). 
     
     
         22 . Candesartan cilexetil of  claim 1  or  13 , which is substantially free of a tetrazolyl protected or unprotected candesartan derivative. 
     
     
         23 . Candesartan cilexetil of  claim 22  wherein the tetrazolyl unprotected candesartan derivative is the ethyl ester of candesartan of formula (IV). 
       
         
           
           
               
               
           
         
       
     
     
         24 . Candesartan cilexetil of  claim 23  characterized in that it comprises an amount of the ethyl ester of candesartan of formula (IV) not greater than 0.15%, preferably not greater than 0.10%.