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.

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       13 . A process for the preparation of candesartan cilexetil which comprises:
 i. transesterification or esterification of the tetrazolyl protected candesartan derivative or the tetrazolyl protected candesartan in its acid form into tetrazolyl protected candesartan cilexetil,   ii. treating a tetrazolyl protected candesartan cilexetil with a Lewis acid selected from the group consisting of boron trifluoride, aluminium trihalide and zinc dihalide in a suitable organic solvent or in a mixture of suitable organic solvents,   iii. adding a second solvent, preferably water, and heating the reaction mixture,   iv. isolation of the obtained candesartan cilexetil.   
   
   
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       15 . A process in according to any of  claims 13  and  14 , characterized in that 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 . A process according to any of  claims 13  and  14 , characterized in that the reaction mixture is heated at a temperature between 0° C. and 120° C., preferably at reflux temperature, for 0.5 hours to 10 hours, preferably for 2 to 5 hours. 
   
   
       17 . A process according to any of  claims 1 ,  13  and  14 , characterized in that alchohols, acetates, ethers, amides, nitriles and mixtures thereof are used as suitable organic reaction solvents. 
   
   
       18 . A process according to  claim 17 , characterized in that methanol is used as the reaction solvent in step (ii). 
   
   
       19 . A process according to any of  claims 1 ,  13  and  14 , characterized in that isolation of the obtained candesartan cilexetil includes crystallization, precipitation, lyophilization, extraction, including extractions under super-critical conditions or by the use of pressurized gasses, spray-drying or any other procedure known to the person skilled in the art. 
   
   
       20 . A process according to  claims 1 ,  13  and  14 , charaterized in that candesartan cilexetil containing less than 5000 ppm residual solvents is obtained. 
   
   
       21 . Candesartan cilexetil prepared according to a process of any of  claims 1  to  20 , which is 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. 
   
   
       22 . Candesartan cilexetil according to  claim 21  characterized in that it comprises an amount of 2-oxo impurities not greater than 0.10%, preferably not greater than 0.05% (w/w). 
   
   
       23 . A process according to any of  claims 1  to  20 , characterized in that the amount of the 2-oxo-candesartan cilexetil in the reaction mixture is less than 2%. 
   
   
       24 . Candesartan cilexetil prepared according to process of any of  claims 1  to  20 , wherein said process starts from tetrazolyl-protected candesartan cilexetil comprising not more than 0.15%, preferably not more than 0.10% of a tetrazolyl protected or unprotected candesartan derivative. 
   
   
       25 . Candesartan cilexetil of  claim 24  wherein the tetrazolyl unprotected 
     
       
         
         
             
             
         
       
     
     candesartan derivative is the ethyl ester of candesartan of formula (IV). 
   
   
       26 . Candesartan cilexetil of  claim 25  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%.