Preparation of candesartan cilexetil

Abstract

The invention encompasses processes for the synthesis of cilexetil trityl candesartan from the reaction of trityl candesartan with cilexetil halide in the presence of a base and a low boiling organic solvent. Optionally, the reaction may be conducted in the presence of a phase transfer catalyst.

1 - 18 . (canceled)  
   
   
       19 . A method of synthesizing cilexetil candesartan comprising: 
 reacting cilexetil trityl candesartan with at least one organic acid to form cilexetil candesartan in at least one organic solvent; and    isolating the crude cilexetil candesartan.    
   
   
       20 . The method according to  claim 19 , further comprising neutralizing the excess acid in the reaction mixture with at least one base, before isolating the crude cilexetil candesartan.  
   
   
       21 . The method according to  claim 19 , further comprising adding mineral acid.  
   
   
       22 . The method according to  claim 19 , wherein the organic acid is selected from the group consisting of: methanesulfonic acid, formic acid, pyridine p-toluene sulphonic acid, trifluoroacetic acid, trichloroacetic acid, or acetic acid.  
   
   
       23 . The method according to  claim 19 , wherein the method is carried out at a reaction temperature of about 15° C. to about 60° C.  
   
   
       24 . The method according to  claim 19 , wherein the organic solvent is substantially dry.  
   
   
       25 . The method according to  claim 24 , wherein the substantially dry organic solvent has less than about 3% by weight of water.  
   
   
       26 . The method according to  claim 25 , wherein the substantially dry organic solvent has less than about 0.5% by weight of water.  
   
   
       27 . The method according to  claim 19 , wherein the substantially dry organic solvent is an C 1 -C 4  alkyl alcohol, ketone, ether, hydrocarbon, or chlorinated solvent.  
   
   
       28 . The method according to  claim 27 , wherein the substantially dry organic solvent is dichloromethane, methanol, toluene, or tert-butyl methyl ether.  
   
   
       29 . The method according to  claim 19 , wherein more than one solvent is used.  
   
   
       30 . The method according to  claim 29 , wherein the ratio of first to second solvents is from about 1:10 to about 10:1.  
   
   
       31 . The process according to  claim 20 , wherein the base is at least one of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) or NaOH.  
   
   
       32 . The process according to  claim 31 , wherein the base is NaOH.  
   
   
       33 . A method of synthesizing cilexetil candesartan comprising: 
 reacting cilexetil trityl candesartan with methanol to form cilexetil candesartan; and    isolating the crude cilexetil candesartan.    
   
   
       34 . The method of  claim 33 , wherein the reaction takes place without an acid.  
   
   
       35 . A method of synthesizing cilexetil candesartan without an acid comprising: deprotecting cilexetil trityl candesartan to form cilexetil candesartan.  
   
   
       36 . The method of  claim 35 , further comprising crystallizing the cilexetil candesartan.  
   
   
       37 . The process according to  claim 33 , further comprising adding at least one organic solvent.  
   
   
       38 . The process according to  claim 33 , further comprising adding water.  
   
   
       39 . The process according to  claim 33 , wherein the process is carried out at a reaction temperature of about 30° C. to about 90° C.  
   
   
       40 . The process according to  claim 39 , wherein the process is carried out at a reaction temperature of about 50° C. to about 90° C.  
   
   
       41 . (canceled)  
   
   
       42 . The method according to  claim 19  further comprising crystallizing the crude candesartan cilexetil in a solvent system to obtain crystalline candesartan cilexetil.  
   
   
       43 . The method according to  claim 42 , wherein the solvent system is C 1 -C 6  alcohol and aromatic compound.  
   
   
       44 . The method according to  claim 43 , wherein the C 1 -C 6  alcohol is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol and 3-pentanol.  
   
   
       45 . The method according to any of  claim 44 , wherein the C 1 -C 6  alcohol is methanol.  
   
   
       46 . The method according to  claim 43 , wherein the aromatic compound is selected from the group consisting of: benzene, toluene, ethyltoluene, xylene or mesitylene.  
   
   
       47 . The method according to  claim 46 , wherein the aromatic compound is toluene.  
   
   
       48 . The method according to  claim 43 , wherein ratio the between the C 1 -C 6  alcohol to the aromatic compound is from about 20% to about 80% by weight.  
   
   
       49 . The method according to  claim 48 , wherein ratio the between the C 1 -C 6  alcohol to the aromatic compound is from about 10% to about 90% by weight.  
   
   
       50 . The method according to  claim 49 , wherein ratio the between the C 1 -C 6  alcohol to the aromatic compound is from about 5% to about 95% by weight.  
   
   
       51 . The method according to  claim 43 , further comprising recrystallizing the crystalline candesartan cilexetil in a solvent to obtain pure candesartan cilexetil.  
   
   
       52 . The method according to  claim 51 , wherein the solvent is a C 1 -C 6  alcohol.  
   
   
       53 . The method according to  claim 52 , wherein the C 1 -C 6  alcohol is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol and 3-pentanol.  
   
   
       54 . The method according to  claim 51 , further comprising drying the pure candesartan cilexetil.  
   
   
       55 - 61 . (canceled)