Process for making amlodipine, derivatives thereof, and precursors therefor

Abstract

Purification of the phthalimidoamlodipine intermediate, especially by recrystallization, can provide an easier route to obtaining pharmaceutically pure amlodipine or its salts.

1 . A process for producing amlodipine, which comprises: 
 (a) isolating in a solid state a compound of formula (2a) from a reaction mixture                          (b) recrystallizing said compound of formula (2a) from a solvent to form a purified compound of formula (2a); and    (c) deprotecting said purified compound of formula (2a) to form amlodipine.    
   
   
       2 . The process according to  claim 1 , wherein said recrystallization step (b) achieves a purity of at least 98%.  
   
   
       3 . The process according to  claim 2 , wherein said recrystallization step (b) achieves a purity of at least 99%.  
   
   
       4 . The process according to  claim 3 , wherein said recrystallization step (b) achieves a purity of at least 99.5%.  
   
   
       5 . The process according to  claim 1 , wherein said recrystallizing is carried out from a solvent selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol, and mixtures of two or more thereof.  
   
   
       6 . The process according to  claim 5 , wherein said solvent is ethyl acetate.  
   
   
       7 . The process according to  claim 6 , wherein said recrystallization step (b) achieves a purity of at least 99%.  
   
   
       8 . The process according to  claim 1 , wherein said isolating step comprises precipitating said compound of formula (2a) from acetic acid to obtain said compound of formula (2a) in solid state.  
   
   
       9 . The process according to  claim 1 , which further comprises forming said compound of formula (2a) in said reaction mixture by reacting a compound of formula (3a)  
     
       
         
         
             
             
         
       
     
     with a compound of formula (B 1)  
     
       
         
         
             
             
         
       
     
     in a suitable solvent.  
   
   
       10 . The process according to  claim 9 , wherein said suitable solvent is isopropanol.  
   
   
       11 . The process according to  claim 9 , wherein said recrystallization step (b) achieves a purity of at least 99%.  
   
   
       12 . The process according to  claim 11 , wherein said recrystallizing is carried out from a solvent selected from ethyl acetate.  
   
   
       13 . The process according to  claim 9 , which further comprises forming said compound of formula (3a) by reacting an o-chlorobenzaldehyde with a compound of formula (C1):  
     
       
         
         
             
             
         
       
     
     in an organic solvent to form said compound of formula (3a).  
   
   
       14 . The process according to  claim 13 , wherein said compound of formula (3a) is recovered from said organic solvent before being reacted with said compound of formula (B1).  
   
   
       15 . The process according to  claim 13 , wherein said solvent is isopropanol.  
   
   
       16 . The process according to  claim 1 , which further comprises converting said amlodipine into a pharmaceutically acceptable salt of amlodipine.  
   
   
       17 . In a process for making amlodipine, or a pharmaceutically acceptable salt thereof, that includes forming phthalimidoamlodipine of formula (2a)  
     
       
         
         
             
             
         
       
     
     and deprotecting it to form amlodipine of formula (1a)  
     
       
         
         
             
             
         
       
     
     the improvement for which comprises: 
 purifying said phthalimidoamlodipine by recrystallization to a purity greater than 98% before said deprotecting step.  
 
   
   
       18 . The process for making amlodipine according to  claim 17 , wherein said phthalimidoamlodipine has a purity of greater than 99% before being subjected to said deprotecting step.  
   
   
       19 . A process, which comprises the steps of: 
 (a) assaying a sample from a batch of phthalimidoamlodipine for at least one phthalimidoamlodipine impurity selected from the group consisting of compounds 2b-2f:                          (b) determining whether said at least one phthalimidoamlodipine impurity is contained in said sample below a predetermined limit; and, if below said predetermined limit,    (c) subjecting said phthalimidoamlodipine batch to deprotection to form a batch of amlodipine.    
   
   
       20 . The process according to  claim 19 , which further comprises crystallizing said batch of phthalimidoamlodipine prior to said assaying step.  
   
   
       21 . The process according to  claim 20 , which further comprises converting said batch of amlodipine to a pharmaceutically acceptable salt of amlodipine; and combining said pharmaceutically acceptable salt of amlodipine with a pharmaceutically acceptable excipient to form pharmaceutical unit dosage forms containing an effective amount of said amlodipine salt.