Chemical Process for the Synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline

Abstract

The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

1 .- 18 . (canceled) 
     
     
         19 . A process for the manufacture of compound of the Formula X: 
       
         
           
           
               
               
           
         
         from a compound of the Formula VII: 
       
       
         
           
           
               
               
           
         
         where R 1  is an acid labile protecting group, 
         the process comprising converting the compound of the Formula VII to a compound of the Formula IX: 
       
       
         
           
           
               
               
           
         
         and 
         reacting the compound of the Formula IX with a compound of the Formula II: 
       
       
         
           
           
               
               
           
         
         
           in the presence of a base to provide a compound of the Formula X or a salt thereof; and 
         
         whereafter the compound of the Formula X obtained in the form of the free base may optionally be converted into a pharmaceutically acceptable salt. 
       
     
     
         20 . The process according to  claim 19 , wherein the base used in reacting the compound of the Formula IX with the compound of the Formula II is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. 
     
     
         21 . The process according to  claim 19 , further including a step of isolating the compound of the Formula X. 
     
     
         22 . A process for the manufacture of a compound of the Formula X: 
       
         
           
           
               
               
           
         
         from a compound of the Formula IX: 
       
       
         
           
           
               
               
           
         
         the process comprising: 
         reacting the compound of the Formula IX with a compound of the Formula II: 
       
       
         
           
           
               
               
           
         
         
           in the presence of a base to provide a compound of the Formula X or a salt thereof; and 
         
         isolating the compound of the Formula X by:
 adding water and allowing crystallization of the compound of the Formula X to occur, collecting the compound of the Formula X and washing the compound of the Formula X with water, followed by a solvent selected from the group consisting of ethyl acetate, butyl acetate and acetonitrile at a temperature in the range of from 25° C. to 55° C.; or 
 adding water and an alcohol selected from the group consisting of methanol, ethanol, isopropanol and n-propanol and allowing crystallization of the compound of the Formula X to occur, collecting the compound of the Formula X and washing the compound of the Formula X with a mixture of water and an alcohol selected from the group consisting of methanol, ethanol, isopropanol and n-propanol, followed by a solvent selected from the group consisting of ethyl acetate, butyl acetate and acetonitrile at a temperature in the range of from 25° C. to 55° C.; and 
 
         whereafter the compound of the Formula X obtained in the form of the free base may optionally be converted into a pharmaceutically acceptable salt. 
       
     
     
         23 . The process according to  claim 22 , wherein the base used in reacting the compound of the Formula IX with the compound of the Formula II is selected from the group consisting of sodium carbonate and potassium carbonate. 
     
     
         24 . The process according to  claim 19 , wherein the compound of the Formula II is prepared from a (C1-C6)alkyl-4-piperidinecarboxylate compound of the Formula III 
       
         
           
           
               
               
           
         
         by:
 reacting the compound of the Formula III with di-tert-butyl dicarbonate in the presence of toluene or xylene to form a first mixture comprising toluene or xylene, tert-butanol and a compound of the Formula IV: 
 
       
       
         
           
           
               
               
           
         
         
           substantially removing the tert-butanol from the first mixture; 
           reacting the compound of the Formula IV with a reducing agent in situ in the presence of toluene or xylene to form a second mixture comprising a compound of the Formula V: 
         
       
       
         
           
           
               
               
           
         
         
           substantially removing alcohol by-products formed in step (c) from the second mixture; and 
           reacting the compound of the Formula V with tosyl chloride in situ to form the compound of the Formula II in the presence of a base and toluene. 
         
       
     
     
         25 .- 30 . (canceled) 
     
     
         31 . The process according to  claim 19 , wherein the compound of the Formula VII is converted to the compound of the Formula IX by converting the compound of Formula VII to a compound of the Formula VI: 
       
         
           
           
               
               
           
         
         where R 1  is an acid labile protecting group, and then removing R 1  from the compound of the Formula VI in situ in the presence of toluene to form the compound of the Formula IX or a salt thereof; 
         and whereafter the compound of the Formula IX obtained in the form of the free base may optionally be converted into a pharmaceutically acceptable salt. 
       
     
     
         32 . The process according to  claim 31 , wherein R 1  is benzyl and the benzyl group is removed from the compound of the Formula VI in situ by reaction with trifluoroacetic acid. 
     
     
         33 . The process according to  claim 31 , wherein the compound of the Formula VII is converted to the compound of the Formula VI by a process which comprises:
 reacting the compound of the Formula VII with a chlorinating agent in the presence of a base and a solvent, wherein the reaction is carried out by:
 adding a mixture of the compound of the Formula VII and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range of from 60° C. to 90° C. over a period of about 60 minutes; or 
 adding the chlorinating agent to a mixture of the compound of the Formula VII and the base in the solvent at ambient temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes to a temperature in the range of from 70° C. to 90° C. and stirring the reaction mixture at that temperature for about 1 hour; or 
 adding the chlorinating agent to a mixture of the compound of the Formula VII and the base in the solvent at a temperature in the range of from 60° C. to 110° C. over a period of about 15 minutes, 
 to form a compound of the Formula VIII: 
   
       
         
           
           
               
               
           
         
          and
 reacting the compound of the Formula VIII with 4-bromo-2-fluoroaniline in situ in the presence of toluene to form the compound of the Formula VI as a hydrochloride salt. 
 
       
     
     
         34 . The process according to  claim 33 , wherein the chlorinating agent is phosphorus oxychloride. 
     
     
         35 . The process according to  claim 33 , wherein the base is selected from the group consisting of trimethylamine and N,N-diisopropylethylamine. 
     
     
         36 . The process according to  claim 24 , wherein the reducing agent is selected from sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride and diisobutylaluminum hydride.