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 . A process for the manufacture of a compound of the Formula IIa: 
       
         
           
           
               
               
           
         
         wherein R is a suitable sulphonate ester; 
         from a (C1-C6)alkyl-4-piperidinecarboxylate compound of the Formula III: 
       
       
         
           
           
               
               
           
         
         which process comprises the steps of: 
         (a) reacting the (C1-C6)alkyl-4-piperidinecarboxylate 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: 
       
       
         
           
           
               
               
           
         
         (b) substantially removing the tert-butanol from the first mixture; 
         (c) reacting the compound of the Formula IV with a suitable reducing agent in situ in the presence of toluene or xylene to form a second mixture comprising toluene, reduction by-products including alcohol by-products and a compound of the Formula V: 
       
       
         
           
           
               
               
           
         
         (d) substantially removing the alcohol by-products from the second mixture; and 
         (e) reacting the compound of the Formula V with a suitable sulphonylating agent in situ to form a sulphonate ester in the presence of a suitable base and toluene to form the compound of the Formula IIa. 
       
     
     
         2 . The process according to  claim 1 , wherein the compound of Formula IIa is a compound of Formula II and the sulphonating agent is tosyl chloride. 
       
         
           
           
               
               
           
         
       
     
     
         3 . The process according to  claim 1 , wherein the (C1-C6)alkyl-4-piperidinecarboxylate compound of the Formula III is ethyl 4-piperidinecarboxylate. 
     
     
         4 . The process according to  claim 1 , wherein in step (c) the reducing agent is selected from sodium bis(2-methoxyethoxy)aluminium hydride, lithium aluminium hydride and diisobutylaluminum hydride. 
     
     
         5 . The process according to  claim 4 , wherein in step (c) the reducing agent is sodium bis(2-methoxyethoxy)aluminium hydride. 
     
     
         6 . The process according to  claim 1 , wherein in step (e) the base is triethylenediamine. 
     
     
         7 . The process according to  claim 1 , further including the step (f) of isolating the compound of the Formula IIa. 
     
     
         8 . The process according to  claim 7 , wherein the step (f) comprises crystallisation using a toluene and isohexane solvent system. 
     
     
         9 . A process for the manufacture of a compound of the Formula VI: 
       
         
           
           
               
               
           
         
         wherein R 1  is an acid labile protecting group 
         from a compound of the Formula VII: 
       
       
         
           
           
               
               
           
         
         which process comprises the steps of: 
         (g) reacting the compound of the Formula VII with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is carried out by: 
         (g-1) 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 to 90° C. over a period of about 60 minutes; or 
         (g-2) 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 to 90° C. and stirring the reaction mixture at that temperature for about 1 hour; or 
         (g-3) 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 to 110° C. over a period of about 15 minutes, 
         to form a compound of the Formula VIII: 
       
       
         
           
           
               
               
           
         
         (h) reacting the compound of the Formula VIII with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a hydrochloride salt of the compound of the Formula VI; 
         and whereafter the compound of the Formula VI obtained in the form of the hydrochloride salt optionally may be converted into the free base or into the form of an alternative salt. 
       
     
     
         10 . The process according to  claim 9 , wherein steps (g) and (h) are both conducted in toluene. 
     
     
         11 . The process according to  claim 9 , wherein the chlorinating agent used in step (g) is phosphorus oxychloride. 
     
     
         12 . The process according to  claim 9 , wherein the base used in step (g) is selected from triethylamine and N,N-diisopropylethylamine. 
     
     
         13 . The process according to  claim 9 , further including the step (i) of isolating the compound of the Formula VI. 
     
     
         14 . A process for the manufacture of 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compound of the Formula IX: 
       
         
           
           
               
               
           
         
         from a compound of the Formula VII: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is an acid labile protecting group 
         which process comprises converting the compound of the Formula VII to a compound of the Formula VI: 
       
       
         
           
           
               
               
           
         
         by the steps of: 
         (g) reacting the compound of the Formula VII with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is carried out by: 
         (g-1) 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 to 90° C. over a period of about 60 minutes; or 
         (g-2) 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 to 90° C. and stirring the reaction mixture at that temperature for about 1 hour; or 
         (g-3) 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 to 110° C. over a period of about 15 minutes, 
         to form a compound of the Formula VIII: 
       
       
         
           
           
               
               
           
         
         (h) reacting the compound of the Formula VIII with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form a hydrochloride salt of the compound of the Formula VI; and 
         (j) removing R 1  from the compound of the Formula VI in situ in the presence of the solvent used in steps (g) and (h) 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 be converted into a salt form and the compound of the Formula IX obtained in the form of a salt optionally may be converted into the free base or into the form of an alternative salt. 
       
     
     
         15 . The process according to  claim 14 , wherein R 1  is benzyl and in step (j) the benzyl group is removed in situ by reaction with trifluoroacetic acid at a temperature in the range of from 60 to 80° C. 
     
     
         16 . The process according to  claim 14  wherein R 1  is benzyl and the benzyl group is removed in the presence of trifluoroacetic acid and the compound of Formula IX is converted into a trifluoroacetic acid salt by addition of potassium hydroxide or the addition of sodium hydroxide and water. 
     
     
         17 - 30 . (canceled)