Process for preparing amino crotonyl compounds

Abstract

The invention relates to an improved process for preparing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylam ino)-1 -oxo-2-buten-1 -yl]am ino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline and related aminocrotonyl compounds and the preparation of a suitable salt of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline for use as a pharmaceutically active substance.

1 . a process for preparing a compound of the formula (VII)  
       
         
           
           
               
               
           
         
       
       wherein x denotes a methyne group or a nitrogen atom, R a  denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group and R 3  and R 4  denote a straight-chain or branched C 1-4 -alkyl group, 
 comprising the following synthesis steps:  
 a) reacting a compound of the formula (V)  
                     
 wherein X denotes a methyne group or a nitrogen atom and Ra denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, in suitable solvents after corresponding activation with di-(C 1-4 -alkyl)-phosphonoacetic acid and  
 b) reacting the resulting compound of the formula (VI)  
                     
 wherein X denotes a methyne group or a nitrogen atom, R a  denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group and R 1  denotes a straight-chain or branched C 1-4 -alkyl group,  
 with the aldehyde of formula  
                     
 wherein R 3  and R 4  in each case represent a straight-chain or branched C 1-4 -alkyl group, while the groups may be identical or different,  
 or a corresponding aldehyde equivalent, using suitable organic or inorganic bases.  
 
     
     
         2 . A process for preparing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethyl-amino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, comprising the following synthesis steps: 
 a) reacting N 4 -(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diamine in suitable solvents after corresponding activation with di-(C 1-4 -alkyl)-phosphonoacetic acid and    b) reacting the resulting dialkylester {[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonate with the aldehyde prepared in situ from the corresponding (dimethylamino)-acetaldehyde-dialkylacetal using suitable organic or inorganic bases.    
     
     
         3 . The process according to  claim 2 , wherein in step a) diethylphosphonoacetic acid is used as reagent.  
     
     
         4 . The process according to  claim 1 , wherein in step b) DBU (1,5-diaza-bicyclo[4.3.0]non-5-ene), sodium hydroxide or potassium hydroxide is used as base.  
     
     
         5 . The process according to  claim 4 , wherein in step b) potassium hydroxide is used as base.  
     
     
         6 . A process for preparing the dimaleates of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, comprising steps a and b according to  claim 1  as well as the following step c): 
 c) converting the resulting 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline into the dimaleate by reacting with maleic acid in a suitable solvent, with heating.    
     
     
         7 . The process according to  claim 6 , wherein ethanol or isopropanol is used as solvent, optionally with the addition of water.  
     
     
         8 . The process according to  claim 6 , wherein at least 2 equivalents of maleic acid are used.  
     
     
         9 . 4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate.  
     
     
         10 . A pharmaceutical composition containing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate optionally together with one or more inert carriers and/or diluents.  
     
     
         11 . A method for treating benign or malignant tumours, diseases of the respiratory tract and lungs as well as for treating diseases of the gastrointestinal tract and the bile duct and gall bladder which comprises administering 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten- 1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate.