Process for producing 4-aminoquinazoline compound

Abstract

A 4-aminoquinazoline derivative can be obtained by the steps of reacting quinazolin-4-one or its derivative with a chlorinating agent in a first organic solvent in the presence of an organic base, and subsequently reacting the reaction product with an amine compound represented by the formula R 5 —NH—R 6 (each of R 5 and R 6 represents hydrogen or an optionally substituted hydrocarbyl group) in the presence of a second organic solvent.

1 . A process for preparing a 4-aminoquinazoline compound having the formula (3):  
       
         
           
           
               
               
           
         
       
       in which each of R 1 , R 2 , R 3  and R 4  independently represents a group not participating the below-mentioned reaction, or R 1 , R 2 , R 3  and R 4  are combined to form a ring, and each of R 5  and R 6  independently represents a hydrogen atom or a hydrocarbyl group which can have a substituent, which comprises: 
 a first step of reacting a quinazolin-4-one compound having the formula (1):  
                     
 in which R 1 , R 2 , R 3  and R 4  have the same meaning as above, with a chlorinating agent in a first organic solvent in the presence of an organic base, and  
 a second step for reacting a reaction product of the first step with an amine compound having the formula (2):  
   R 5 —NH—R 6   (2)  
 in which R 5  and R 6  have the same meaning as above, in the presence of a second organic solvent.  
 
     
     
         2 . The process of  claim 1 , wherein each of R 1 , R 4  and R 6  is hydrogen, each of R 2  and R 3  is 2-methoxyethoxy, and R 5  is 3-ethynylphenyl.  
     
     
         3 . The process of  claim 1 , wherein each of R 1 , R 4  and R 6  is hydrogen, R 2  is methoxy, R 3  is 3-morpholinopropoxy, and R 5  is 3-chloro-4-fluorophenyl.  
     
     
         4 . The process of  claim 1 , wherein the quinazolin-4-one compound of formula (1) is 6-halogenoquinazolin-4-one of the following formula (4), the amine compound of formula (2) is arylamine of the following formula (5), and the 4-arylaminoquinazoline compound of formula (3) is 6-halogeno-4-arylaminoquinazoline of the following formula (6):  
       
         
           
           
               
               
           
         
       
       in which X is a halogen atom, and Ar is an aryl group which can have a substituent.  
     
     
         5 . The process of  claim 4 , wherein X is iodine.  
     
     
         6 . The process of  claim 5 , wherein Ar is 3-chloro-4-(3-fluorobenzyloxy)phenyl.  
     
     
         7 . The process of  claim 1 , wherein the reaction of the first step is performed by adding the organic base to a mixture of the quinazolin-4-one compound, first organic solvent, and chlorinating agent.  
     
     
         8 . The process of  claim 1 , wherein the organic base is used in an amount of 0.8 to 2.5 moles, based on one mole of the quinazolin-4-one compound.  
     
     
         9 . The process of  claim 1 , wherein the first organic solvent is an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, ether, or amide.  
     
     
         10 . The process of  claim 1 , wherein the first organic solvent is an aromatic hydrocarbon.  
     
     
         11 . The process of  claim 1 , wherein the chlorinating agent is phosphorus oxychloride.  
     
     
         12 . The process of  claim 1 , wherein the chlorinating agent is used in an amount of 1.0 to 2.5 moles, based on one mole of the quinazolin-4-one compound.  
     
     
         13 . The process of  claim 1 , wherein the second organic solvent is a halogenated aliphatic hydrocarbon, a halogenated aromatic hydrocarbon, nitrile, ketone, or ether.  
     
     
         14 . The process of  claim 1 , wherein each of the reactions of the first and second steps is performed at a temperature of 10 to 150° C.  
     
     
         15 . The process of  claim 1 , wherein the reaction product of the first step is subjected to the second step without isolating the reaction product from a reaction mixture of the first step.  
     
     
         16 . A process for preparing 6-halogeno-4-chloroquinazoline having the formula (7):  
       
         
           
           
               
               
           
         
       
       in which X is a halogen atom,  
       which comprises reacting 6-halogenoquinazolin-4-one having the formula (4):  
       
         
           
           
               
               
           
         
       
       in which X has the same meaning as above,  
       with a chlorinating agent in an organic solvent in the presence of an organic base.  
     
     
         17 . The process of  claim 16 , wherein X is iodine.  
     
     
         18 . The process of  claim 16 , wherein the reaction is performed by adding the organic base to a mixture of the quinazolin-4-one compound, organic solvent, and chlorinating agent.  
     
     
         19 . The process of  claim 16 , wherein the organic base is used in an amount of 0.8 to 2.5 moles, based on one mole of the quinazolin-4-one compound.  
     
     
         20 . The process of  claim 16 , wherein the organic solvent is an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, ether, or amide.  
     
     
         21 . The process of  claim 16 , wherein the first organic solvent is an aromatic hydrocarbon.  
     
     
         22 . The process of  claim 16 , wherein the chlorinating agent is phosphorus oxychloride.  
     
     
         23 . The process of  claim 16 , wherein the chlorinating agent is used in an amount of 1.0 to 2.5 moles, based on one mole of the quinazolin-4-one compound.  
     
     
         24 . The process of  claim 16 , wherein the reaction is performed at a temperature of 10 to 150° C.