Process for the synthesis of morpholinylbenzenes

Abstract

A new improved process for synthesizing morpholinylbenzenes of the formula I by reacting morpholine of formula II with a substituted benzene of formula III, wherein morpholine is used as a reactant and as the only one solvent.

1 . An improved process for synthesizing 4-morpholinylbenzene of the formula I  
       
         
           
           
               
               
           
         
       
       by reacting morpholine of formula II with a substituted benzene of formula III,  
       
         
           
           
               
               
           
         
       
       wherein 
 Y and Y 1  are a substituent in 2- or 4-position and  
 Y is Y 1  or COOH,  
 Y 1  is CN, NO 2 , CF 3 , COOR 1 , COR 1 , CONR 2 R 3    
 where R 1  is H, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-3  alkylC 3-6  cycloalkyl, C 6 -C 10  aryl or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, and said heterocyclic ring may optionally be substituted;  
 where R 2 , R 3  is H, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-3  alkylC 3-6  cycloalkyl and C 6 -C 10  aryl or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, and said heterocyclic ring may optionally be substituted, or may together with the nitrogen atom form a heterocyclic ring;  
 with the provisio that Y 1  is not COOH,  
 X is a leaving group,  
 characterized in that the morpholine is used as reactant and the only one solvent, if solvent is present,  
 and, if necessary, hydrolysis to form a compound wherein Y is COOH.  
 
     
     
         2 . A process according to  claim 1 , wherein 
 X is F, Cl, Br, I, or CF 3 SO 3 .    
     
     
         3 . A process according to  claim 1 , wherein 
 X is F, and    Y 1  is CN, CONH 2 , COOC 2 H 5 , or COCH 3 .    
     
     
         4 . A process according to  claim 1 , wherein 
 X is F, and    Y 1  is NO 2 .    
     
     
         5 . A process according to any one of the proceeding claims, wherein the substituent Y and Y 1  is in the 4-position.  
     
     
         6 . A process according to any one of the proceeding claims, wherein the molar ratio of the reactant morpholine to substituted benzene ranges preferably in the ranges from 6.7:1 to 1:1, more preferably from 3.5:1 to 1:1.  
     
     
         7 . A process according to claims  4  or  6 , wherein the molar ratio of the reactant morpholine to substituted benzene is 1:1.  
     
     
         8 . A process according to any one of the proceeding claims performed in absence of an additional base.  
     
     
         9 . A process according to any one of the proceeding claims performed in the absence of a catalyst.  
     
     
         10 . A process according to any one of the proceeding claims, wherein the process is performed under normal pressure and at a temperature range from 20° C. to 130° C.  
     
     
         11 . A process according to  claim 10  wherein the temperature is about 120° C., when Y 1  is CN, CONH 2 , COOC 2 H 5  and COCH 3 .  
     
     
         12 . A process according to any one of claims  4  and  7 , wherein the temperature is about 40° C., when Y 1  is NO 2 .  
     
     
         13 . A process according to  claim 1 , wherein the said desired 4-morpholinyl benzenes is 4-morpholinyl benzoic acid.  
     
     
         14 . A process according to  claim 13  using a one-pot method.  
     
     
         15 . Use of the process according to any one of  claims 1  to  14 , for synthesizing morpholinylbenzene of formula I, wherein Y, R 1 , R 2  and R 3  are defined as in  claim 1 .  
     
     
         16 . Use of the process according to  claim 15  for synthesizing 4-morpholinylbenzene of formula I, wherein Y is COOH.  
     
     
         17 . A compound of formula I of  claim 1  prepared by the process according to anyone of claim  1 - 14 .