Process for synthesizing heterocyclic compounds

Abstract

The invention provides the process illustrated in scheme 1 for synthesizing heterocyclic compounds of formula I. In the process, an isothiocyanate of formula II is initially reacted with a primary amine of formula III to give a thiourea of formula IV. Subsequently, the thiourea of formula IV is converted to the corresponding heterocycle of formula I using a base and a sulfonyl chloride.

What is claimed is:  
     
         1 . A process for preparing heterocycles of formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is sulfur, oxygen or NR5 
 wherein R5 is hydrogen or (C1-C4)alkyl;  
 
 m and o are each independently zero, 1 or 2;  
 A is either a) phenyl, naphthyl or heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 R11 radicals 
 wherein R11 is, in each case, independently selected from the group consisting of (C1-C4)alkyl, F, Cl, Br, I, CN, NO 2 , OH, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;  
 
  or b) selected from (C1-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C3-C8)cycloalkyl, and (C4-C8)cycloalkenyl radicals 
 wherein said radicals may each independently be substituted by (C1-C4)alkyl or (C3-C6)cycloalkyl, and  
 wherein some or all of the hydrogen atoms of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals may be replaced by fluorine atoms;  
 
 R14, R15, R16 and R17 
 are each independently selected from hydrogen, F and (C1-C4)alkyl, wherein some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or  
 
 R14 and R16 together are a bond, and  
 R15 and R17, together with the two carbon atoms to which they are bonded, form an aromatic six-membered carbocycle, in which one or two carbon atoms may be replaced by nitrogen, or a thiophene ring, 
 wherein the aromatic six-membered carbocycle and the thiophene ring is optionally substituted by 1, 2, 3 or 4 R7 radicals,  
 wherein R7 is, in each case, independently selected from the group consisting of (C1-C4)alkyl, F, Cl, Br, I, CN, NO 2 , OH, O(C1-C4)-alkyl and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; or  
 
 R14 and R16 are each independently hydrogen or (C1-C4)alkyl, 
 wherein some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms; and  
 
 R15 and R17, together with the two carbon atoms to which they are bonded, form a saturated 5-, 6-, 7- or 8-membered carbocycle in which one or two carbon atoms may each independently be replaced by O, S, NH or N(C1-C4)alkyl and may be substituted by 1, 2, 3, 4, 5 or 6 R8 radicals 
 wherein R8 is, in each case, independently selected from the group consisting of (C1-C4)alkyl, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;  
 
 R10, R11, R12 and R13 
 are each independently hydrogen, F or (C1-C4)alkyl, 
 wherein some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;  
 
 
 wherein, either (i) A is an aromatic ring system, or (ii) the ring formed from R15 and R17 is an aromatic system and m is zero, or (iii) each of A and the ring formed from R15 and R17 is an aromatic ring system;  
 and their tautomers and their salts;  
 provided, however, that compounds in which A is unsubstituted phenyl or (C 1 -C4)alkyl; and X is oxygen; and R14 and R15 are each independently hydrogen, (C1-C4)alkyl or benzyl; and R16 and R17 are each hydrogen; and m and o are each zero are excluded;  
 which process comprises, as shown in scheme 1,  
                     
 a) reacting an isothiocyanate of formula II with a primary amine of formula III to give a thiourea of formula IV, and  
 b) converting the thiourea of formula IV, using a sulfonyl chloride R6SO 2 Cl in the presence of a base, to said compound of formula I,  
 where, in the compounds of the formulae II, mfi and IV,  
 A, X, n, m and R10 to R17 are each as defined in formula I and  
 R6 is (C1-C4)alkyl, trifluoromethyl or phenyl which is unsubstituted or substituted by methyl, trifluoromethyl, F, Cl, Br or a polymeric support.  
 
     
     
         2 . The process of  claim 1 , in which the reaction is carried out as a one-pot reaction.  
     
     
         3 . The process of  claim 1 , wherein steps a) and b) are each independently conducted continuously or batchwise.  
     
     
         4 . The process of  claim 1 , wherein X is oxygen or NR5.  
     
     
         5 . The process of  claim 1 , wherein X is NR5.  
     
     
         6 . The process of  claim 1 , wherein A is phenyl, thienyl or isoxazolyl, each of which may be substituted as specified in  claim 1 .  
     
     
         7 . The process of  claim 1 , wherein R6 is phenyl or p-methylphenyl.  
     
     
         8 . The process of  claim 1 , wherein the base used in step b) is sodium hydroxide or potassium hydroxide.  
     
     
         9 . A process for preparing a compound of the formula I as defined in  claim 1   
       
         
           
           
               
               
           
         
       
       which comprises 
 converting a thiourea of the formula IV to a compound of formula I using a sulfonyl chloride R6SO 2 CI in the presence of a base  
                     
  wherein  
 A, X, o, m, R6 and R10 to R17 are each as defined in  claim 1.