Process for preparing nitrooxyalkyl substituted esters of carboxylic acids, intermediates useful in said process and preparation thereof

Abstract

The present invention refers to a process for preparing a compound of general formula (A), as reported in the description, wherein R is a radical of a drug and R1-R12 are hydrogen or alkyl groups, m, n, o, q, r and s are each independently an integer from 0 to 6, and p is 0 or 1, and X is O, S, SO, SO2, NR13 or PR13 or an aryl, heteroaryl group, said process comprising reacting a compound of formula (B) R—COOZ (B) wherein R is as defined above and Z is hydrogen or a cation selected from: Li+, Na+, K+, Ca++, Mg++, tetralkylammonium, tetralkylphosphonium, with a compound of formula (C), as reported in the description, wherein R1-R12 and m, n, o, p, q, r, s are as defined above and Y is a suitable leaving group.

1 . A process for preparing a compound of general formula (C) 
     
       
         
         
             
             
         
       
       wherein R 1 -R 12  are the same or different and independently are hydrogen, straight or branched C 1 -C 6  alkyl, optionally substituted with aryl; 
       m, n, o, q, r and s are each independently an integer from 0 to 6, and p is 0 or 1, and 
       X is O, S, SO, SO 2 , NR 13  or PR 13 , in which R 13  is hydrogen, C 1 -C 6  alkyl, or X is selected from the group consisting of:
 saturated or unsaturated C 5 -C 7  cycloalkylene, optionally substituted with one or more straight or branched C 1 -C 3  alkyl groups; 
 arylene, optionally substituted with one or more halogen atoms, straight or branched alkyl groups containing from 1 to 4 carbon atoms, or a straight or branched C 1 -C 3  perfluoroalkyl; 
 a 5 or 6 member saturated, unsaturated, or aromatic heterocyclic ring selected from 
 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       Y is selected from
 a Br, Cl, I; 
 —BF 4 , —SbF 6 , FSO 3 —, R A SO 3 —, in which RA is a straight or branched C 1 -C 6  alkyl, optionally substituted with one or more halogen atoms, or a C 1 -C 6  alkylaryl; 
 R B COO—, wherein R B  is straight or branched C 1 -C 6  alkyl, aryl, optionally substituted with one or more halogen atoms or NO 2  groups, C 4 -C 10  heteroaryl and containing one or more heteroatoms, which are the same or different, selected from nitrogen, oxygen sulfur or phosphorus; 
 aryloxy optionally substituted with one or more halogen atoms or NO 2  groups, or heteroaryloxy; 
 
       comprising reacting a compound of the following formula (E), 
     
     
       
         
         
             
             
         
       
       wherein R 1 -R 12 , m, n, o, p, q, r, s, X, Y are as defined above with a nitrating agent. 
     
   
   
       2 . A process for preparing a compound of formula (C) according to  claim 1  wherein the nitrating agent is selected from alkaline metal nitrates, quaternary ammonium nitrates, quaternary phosphonium nitrates, AgNO 3 , Zn(NO 3 ) 2 6H 2 O. 
   
   
       3 . A process for preparing a compound of formula (C) according to  claim 1  wherein the compound (E) and the nitrating agent are at molar ratio of 20:2. 
   
   
       4 . A process for preparing a compound of formula (C) according to  claim 1  wherein the reaction is performed at a temperature ranging from 0° C. to 100° C. 
   
   
       5 . A process for preparing a compound of formula (C) 
     
       
         
         
             
             
         
       
       wherein R 1 -R 12 , m, n, o, p, q, r, s, X, are as defined in  claim 1 , and is selected from 
       —BF 4 , —SbF 6 , FSO 3 —, R A SO 3 —, in which R A  is a straight or branched C 1 -C 6  alkyl, optionally substituted with one or more halogen atoms, or a C 1 -C 6  alkylaryl; 
       R B COO—, wherein R B  is straight or branched C 1 -C 6  alkyl, aryl, optionally substituted with one or more halogen atoms or NO 2  groups, C 4 -C 10  heteroaryl and containing one or more heteroatoms, which are the same or different, selected from nitrogen, oxygen sulfur or phosphorus; 
       aryloxy optionally substituted with one or more halogen atoms or NO 2  groups, or heteroaryloxy; 
     
     comprising reacting a compound of the following formula (F), 
     
       
         
         
             
             
         
       
     
     wherein R 1 -R 12 , m, n, o, p, q, r, s, X, are as defined above, W is OH or halogen, with a compound selected from alkanoylsulfonylchloride and trifluoromethansulfonic anhydride when W is OH or with AgSbF 6 , AgBF 4 , CF 3 SO 3 Ag, AgSO 3 CH 3 , CH 3 C 6 H 4 SO 3 Ag when W is halogen. 
   
   
       6 . A process for preparing a compound of formula (C) according to  claim 5  wherein the compound (F) and the nitrating agent are at molar ratio of 2:0.5. 
   
   
       7 . A process for preparing a compound of formula (C) according to  claim 5  wherein the reaction is performed at a temperature ranging from 0° C. to 100° C.