Process for preparing nitrooxyderivatives of naproxen

1. A process for preparing a compound of general formula (A)

wherein:

R is

 in which R′ is a hydrogen atom or Br

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:

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being eventually substituted with side chains T, wherein T is straight or branched alkyl with from 1 to 10 carbon atoms;

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

said process comprising:

i) reacting a compound of formula (B)

R—COOZ  (B)

wherein R is as above defined and Z is hydrogen or a cation selected from Li+, Na+, Ca++, Mg++, tetralkylammonium, tetralkylphosphonium, with a compound of formula (C)

wherein R 1 –R 12 and m, n, o, p, q, r, s are as defined above and

Y is selected from

a halogen atom

—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 C1–C6 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 and

ii) optionally converting a compound of formula (A) wherein R′ is Br in a compound of formula (A) wherein R′ is hydrogen.

2. A process for preparing a compound of formula A according to claim 1 wherein:

the substituents R 1 –R 12 are the same or different and independently are hydrogen or straight or branched C 1 –C 3 alkyl,

m, n, o, p, q, r and s are as defined above,

X is O, S or

3. A process for preparing a compound of formula A according to claim 1 wherein R 1 –R 4 and R 7 –R 10 are hydrogens, m, n, q, r, are 1, o and s are 0, p is 0 or 1, and X is O or S.

4. A process for preparing a compound of formula A according to claim 1 wherein Y is selected from the group consisting of Br, Cl, I, —BF 4 , —SbF 6 , FSO 3 —, ClO 4 , CF 3 SO 3 —, C 2 F 5 SO 3 —, C 3 F 7 SO 3 —, C 4 F 9 SO 3 —, p-CH 3 C 6 H 4 SO 3 —.

5. A process for preparing a compound of formula A according to claim 1 wherein the reaction is performed in an organic solvent selected from acetone, tetrahydrofurane, dimethylformamide, N-methylpyrrolidone, sulfolane and acetonitrile.

6. A process for preparing a compound of formula A according to claim 1 wherein the reaction is performed in a biphasic system comprising an aprotic dipolar solvent selected from toluene, chlorobenzene, nitrobenzene, tert-butylmethylether and a water solution wherein the organic solution contains (C) and the water solution contain an alkaline metal salt of (B), in presence of a phase transfer catalyst.

7. A process for preparing a compound of formula A according to claim 1 wherein the reaction is performed at a temperature ranging from 0° C. to 100° C.

8. A process for preparing a compound of formula A according to claim 1 wherein the compounds of formula B and C are reacted at a (B)/(C) molar ratio of 2–0.5.

9. 2-(S)-(5-bromo-6-methoxy-2-naphthyl)propanoic acid,4-(nitrooxy)butyl ester.