Synthesis method of nitroxymethylphenyl esters of aspirin derivatives

A process for obtaining (nitroxymethyl)phenyl esters of aspirin derivatives of formula R—COOH wherein R is selected from one of the radicals having the following formula:

• wherein:
• R1 is the OCOR3 group;
• wherein R3 is methyl, ethyl or alkyl C3-C5 linear or branched, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, containing hetero-atoms independently selected between O and N;
• R2 is hydrogen, halogen, C1-C4alkyl, linear or branched when possible, C1-C4 alkoxyl, linear or branched when possible;
• C1-C4 perfluoroalkyl, linear or branched when possible;
• nitro, mono- or di-(C1-4) alkylamino;
• R1 and R2 taken together are the dioxymethylene group, with the proviso that in the formula Ib) R1 cannot be OCOR3 in position 2 when R3 is methyl;
• nI is an integer and can take the values 0 or 1;
• said synthesis process comprising the following steps:
• (1) reaction between the halide R—C(O)—XI (A) wherein:
• XI is Cl, Br, R being a radical as above defined, with an isomer of the hydroxy-benzaldehyde, in the presence of a base, with formation of a (carbonyl)phenyl ester;
• (2) reduction of aldehydic group of the (carbonyl)phenyl ester with formation of an (hydroxymethyl)phenyl ester;
• (3) reaction between (hydroxymethyl) phenyl ester of formula (II) with:
• a) SoX2, X being an halogen selected between Cl and Br, or
• b) tosyl chloride or mesyl chloride
• (4) reaction between the ester isolated at the previous step with an inorganic nitrate salt, which metal cation belongs to the group IB or IIB, with formation of the (nitroxymethyl) phenyl ester.