SYNTHESIS FROM NIMESULIDE OF THE BASIC PRODUCTS OF ITS METABOLISM
Conditions for the synthesis of nimesulide metabolites in vitro (the product of the reduction of nimesulide and its acetyl derivative), present in living biological biomaterials, are determined. The conditions for the synthesis of two biologically active compounds, two biologically active compounds close to the structure of nimesulide - 4-nitro-2-phenoxyaniline and N-(4-hydroxy-2-phenoxyphenyl) methanesulfonamide. The reduced nimesulide was synthesized in a boiling hydrochloric acid medium in the presence of tin. The acetyl derivative of the reduced nimesulide was prepared by dissolving the reduced nimesulide in acetic anhydride at room temperature. Synthesis of 4-nitro-2-phenoxyaniline was carried out in a 60 % solution of sulfuric acid at a temperature control in the range of 145-150 °C. The preparation of N-(4-hydroxy-2-phenoxyphenyl) methanesulfonamide was carried out in two steps. First, a diazo compound stabilized with the sulfate anion was obtained from the reduced nimesulide, and the nitrite particle was removed with a 50% carbamide solution. Then, to facilitate the nucleophilic substitution reaction and the attack of the electrophilic center in the benzene ring of the diazo compound with hydroxyl ion, a Cu2O + Cu2SO4 catalyst was introduced. An additional condition was the heating of the reaction mixture to 95-100 °C. After synthesis, the control over the reaction and the purity of the compounds obtained was carried out by thin-layer chromatography on Sorbfil plates with an aluminum substrate in toluene-acetonitrile (4:1) systems and hexane-acetone (3:2), taken by v/v. The time of synthesis of metabolites did not exceed 2.5 hours at a yield of 94-97%. For each synthesis product, the conditions for chromatographic purification on macrocolumns with silicagel LaChema (Czech Republic) of 250/100 μm particle size are proposed. The compounds obtained after chromatographic purification were recrystallized from acetone or acetone mixtures with hexane or ethyl acetate. To confirm the structure of the obtained substances methods of NMR 1H, IR, UV and mass spectroscopy were used. NMR 1H spectra were recorded at 300 MHz in DMSO-d6, standard - tetramethylsilane. Mass spectra were obtained on a gas chromatograph with a quadrupole mass-selective detector. The mass-selective detector operated in the electron impact mode (70 eV). IR spectra were recorded on an infrared Fourier spectrometer in potassium bromide tablets in the wavenumber interval 4000-450 cm-1. The UV spectrum was taken on a spectrophotometer in the wavelength range 200-400 nm in ethanol.