Ozonation of 4-aminotoluene as a new method of synthesis of 4-aminobenzaldehyde – an intermediate for the production of anti-tuberculosis drugs

Abstract

Solutizon is an original anti-TB drug that is effective in resisting mycobacteria to other anti-TB drugs, which is obtained by the interaction of thiosemicarbazone 4-aminobenzaldehyde and sodium oxymethylene sulfonate. 4-Aminobenzaldehyde is synthesized by redox conversion of 4-nitrotoluene in the presence of sodium polysulfide. The reaction is carried out in boiling alcohol, and 4-aminobenzaldehyde is separated after steam distillation with a yield of 40–50 %. However, today this method loses its practical, environmental and economic attractiveness, as it has significant disadvantages – low product yield, high reaction temperature (80–120 °C), the formation of sulfur-containing wastewater. Therefore, the development of low-temperature, environmentally friendly methods for obtaining 4-aminobenzaldehyde is an urgent task.

The aim of the work is to study the kinetic features and mechanism of the liquid-phase reaction of ozone with 4-aminotoluene to create a new low-temperature, environmentally friendly method for the synthesis of 4-aminobenzaldehyde.

Materials and methods. Sigma acetic anhydride of сh.р. qualification was used for the experiments. 4-Aminotoluene company “Sinbias” qualification “сh.р.”; 4-Acetamidotoluene and its derivatives were used chromatographically pure. Acetates of metals of qualification “сh.р.”, potassium bromide of qualification “pharmacopoeial” were used without additional purification. Continuous control of the current ozone concentration and recording the results in the form of a kinetic curve was carried out when passing ozone-containing gas through the container of the spectrophotometer “SF-46 LOMO” at a certain wavelength of a monochromatic light source. The results of the analysis were recorded using the KSP-4 potentiometer included in the spectrophotometer optical density reference circuit. This device automatically compensated the photocurrent by recording its value. The scale KSP-4 was calibrated in units of optical density, and the conversion into absolute ozone concentration was carried out according to the Lambert-Ber equation using molar extinction coefficients. Relative analysis error ≤5 %. At the optical stroke length of the container 10 ÷ 100 mm, the sensitivity of the device was ~10^-7mol·l^-1 ozone.

Results. The kinetic features and mechanism of the liquid-phase reaction of ozone with 4-aminotoluene have been studied. It is shown that the developed catalytic system Mn(II)-KBr-H₂SO₄-Ac₂O significantly increases the depth, rate, and selectivity of oxidation of 4-aminotoluene and the main reaction product is 4-aminobenzaldehyde in the form of the corresponding benzylidenediacetate with a yield of 69.5 %. The active particle responsible for the inclusion of the substrate in the oxidation of the methyl group in the presence of manganese (II) acetate and potassium bromide is manganese bromide ion radical (Mn(II)Br^•), which is more active than Mn (III) and therefore more high-speed initiates oxidation by the methyl group.

Conclusions. Catalytic systems have been developed that allow the oxidation of ozone to be directed mainly to the methyl group of 4-aminotoluene and to stop the reaction at different oxidation depths. It was found that manganese (II) acetate, which has a relatively low redox potential, in the system Ac₂O-ArCH₃-H₂SO₄-O₃ at a temperature of 20 °C has a high substrate selectivity in the reactions of formation of 4-aminobenzyl alcohol. Manganese (II) acetate in the presence of potassium bromide forms a manganese bromide complex with increased catalytic activity, which under the same conditions contributes to the predominant production of 4-aminobenzaldehyde.