REACTIVITY OF PHENYLANTHRANILIC ACIDS DERIVATIVES. XXIII. SYNTHESIS AND ACID-BASE PROPERTIES OF 4,5-DYMETHOXY-N-(2 ´ -CARBOXYPHENYL)ANTHRANILIC ACIDS

The alternative ways of synthesis of new 4,5-dymethoxy-N-(2´-carboxyphenyl)anthranilic acids have been con-sidered nad new ways for their obtaining have been suggested. The structure of the compounds synthesized has been proven by the elemental analysis, IR- and NMR-spectroscopy. The purity has been controlled by the method of thin-layer chromatography. The reactivity of 4,5-dymethoxy-N-(2´-carboxyphenyl)anthranilic acids has been researched by studying the acid-base properties in the binary solvent of dioxane-water (60 vol% of dioxa- ne). It has been found that the substances synthesized are dibasic subacids, which strength depends upon the nature and position of substituents. The quantitative assessment of the influence of substituents on two reactive centres of the acids synthesized has been carried out by the method of correlative analysis according to the Gamete equation. It has been proven that the reactive centres sensitivity is substantially different and dependent on the substituent distance. In addition, appearance of another reactive centre does not practically influence on sensitivity of the first one. It has been determined that the substances synthesized reveal the anti-inflammatory, analgesic, diuretic, bacteriostatic, and fungistatic effects. According to the classification by K.K. Sydorov the substances synthesized when introducing intragastrically belong to low-toxic compounds (DL 50 >3000 mg/kg).

In the NMR-spectra of acids (5a-f) signals of aromatic protons in the range of 6.50-7.90 ppm have been identified. The proton signals of the secondary amino group appear as a broad singlet in the region of 8.05-11.18 ppm. The proton signals of the methoxy group are one or two singlets at 3.60-3.80 ppm ( Table 3).
Analysis of the structure of compounds of the isostructural series has demonstrated that dissociation of 2'-carboxyphenylic radical is stronger comparing with the ionogenic carboxyl group of the anthranilic fragment of the molecule (А) due to the presence of strong acceptor substitutes (NO 2 , Cl, Br) in the ring (В), and two donor methoxygroups in the ring (А).
The data presented in Table 2 testify that the nature and position of substitutes have influence upon the acid-base balance of both 4,5-dymethoxy-N-(2´-carboxyphenyl)anthranilic acids. Introduction of electron-acceptor substitutes strengthens dissociation of acids due to the greater anion stabilization. Electron donor substitutes cause an opposite effect. However, the reactive centres sensitivity to the influence of substitutes differs greatly. For balance (І) -рКа(6) = 1.23, and for balance (ІІ) -рКа(1) -рКа(6) = 0.40, i.e. the carboxyl group sensitivity in the ring (В) of 4,5-dymethoxy-N-(2´-carboxyphenyl) anthranilic acids molecules to the influence of substitutes is much greater than sensitivity of the same ionogenic group in the anthranilic fragment (А).
The quantitative assessment of the influence of substitutes in the nonanthranilic fragment of 4,5-dymethoxy-N-(2´-carboxyphenyl)anthranilic acids (5a-f) molecule has been carried out in the range of the principle of linear free energy (LFE) by the Gamete equation (Fig.).
The рКа indices of all compounds studied were used for correlation because schemes of рКа(І) -f(σ), Table 3 The proton chemical shift value of 4,5-dymethoxy-N-(2´-carboxyphenyl)anthranilic acids Comparison of the reaction constants ρ І =1.78 and ρ ІІ =0.78 shows that sensitivity of the reactive centre І (carboxyl group in the ring В) is 2.3 times higher than sensitivity of the reactive centre ІІ (carboxyl group in the ring А). Probably, it is connected with the different distance between carboxyl groups and substitutes in the ring В. It should be noted that appearance of another reactive centre does not practically influence upon sensitivity (within the limits of experimental error ρ ІІ corresponds to ρ from the other isostructural series of N-phenylanthranilic acids) [12,13,[18][19][20]. For balance І sensitivity of the reactive centre is sufficiently high because of closeness of substitutes.
It has been found that the substances synthesized have the anti-inflammatory, analgesic, diuretic, bacteriostatic and fungistatic activity. According to the classification by K.K. Sydorov the substances synthesized when introducing intragastrically belong to lowtoxic compounds (DL 50 > 3000 mg/kg).

Experimental Part
Melting points (ºC) were measured with the Koeffler's point apparatus and were not corrected. IR-spectra were recorded by the FT-IR Bruker Tensor 27 spectrometer in KBr. 1  The derivatives of 4,5-dymethoxy-N-(2'-carboxyphenyl)anthranilic acid were synthesized by a modified Ullmann reaction [1,3]. The compounds obtained were recrystallized three times from ethanol and dried to 105ºC up to the constant weight. The purity of the compounds was checked by thin-layer chromatography.
For preparing mixed solutions a fresh boiled bidistillate liberated from CO 2 was used [21].
The methods of measurements were similar to those described in [21]. 0.05 M aqueous solution of KOH purified from CO 2 served as a titration agent. The concentration of titration solutions was 0.005 mol/l. Potentiometric titration was conducted at 25ºC on an EV-74 ionometer using a glass electrode ESP-43-074 and a silver chloride electrode EVL-1 M. The pKa of acetic acid in the binary solvent of dioxane-water solution (60 vol% of dioxane) was determined as a standard (pKa exp. = 7.50; 5.52; 7.49).
The pKa measurements were conducted for each compound independently. The accuracy of the results obtained was estimated by the methods of mathematical statistics (with the reliability level of 0.95) [22].

Conclusions
1. The preparative methods for synthesis of 4,5dymethoxy-N-(2´-carboxyphenyl)anthranilic acids in the solid phase and in the aqueous medium with the use of a phase transfer catalyst -sodium oleate have been developed.
2. Reactivity of 4,5-dymethoxy-N-(2´-carboxyphenyl) anthranilic acids (6 compounds) has been investigated by studying the acid-base balance of these compounds in the binary solvent of dioxane-water. 3. It has been found that 4,5-dymethoxy-N-(2´carboxyphenyl) anthranilic acids are dibasic subacids, 4. The quantitative assessment of the influence of substitutes on two reactive centres of the acids synthesized has been carried out by the method of correlation analysis according to the Gamete equation. 5. It has been proven that sensitivity of the reactive centres substantially differs and depends on the distance of the substitutes. Herewith, appearance of another reactive centre does not practically influence on sensitivity of the first centre.