Synthesis and physical-chemical properties of 3-benzyl- 8-propylxanthinyl-7-acetic acid and its derivatives

Introduction. Heterocyclic compounds play an important role in the metabolic processes of human organism. Structures of vitamins, nucleotides, chromoproteins are based on Nitrogen-containing heterocycles (purine, pyrimidine, thiazole etc). Thus, it was obvious to use these organic substances as basic molecules for synthetic research of biologically active compounds which could be used for treatment of different pathological processes. In their research, some scientist pay special attention to xanthine derivatives that are well-known low toxic natural compounds with wide spectrum of pronounced pharmacological properties (antioxidant, diuretic, antibacterial, anti-inflammatory etc). Insertion of carboxyl group in the structure of xanthine molecule is a prospective ability of its synthetic potential increasing. Aim of our research was the development of method of 3-benzyl-8-propylxanthinyl-7-acetic acid and its derivatives synthesis and studying their physical-chemical properties. Materials and methods. Melting points were determined using capillary method on DMP (M). 1Н NMR-spectra were recorded by Varian Mercury VX-200 device (company «Varian», USA) solvent – (DMSO-d6), internal standard – ТМS. Elemental analysis of obtained compounds was produced on device Elementar Vario L cube. Results and discussion. We selected 3-benzyl-8-propyl xanthine as initial compound for our study. By its interaction with chloroacetic acid, chloroacetamide or propyl chloroacetate in DMF in the presence of calculated amount of NaHCO3 we synthesized 3-benzyl-8propylxanthinyl-7-acetic acid its ester and amide. At the same time we found that obtaining of xanthinyl-7-acetic acid by hydrolysis of its ester produced with higher yield. On the next stage of our research we synthesized a number of water-soluble salts of 3-benzyl-8propylxanthinyl-7-acetic acid by reaction of acid with different primary and secondary amines. The structures of all obtained compounds were proved by the elemental analysis and 1H NMR-spectroscopy. Conclusions. Obtained results of our work can be used for further search of biologically active compounds among xanthine derivatives with carboxyl residue.

Thus, it was obvious to use these organic substances as basic molecules for synthetic research of biologically active compounds that could be used for treatment of different pathological processes [2,3].In their research, some scientist paid special attention to xanthine derivatives that are wellknown low toxic natural compounds with wide spectrum of pronounced pharmacological properties (antioxidant, diuretic, antibacterial, anti-inflammatory etc).It should be noted, that xanthines have also high variability of chemical modification [4][5][6][7][8], that make them good objects for pharmaceutical research.
Carboxyl group is one of the most chemically active functional group.It easily interacts with reagents in reactions of nucleophilic substitution.At the same time this functional group shows acidic properties that could be used for obtaining water-soluble derivatives of insoluble acids.Thus, insertion of carboxyl group in the structure of xanthine molecule is a prospective ability of its synthetic potential increasing [9].

Aim of the work
The aim of work is the development of method of 3-benzyl-8-propylxanthinyl-7-acetic acid and its derivatives synthesis and studying their physical-chemical properties.

Materials and methods
Melting points were determined using capillary method on DMP (M). 1 Н NMR-spectra were recorded by Varian Mercury VX-200 device (company «Varian», USA) solvent -(DMSO-d6), internal standard -ТМS.Elemental analysis of obtained compounds was produced on device Elementar Vario L cube.
Method B. Mixture of 1.71 g (0,005 mole) acid 2, 0.005 mole of appropriative amine, 5 ml of water and 20 ml of propanol was heated up to dissolution and filtered.Filtrate was cooled up to 0 ºС and left for 24 h.Precipitate was filtered out and washed by acetone, diethyl ether and dried at 80-85 °С.

Results and their discussion
As initial compound for synthesis of 3-benzyl-8-propylxanthinyl-7-acetic acid 2 we used 3-benzyl-8-propylxanthine 1, which had been obtained by the method described by us earlier [10].
It should be noted, that xanthinyl-7-acetic acid 2 was obtained with higher yield as result of hydrolysis of ester 3 and amide 4. Ester 3 was also synthesized by interaction of acid 2 and propanol in the presence of dioxane and catalytic amount of concentrated sulfuric acid.Samples of compounds, that were obtained by different methods, didn't show depression of melting points and their 1 H NMR-spectra were identical.
3-Benzyl-8-propylxanthinyl-7-acetic acid 2 is pale yellow crystal compound, that is soluble in propanol, dioxane, DMF, DMSO, and aqueous solution of NaOH.Acid 2 also interact with NaHCO 3 with CO 2 gassing that proved presence of carboxyl group in the structure of compound 2. Synthesis and physical-chemical properties of 3-benzyl-8-propylxanthinyl-7-acetic acid and its derivatives In 1 Н NMR-spectrum of acid 2 (Table 1) we registered signal of carboxyl group proton as low intensive singlet at weak filed at 12,61 ppm, and intensive singlet of CH 2 -group at 4,97 ppm, that confirmed acetate residue presence.Other signals corresponded to the protons of NH-group of xanthine heterocycle and methyl, methylene and aromatic groups of side-chain residues.
In 1 Н NMR-spectrum of ester 3 were absent signals of NHgroup of imidazole fragment or hydroxyl group of carboxyl, that were present in spectra of initial 8-propylxanthine 1 [10] or acid 2. Instead of this we registered: intensive singlets of two methylene groups protons (2H), that associated with Nitrogen atoms at position 3 and 7 of xanthine molecule at 5.02 ppm and 5.14 ppm; protons of methyl and methylene groups of ester fragment resonated as two triplets at 4.01 ppm (2Н) and at 0.67 ppm (6Н) and one multiplet at 1.67 ppm (2Н) respectively.
In 1 Н NMR-spectrum of amide 4 the presence of acetamide residue was confirmed by the next signals: singlets of amide protons at 7.63 ppm (1H) and 7.11 ppm (1H) and intensive singlet of methylene group at 4.82 ppm.
The next stage of our synthetic research was obtaining water-soluble salts of 3-benzyl-8-propylxanthinyl-7-acetic acid 5-15 by heating of acid 2 with different primary, secondary aliphatic amines in water or aqueous propanol (Fig. 2).
Synthesized ammonium salts were white or pale yellow crystal compounds, soluble in water and insoluble in diethyl ester and acetone.
Physical-chemical properties of synthesized compounds 5-15 are represented in the Table 1. with the higher yield.
3. A number of water-soluble salts of 3-benzyl-8-propylxanthinyl-7-acetic acid have been obtained by reaction of acid with different primary and secondary amines.
4. The structures of all obtained compounds have been proved by the elemental analysis and 1H NMR-spectroscopy.