Vol. 20 No. 3 (2022)

Aim. To study the possibility of the N-difluoromethylation and separation of 1-difluoromethyl and 2-difluoromethyl isomers of C-substituted indazoles, as well as some possibilities of functionalization of such molecules.
Results and discussion. The N-difluoromethylation of indazole derivatives containing bromine, iodine, and nitro groups in various positions of the heterocyclic ring was studied. In all cases, the conditions for the separation of isomers – N-difluoromethylation products – in positions 1 and 2 were found. The corresponding amines, esters of carboxylic and boric acids were obtained as a result of further functionalization of 1- and 2-difluoromethylindazole derivatives.
Experimental part. The structure of the compounds synthesized was proven by ¹H and ¹⁹F NMR spectroscopy methods, as well as by the elemental analysis. The structure of isomeric difluoromethylindazoles was finally confirmed by the SELNOESY and ¹H-¹³C HMBC experiments.
Conclusions. A convenient method for the difluoromethylation of substituted indazoles has been found; difluoromethyl derivatives in positions 1 and 2 of the indazole ring have been obtained in high yields. The method for the efficient separation of isomeric difluoromethylindazoles has been found; some possibilities of their further functionalization have been described.

Aim. To generalize and systematize information on titrimetric methods for determining quaternary ammonium compounds (QACs).
Results and discussion. The review summarizes and systematizes information on the properties of surfactants, provides their classification, shows the main ways of use in the national economy, and their role in pharmacy and medicine. Currently known titrimetric methods for determining cationic surfactants (СS), in particular quaternary ammonium compounds, which are widely used in medicine and pharmacy, are described and summarized.
Conclusions. As a result of the study, the main directions of developing methods for determining QACs by titrimetry methods have been summarized; the disadvantages and advantages of each of the methods described have been shown. In the future, it can be the basis for developing new and more effective methods of analysis.

Aim. To synthesize 4-fluoro-1,8-naphthalic acid imide and its derivatives substituted in the imide ring.
Results and discussion. 4-Fluoro-1,8-naphthalimide was obtained using acenaphthene as the starting material. N-alkyl-4-fluoro-1,8-naphthalimides were synthesized via the phase transfer catalytic alkylation of 4-fluoro-1,8-naphthalimide with haloalkanes. Imidation of 4-fluoro-1,8-naphthalic anhydride with aminoacids resulted in the formation of N-carboxyalkyl-1,8-naphthalimides. These substances can be considered as potential fluorescent labels capable of binding to amino groups of various biological molecules as they contain carboxylic functionality in their structure.
Experimental part. The structure of the compounds synthesized was confirmed by FT-IR, ¹H NMR and ¹³C NMR spectroscopy, and mass-spectrometry.
Conclusions. It has been shown that 4-fluoro-1,8-naphthalinedicarboxylic acid imide can be obtained following the synthetic route “acenaphthene – 5-fluoroacenaphthene – 4-fluoro-1,8-naphthalic anhydride – 4-fluoro-1,8-naphthalimide”. 4-Fluoro-1,8-naphthalimide can be alkylated by butyl iodide and octyl bromide using tetraalkylammonium salts as a phase transfer catalyst resulted in N-butyl-4-fluoro-1,8-naphthalimide and N-octyl-4-fluoro-1,8-naphthalimide. As a result, N-carboxyalkyl-4-fluoro-1,8-naphthalimides have been obtained for the first time by aminolysis of 4-fluoro-1,8-naphthalic anhydride with glycine, β-alanine and 6-aminocaproic acid.

Aim. To study the elemental and amino acid composition of Cetraria islandica (L.) Ach. thalli batches harvested in Ukraine.
Materials and methods. Seven batches of C. islandica thalli harvested in different regions of Ukraine in late summer/early fall 2019 were used for the study. The elemental composition of the raw material was studied by atomic absorption spectrometry with photographic registration. The component composition of free and bound amino acids in the raw material was determined by the HPLC method.
Results and discussion. The presence of at least 19 macro-, trace and ultra-trace elements was determined in 7 batches of the raw material. The predominance of the following elements was found: potassium 190 mg/100 g (batch 6) – 325 mg/100 g (batch 7); silicon 30 mg/100 g (batch 1) – 115 mg/100 g (batch 4); calcium 37 mg/100 g (batch 6) – 86 mg/100 g (batch 4). It was determined that the quantitative content of molybdenum and cobalt did not exceed 0.03 mg/100 g, the content of cadmium, astatine and mercury did not exceed 0.01 mg/100 g. The quantitative content of lead met the requirements of the monograph of the State Pharmacopoeia of Ukraine (SPhU) 2.0. The total ash content in the batches of the raw material ranged from 0.61 ± 0.02 % to 1.43 ± 0.05 %, meeting the requirements of the monograph of the SPhU 2.0. The presence of 7 amino acids was determined; 5 of them were nonessential (aspartic and glutamic acids, serine, arginine, and alanine) and 2 were essential (threonine and valine). The quantitative content of the total amount of free amino acids was 0.794 μg mg^-1, the total amount of bound ones was 3.276 μg mg^-1.
Conclusions. For the first time, the elemental composition of 7 batches of C. islandica thalli harvested in Ukraine was determined. In each batch, potassium was the predominant element (from 190 mg/100 g to 325 mg/100 g depending on the batch). The component composition of free and bound nonessential and essential amino acids was determined (the quantitative content of the total amount of free amino acids was 0.794 μg mg^-1, the total amount of bound ones was 3.276 μg mg^-1); alanine (0.289 μg mg^-1) was the dominant component among free amino acids, while arginine (0.993 μg mg^-1) prevailed among bound ones. The results obtained will be used for further studies of the raw material of C. islandica harvested in Ukraine.

Aim. To determine the parameters of standardization of a dry extract from large cranberry (Oxycoccus macrocarpus (Ait.)) leaves and a dry extract modified with arginine and develop projects of Drug Quality Control Methods (DQCM) for these substances.
Materials and methods. The study object was dry extracts from large cranberry leaves. Leaves were harvested in October 2021 in the Zhytomyr region (Kostivtsi village, 50.326862437345945, 29.54310845594284). The extracts were obtained with a 50 % solution of ethyl alcohol in the ratio of 1:30 by double maceration. Half of the combined extract was dried to a dry extract (Extract 1), and the other half was modified with arginine in the threefold equimolar amount relative to the total amount of phenolic compounds and evaporated to a dry extract (Extract 2). Standard pharmacopoeial methods were used to determine standardization parameters. The quantitative determination was carried out using the spectrophotometric method by the content of flavonoids calculated with reference to hyperoside and hydroxycinnamic acids calculated with reference to chlorogenic acid on an Evolution 60S spectrophotometer (Thermo Scientific Spectronic, USA).
Results and discussion. The parameters of standardization of dry extracts from large cranberry leaves were determined. The project of DQCM was proposed according to the following indicators: description, solubility, identification using the thin-layer chromatography method (by the content of flavonoids, hydroxycinnic acids and arginine), loss on drying, the residual amount of organic solvents (ethanol), microbiological purity, and the content of heavy metals. The assay was carried out using spectrophotometry by the content of flavonoids and derivatives of hydroxycinnic acids. Three batches of the extracts obtained, which fully corresponded to the projects of DQCM developed, were analyzed.
Conclusions. The parameters of standardization of dry extracts from large cranberry leaves have been determined, and projects of DQCM for the substances obtained have been developed. It is the basis for creating new medicines for the correction of insulin-resistant conditions in Type 2 diabetes mellitus.