Method for obtaining 2,3-diphenyl-6-{[5-(trifluoromethyl)pyridine-2-yl]oxy}-6,7-dihydro-5h-imidase[2,1-b][1,3]thiazine

Abstract

Method for obtaining 2,3-diphenyl-6-{[5-(trifluoromethyl)pyridine-2-yl]oxy}-6,7-dihydro-5H-imidase[2,1-b][1,3]thiazine involves the reaction of starting material, 6-hydroxy-2,3-diphenyl-6,7-dihydro-5H-imidase[2,1-b][1,3]thiazine, with halogen-substituted pyridine in dimethylformamide. Previously obtained solution of 2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazine-6-ol and NaH in dimethylformamide is stirred for 0.5 hours at room temperature; only then is 5-(trifluoromethyl)-2-chloropyridine added in a 1:1 ratio, and mixture is subjected to intensive stirring for 24 hours. Then reaction mixture is poured onto ice; resulting precipitate is filtered off and identified as 2,3-diphenyl-6- {[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]-thiazine. Thus, the synthesis is carried out by first preparing solution of starting compound with NaH using the method of prolonged stirring, followed by the main synthesis with a reaction time of 24 hours.

Description

The utility model belongs to the field of organic chemistry, in particular the chemistry of heterocyclic compounds, and concerns condensed imidazo[2,1-b]thiazine derivatives, which can be used as promising structural platforms for the creation of biologically active substances. Functionally substituted imidazo[2,1-b]thiazine systems are known to exhibit a wide range of biological activity, including antimicrobial, antimycobacterial and antiprotozoal, as well as may exhibit anti-inflammatory, antioxidant and cytostatic properties [see Samala, G., Devi, P. B., Saxena, S., Meda, N., Yogeeswari, P., Sriram, D. Design, synthesis and biological evaluation of imidazo[2,1-b]thiazole and benzo[d]imidazo [2, 1-b]thiazole derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors. Bioorganic & medicinal chemistry. 2016, 24(6), 1298-1307. Thompson, AM; Marshall, AJ; Maes, L.; Yarlett, N.; Bacchi, CJ Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1- b][1,3]thiazine 8-oxides. Bioorg. Med. Chem. Lett. 2018, 28, 207-213]. Due to the peculiarities of the chemical structures, such compounds are suitable for use as active ingredients, intermediates or building blocks in the synthesis of drugs and other biologically active substances and can be applied in scientific research and industrial practice. A known method for the synthesis of 3-benzyloxy-substituted 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazoles is based on the alkylation of the corresponding 3-hydroxy derivatives with arylating reagents. Implementation The method involves treating a solution of 3-hydroxy-3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole in anhydrous dimethylformamide with sodium hydride in an inert atmosphere of argon followed by by adding bromobenzyl derivatives at reduced temperatures [see El-Ashry El-Sayed H., Kilany Y. El, Nahas NM, Barakat A., Al-Qurashi N., Ghabbour HA, Fun H.-K. Synthesis and Crystal Structures of Benzimidazole-2-thione Derivatives by Alkylation Reactions. Molecules. 2015, 21(1), 12]. After completion the reaction mixture is subjected to multi-stage extraction, drying of organic phases and purification of products by column chromatography on silica gel, resulting in the target 3- benzyloxy-substituted derivatives in the form of solids. The disadvantage of this approach is its significant technological complexity due to the need to work in an inert gas atmosphere, as well as multi-stage processes of isolation and purification of individual products. In addition, the described the method is used mainly for the synthesis of benzyloxy-substituted derivatives and is not focused on Preparation of 6-pyridinyloxy-substituted imidazo[2,1-b][1,3]thiazines. A method for obtaining 6-{[4-(trifluoromethoxy)benzyl]oxy}- and 6-{[4- benzyloxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines, which does not require the use of inert atmosphere. In this case, the 6-hydroxy derivative is treated with sodium hydride and the corresponding benzyl halides in dry dimethylformamide at room temperature followed by neutralization, extraction and purification of products by column chromatography [see Thompson, AM, Blaser, A., Anderson, RF, Shinde SS Synthesis, Reduction Potentials, and Antitubercular Activity of Ring A / B Analogues of the Bioreductive Drug (6S)-2-Nitro-6-{[4- (trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). Journal of Medicinal Chemistry. 2009, 52, 3, 637-645]. However, the disadvantage of this approach is the duration and complexity of the procedures. isolation and purification, especially in the case of the synthesis of 6-pyridinyloxy-substituted 6,7-dihydro-5H- imidazo[2,1-b][1,3]thiazines. The closest in technical essence to the proposed method is the method of obtaining 6- pyridinyloxy-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines by the reaction of 6- hydroxy derivative with halogen-substituted pyridine derivatives in dimethylformamide medium by presence of 60% sodium hydride with constant stirring [see Thompson AM, Marshall AJ, Maes L., Yarlett N., Bacchi CJ Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to- lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides. Bioorganic and Medicinal Chemistry Letters. 2018, 28, 207-213.] However, the aforementioned work lacks a detailed description of the stages of isolation and purification of final products, which in other methods are technologically complex and laborious, which makes it impossible to use this approach as a universal model in practice for the synthesis of 6-pyridinyloxy-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines. The objective of the utility model is to improve the method of synthesis and isolation of 2,3-diphenyl-6-{[5- (trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine, in particular by optimization of reaction parameters and introduction of additional technological operations, which provide increased process reproducibility and simplification of target isolation stages product. The problem is solved by the fact that in the method of obtaining 6-pyridinyloxy-substituted 6,7- dihydro-5H-imidazo[2,1-b][1,3]thiazines, which involves the interaction of the starting 6-hydroxy-2,3-diphenyl- 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine with halogen-substituted pyridine in the presence of sodium hydride in in dimethylformamide medium, to obtain 2,3-diphenyl-6-{[5-(trifluoromethyl)pyridine-2- yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine, according to the utility model, previously obtained solution of 2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-6-ol and NaH in dimethylformamide stirred for 0.5 h at room temperature, only then add 5-(trifluoromethyl)-2- chloropyridine in a ratio of 1:1; the mixture is subjected to intensive stirring for 24 hours, after which the reaction mass is poured onto ice; the precipitate formed is filtered off and identified as 2,3- diphenyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]-thiazine. The claimed method can be illustrated by the following non-limiting example. utility model. A round-bottom flask equipped with a magnetic stirrer is charged with 0.0025 mol of 2,3-diphenyl- 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-6-ol and 0.1 g sodium hydride (60% dispersion in mineral oil, 0.004 mol). The mixture is stirred at room temperature for 0.5 h, after which it is added 0.0025 mol of 5-(trifluoromethyl)-2-chloropyridine and continue stirring for 24 h. The reaction mixture is poured onto ice, the precipitate formed is filtered off and recrystallized from methanol. Establishing the structure of the reaction product confirmed the production of 0.76 g (67%) of 2,3-diphenyl- 6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo-[2,1-b][1,3]thiazine. T. fuel 154-155 °C. Elemental analysis for C24H18F3N3OS. Found, %: 63.75; H, 3.97; N, 9.19. Covered, %: C, 63.57; H, 4.00; N, 9.27. NMR 1H spectrum, CDCl3, δ, m. h. (spin coupling constant, J, Hz): δ = 8.54 (s, 1H, Ar), 8.05 (d, 3J=9.0 Hz, 1H, Ar), 7.43-7.44 (m, 3H, Ar), 7.33-7.34 (m, 2H, Ar), 7.28-7.29 (m, 2H, Ar), 7.14-7.17 (m, 2H, Ar), 7.07-7.10 (m, 1H, Ar), 7.05 (d, 3J=8.4 Hz, 1H, Ar), 5.80-5.82 (m, 1H, CH), 4.13-4.16 (m, 1H, NCH2), 3.92-3.95 (m, 1H, NCH2), 3.62-3.64 (m, 1H, SCH2), 3.53-3.57 (m, 1H, SCH2). NMR spectrum 13C, CDCl3, δ, m. p.: δ = 164.49 (Py), 145.22 (q, 3JCF=4.5 Hz, Py), 137.38 (q, 4JCF=3.0 Hz, Py), 137.01 (C8a), 136.83 (C3), 134.62, 130.97, 130.19 (Ar), 129.85 (C2), 129.54, 129.22, 128.51, 126.67, 126.40 (Ar), 124.39 (d, 1JCF=270.0 Hz, CF3), 119.95 (q, 2JCF=33.0 Hz, Py), 112.47 (Py), 65.92 (C6), 47.33 (C5), 28.40 (C7). LC-MS: m / z=454 [M+1] (100%). From the experimental data presented, it follows that the proposed method provides possibility of targeted production of 2,3-diphenyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7- dihydro-5H-imidazo[2,1-b][1,3]thiazine in one step with high yield and satisfactory purity without application of multi-stage purification procedures. Replacement of halogen-substituted pyridine derivatives allows you to vary the structure of the substituent without changing the fundamental conditions of the synthesis. The proposed utility model can be used for the synthesis of the specified compound, as well as related 6-pyridinyloxysubstituted imidazo[2,1-b][1,3]thiazine derivatives and substitution products other hydroxy derivatives of heterocyclic compounds in research and production laboratories, in particular for the creation of libraries of biologically active substances.

Claims

Method for preparing 2,3-diphenyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H- imidazo[2,1-b][1,3]thiazine, which involves the reaction of the starting 6-hydroxy-2,3- diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine with halogen-substituted pyridine in in a dimethylformamide medium, which is characterized in that the previously obtained solution 2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-6-ol and NaH in dimethylformamide stirred for 0.5 h at room temperature, only then add 5- (trifluoromethyl)-2-chloropyridine in a ratio of 1:1, the mixture is subjected to intensive stirring for 24 h, after which the reaction mass is poured onto ice formed The precipitate is filtered off and identified as 2,3-diphenyl-6-{[5-(trifluoromethyl)pyridine-2- yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]-thiazine; thus the synthesis is carried out at preliminary preparation of a solution of the starting compound with NaH by prolonged stirring and carrying out the main synthesis with a holding time of 24 hours.