METHOD FOR OBTAINING 3-(n-TOLYL)-5,6-DIHYDROIMIDASE[2,1-b][1,3]THIAZOLE

Abstract

Method for obtaining 3-(n-tolyl)-5,6-dihydroimidase[2,1-b][1,3]thiazole involves the reaction of imidazolidine-2-thione with α-bromoacetophenone. Starting imidazolidine-2-thione is dissolved in ethanol, and α-bromoacetophenone is added. Then reaction mixture is boiled for 4 hours without catalyst. After the reaction is complete, solvent is removed, solid residue is dissolved in 30 mL of acetone, neutralized with aqueous solution of NaHCO₃ , and extracted with chloroform three times in 10-mL portions. The combined organic phases are dried over Na₂ SO₄ and evaporated to obtain the target product, which is identified as 3-(n-tolyl)-5,6-dihydroimidase[2,1-b][1,3]thiazole.

Description

The utility model belongs to the field of chemical technology, and more precisely to organic chemistry, and can be used to obtain azole-thiazole compounds with a pronounced pharmacological profile. The imidazothiazole nucleus is an important structural component of a number of biologically active compounds and medicinal products. In particular, the specified heterocyclic fragment is part of anthelmintic and immunomodulatory drugs, as well as compounds that exhibit antitumor activity activity, including against acute myeloid leukemia [see Amarouch H., Loiseau PR, Bacha C., Caujolle R., Payard M., Loiseau PM, Bories C., Gayral P. Imidazo[2,1-b]thiazoles: analogues du levamisole. Eur. J. Med. Chem. 1987, 22 (5), 463-466. Montalban-Bravo G., Jabbour E., Chien K., Hammond D., Short N., Ravandi F., Konopleva M., Borthakur G., Daver N., Kanagal-Shammana R., Loghavi S., Qiao W., Huang X., Schneider H., Meyer M., Kantarjian H., Garcia-Manero G. Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS / MPN. Leuk. Res. 2024, 142, 107518]. In addition, the imidazothiazole motif is present in the structures of substances with anxiolytic, antineoplastic and neuroprotective effects, as well as modulators enzymatic activity, in particular sirtuins and lipoxygenases, and inhibitors of enzymes involved in immune processes [see Krueger JG, Suárez-Fariñas M, Cueto I, Khacherian A, Matheson R, Parish LC, Leonardi C., Shortino D., Gupta A., Haddad J., Vlasuk GP, Jacobson EW A Randomized, Placebo- Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis. PloS One. 2015, 10 (11), e0142081. Dianat S., Moghimi S., Mahdavi M., Nadri H., Moradi A., Firoozpour L., Emami S., Mouradzadegun A., Shafiee A., Foroumadi A. Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase. J. Enzyme Inhib. Med. Chem. 2016, 31, 205-209]. In addition to pharmacological applications, functionalized imidazothiazoles are attracting attention as promising objects for creation of selective organocatalysts, as well as potential components of electroluminescent materials suitable for use in OLED devices and LED light sources [see Yin X., Yang Z., Huang G., Bian J., Wang D., Wang Q., Teng M., Wang Z., Zhang J. Synthesis and properties of a series of iridium complexes with imidazolo[2,1-b]thiazole derivatives as primary ligands. New J. Chem. 2019, 43, 5849-5856]. The combination of these properties causes increased interest in development of new imidazothiazole derivatives and improvement of methods for their preparation. A known method for constructing the imidazo[2,1-b]thiazole nucleus and its condensed derivatives is cyclocondensation reactions between 2-aminothiazoles and alkyl- or (het)aryl bromoketones, which are carried out under heating conditions in polar organic solvents and include a stage intramolecular nucleophilic substitution with subsequent formation of an imidazole ring. However, this approach requires the use of reactive and chemically unstable bromoketones, which complicates their storage and handling, and also limits their environmental safety process. In addition, such reactions are often characterized by limited functional tolerance, which reduces the possibility of introducing sensitive or bulky substituents into the heterocyclic framework and can lead to the formation of by-products and reduced yields of target compounds. For the synthesis of functionalized imidazothiazoles, methods based on using halogen-containing oxoacids and their esters, which interact with thiazole or nitrogen-containing substrates with the formation of substituted or condensed heterocyclic systems. At the same time, such methods, as a rule, involve multi-stage processes using activators, excess reagents or harsh reaction conditions, which negatively affects the selectivity of the transformations and complicates the purification of the final products. Additional disadvantages are limited reproducibility of results when scaled up, as well as the formation of a significant amount of by-products, which reduces the total yield of functionalized imidazothiazoles. The closest in essence to the proposed method is the method for obtaining 3-aryl-5,6- dihydroimidazo[2,1-b][1,3]thiazoles by the interaction of 1 mmol of imidazolidine-2-thione and 1 mmol of α- of tosyloxyketone in the presence of 1 mmol of montmorillonite K-10 clay as a catalyst. The obtained The reaction mass was subjected to microwave irradiation for 3 minutes with periodic The thiazole salt formed during the reaction was neutralized by adding diluted aqueous sodium hydroxide solution. After that, the product was extracted with methylene chloride twice in portions 10 ml each. The organic phase was dried over anhydrous sodium sulfate, after which the solvent was removed under reduced pressure. The resulting residue was purified by crystallization from a mixture of benzene- hexane, resulting in the corresponding 3-aryl-5,6-dihydroimidazo[2,1-b][1,3]thiazoles [see Varma RS, Kumar D., Liesen PJ Solid state synthesis of 2-aroylbenzo[b]furans, 1,3-thiazoles and 3-aryl-5,6- dihydroimidazo[2,1-b][1,3]thiazoles from α-tosyloxyketones using microwave irradiation. J. Chem. Soc. Perkin Trans. 1998, 1, 4093-4096]. However, this method has a number of disadvantages, in particular it involves the use of microwave radiation, which requires specialized equipment and limits process scalability. Application of heterogeneous montmorillonite clay catalyst K-10 complicates the reproducibility of results and purification of the reaction mass. The method is characterized by multi-stage post-reaction treatment, including neutralization, extraction and recrystallization, which reduces the overall efficiency of the process. Additional disadvantages include the use of toxic organic solvents, in particular methylene chloride and benzene, and also the need for preliminary preparation of α-tosyloxy ketones, which complicates the synthetic scheme and increases the cost of the method. The problem to which the claimed utility model is aimed is the development of a method synthesis and isolation of the target product, which ensures a reduction in the number of process stages, increasing reproducibility and environmental safety, as well as expanding opportunities scaling. The task is solved as follows. In the method for preparing 3-(n-tolyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole, according to the claimed utility model, the starting imidazolidine-2-thione is dissolved in ethanol, α-bromoacetophenone is added, after which the reaction mixture is boiled in the absence of a catalyst for 4 hours; after completion of the reaction The solvent is removed, the solid residue is dissolved in 30 ml of acetone, neutralized with an aqueous solution. NaHCO3 and extracted with chloroform three times in 10 ml portions; the combined organic phases are dried over Na2SO4 and evaporated to obtain the target product, which is identified as 3-(n-tolyl)-5,6- dihydroimidazo[2,1-b][1,3]thiazole. The claimed method can be illustrated by an example carried out in laboratory conditions. In a round-bottom flask equipped with a magnetic stirrer and a water-cooled reflux condenser cooling, charge 0.5 g (4.96 mmol) of the starting imidazolidine-2-thione in 20 ml of ethanol, 4.96 mmol of the corresponding α-bromoacetophenone are added, after which the reaction mixture is boiled at oil bath for 4 hours. After the reaction is complete, the solvent is removed, the solid residue dissolved in 30 ml of acetone, neutralized with aqueous NaHCO3 solution and extracted with chloroform three times 10 ml. The combined organic phases are dried over Na2SO4 and evaporated to obtain target product. The establishment of the structure of the reaction product confirms the obtaining of 0.29 g, 69% of the precipitate of 3-(n-tolyl)- 5,6-dihydroimidazo[2,1-b][1,3]thiazole (mp 66-67 °C). Elemental analysis for C12H12N2S. Found, %: C 66.82; H 5.64; N 12.83. Calculated, %: C 66.63; H 5.59; N 12.95. 1H NMR spectrum (300 MHz, DMSO-d6): δ 2.32 (singlet, 3H), 3.84 (triplet, ³J=9.0 Hz, 2H), 4.07 (triplet, ³J=9.0 Hz, 2H), 6.06 (singlet, 1H), 7.25 (doublet, ³J=9.0 Hz, 2H), 7.43 (doublet, ³J=6.0 Hz, 2H). 13C NMR (125 MHz, DMSO-d6): δ=20.8; 47.7; 56.0; 101.3; 126.4; 126.5; 129.5; 136.9; 139.1; 169.6. Mas- spectrum, m / z: =217 [M+1] (100%). From the above data it follows that the proposed method provides the synthesis of 3-(n-tolyl)-5,6- dihydroimidazo[2,1-b][1,3]thiazole in one step with high yields, with changes in the structure of the product are achieved only by replacing the corresponding phenacyl bromide. The proposed method is simple, reproducible, and scalable, which makes its effective for use in both research and production laboratories for obtaining functionalized derivatives of imidazo[2,1-b][1,3]thiazoles.

Claims

Method for preparing 3-(n-tolyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole, involving the interaction imidazolidine-2-thione with α-bromoacetophenone, which is characterized in that the starting imidazolidine-2-thione is dissolved in ethanol, α-bromoacetophenone is added, after which the reaction mixture the mixture is boiled for 4 hours without using a catalyst, after the reaction is complete The solvent is removed, the solid residue is dissolved in 30 ml of acetone, neutralized with aqueous NaHCO3 solution and extracted with chloroform three times in 10 ml portions, the combined organic phases are dried over Na2SO4 and evaporated to obtain the target product, which identified as 3-(n-tolyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole.