METHOD FOR OBTAINING 3-BROMO-4,4-DIMETHYL-3,4-DIHYDRO-2H-BENZO[4,5]IMIDASE[2,1-b][1,3]THIAZINE-1,1-DIOXIDE

Abstract

Method for obtaining 3-bromo-4,4-dimethyl-3,4-dihydro-2H-benzo[4,5]imidase[2,1-b][1,3]thiazine-1,1-dioxide involves the cyclization of 2-(2,3-dibromopropyl)thiobenzimidazole sulfone in the presence of sodium acetate in chloroform under continuous stirring. First, solution of dibromide sulfon in dimethyl sulfoxide, cooled to 5-10 °C, is prepared; sodium acetate is then added in a molar ratio of 1:10, and the reaction is carried out under stirring for 30-50 min. After the synthesis is complete, resulting crystalline precipitate is filtered, rinsed with diethyl ether, and dried.

Description

The utility model belongs to the field of chemical technology, namely to organic chemistry and pharmaceutical synthesis, and relates to methods for preparing cyclic thiazinobenzimidazole derivatives. These compounds are characterized by a high level of physiological activity and can be used in the pharmaceutical industry as biologically active substances or intermediates for the synthesis of medicines. Electrophilic intramolecular cyclization (EIC) reactions of functionally unsaturated substituted compounds are widely used in modern organic synthesis as an effective tool construction of various cyclic heterocyclic systems. High selectivity, mild conditions The conduct and possibility of purposeful formation of new -connections determine their key role in the synthesis of structurally complex condensed heterocycles. Within the framework of this approach, a special attention is paid to the reactions of EWC involving the nitrogen atoms of the benzimidazole fragment, which are intramolecular nucleophilic centers. Under the action of electrophilic reagents, in particular molecular bromine and iodine, the cyclization process is initiated with the formation of new condensed systems characterized by increased structural diversity and synthetic appeal [see Gevaza, YI, Staninets, VI Electrophilic heterocyclization of unsaturated amino compounds in the synthesis of nitrogen-containing heterocycles (review). Chem Heterocycl Compd. 1985, 21, 359-371]. In the studied reactions of halogenation of the alkenyl substituent the process proceeds according to the AE2 mechanism, which involves an electrophilic attack of the molecule of halogen to a multiple bond to form a cyclic onium cation intermediate. The formed the intermediate onium cation is characterized by high reactivity and undergoes further intramolecular nucleophilic substitution on the nitrogen atom of benzimidazole fragment that acts as a nucleophilic center. The spatial structure and length of the alkenyl substituent significantly affect the direction and outcome of cyclization. In the presence of an allylic substituent geometric conditions favor the closure of the five-membered ring, leading to the formation of a thiazole ring. Instead, in the case of the cinnamyl substituent, cyclization occurs with the formation of a more thermodynamically stable six-membered thiazine ring. Therefore, the regio- and cycle selectivity process is determined by the structural features of the alkenyl substituent, which determine the preferred route of intramolecular attack and the size of the newly formed heterocycle. This dependency makes it impossible to implement alternative cyclization paths and, accordingly, does not allow obtain 3-bromo-4,4-dimethyl-2,3,4-trihydro-1,1-dioxothiazino[2,3-b]benzimidazole under these conditions reactions. The closest in essence to the proposed method is the method for obtaining thiazine derivatives benzimidazole with a six-membered ring in its structure by cyclization of hydrobromides 2-(2,3- dibromopropylthio)benzimidazoles in chloroform in the presence of sodium acetate from the calculation of hydrobromide: CH3COONa=1:4 and with constant stirring for 1 hour. Then the chloroform layer is several washed once with water, dried with anhydrous sodium sulfate, evaporated in vacuo to form solid residue [see Krotkykh NI, Raenko GF, Shvaika OP Heterocyclizations of 2- allylthiobenzimidazoles into benzimidazo[2,1-b]-1,3-thiazine derivatives. Chemistry of Heterocyclics Compounds. 1995, 3, 410-415.]. The method described in this article is not without significant drawbacks. In particular, under the described conditions The cyclization reaction of dibromide produces a complex mixture of products, resulting in the target compound - 3-bromo-4,4-dimethyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine-1,1-dioxide, which belongs to condensed derivatives of thiobenzimidazole, it can be isolated in pure form only from limited output, not exceeding 50%. The problem to which the claimed utility model is aimed is the development of a method preparation of cyclic thiazinobenzimidazole - 3-bromo-4,4-dimethyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1- b][1,3]thiazine-1,1-dioxide without foreign impurities by improving the technological scheme and rational choice of conditions for the cyclization reaction. The problem is solved by the fact that in the method of obtaining 3-bromo-4,4-dimethyl-3,4-dihydro-2H- benzo[4,5]imidazo[2,1-b][1,3]thiazine1,1-dioxide, involving the cyclization of the sulfone 2-(2,3- dibromopropyl)thiobenzimidazole in the presence of sodium acetate in chloroform under continuous stirring, according to the utility model, a solution cooled to 5-10 °C is pre-prepared of sulfone dibromide in dimethyl sulfoxide, to which sodium acetate is added in molar in a ratio of 1:10 and carry out the reaction under stirring conditions for 30-50 minutes; after Upon completion of the synthesis, the formed crystalline precipitate is filtered off, washed with diethyl ether, dried. The claimed method is implemented in laboratory conditions as follows. To a solution of 0.0025 mol of 2-(2, 3-dibromopropyl)thiobenzimidazole sulfone in 20 ml dimethyl sulfoxide, cooled to 5-10 °C, with stirring add sodium acetate in 10 ml water in a ratio of 1:10, carry out the synthesis with stirring for 30-50 minutes. Upon completion The precipitate formed during the reaction is washed with water, diethyl ether, filtered and Recrystallization from a methanol-water mixture (1:2) yielded 0.57 g, 69% of a white precipitate of 3-bromo-4,4- dimethyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine-1,1-dioxide. Tmp. 172-173 °C Elemental analysis for C12H13BrN2O2S. Found, %: C 43.85; H 4.10; Br 24.36; N 8.45; S 9.67. Calculated, %: C 43.77; H 3.95; Br 24.27; N 8.51; S 9.74. 1H-NMR spectrum in DMSO-D6 (δ, ppm, J, Hz): 1.48 (3H, s, CH3); 1.62 (3H, c, CH3); 3.72 (2H, m, SCH2); 5.48 (1H, m, CHBr); 7.34…7.93 (4H, m, Narom.). Found, %: C 43.85; H 4.10; Br 24.36; N 8.45; S 9.67. C12H13BrN2O2S. Calculated, %: C 43.77; H 3.95; Br 24.27; N 8.51; S 9.74. The experimental data presented indicate that the proposed method for obtaining cyclic thiazinobenzimidazole sulfone - 3-bromo-4,4-dimethyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine- 1,1-dioxide provides selective formation of the target product with high purity and stable reproducibility of results. Optimized cyclization reaction conditions allow minimize the formation of by-products and significantly increase the efficiency of the process compared to known methods. In particular, the use of dimethyl sulfoxide as a reaction medium and a tenfold molar excess of sodium acetate creates favorable conditions for complete cyclization oxidized 2-(2,3-dibromopropyl)substituted thiobenzimidazole derivatives, which provides the preparation of condensed thiazinobenzimidazole sulfones with increased yield and without impurities. The utility model can be used to obtain condensed thiazine derivatives benzimidazole or cyclization products of other heterocyclic compounds in industrial and research facilities laboratories, as well as in serial production, suitable for the manufacture of pharmaceuticals components with antimicrobial, antiallergic and other types of pharmacological action, which determines the feasibility of their use in medical practice and pharmaceutical production.

Claims

Method for preparing 3-bromo-4,4-dimethyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine-1,1- dioxide, which involves the cyclization of 2-(2,3-dibromopropyl)thiobenzimidazole sulfone in presence of sodium acetate in chloroform with continuous stirring, which differs in that a sulfone solution cooled to 5-10 °C is prepared in advance dibromide in dimethyl sulfoxide, to which sodium acetate is added in molar in a ratio of 1:10 and carry out the reaction under stirring conditions for 30-50 minutes; after Upon completion of the synthesis, the formed crystalline precipitate is filtered off, washed with diethyl ether. ether, dried.