Method for synergistically preparing 3, 4-dihydro-2H-benzo [b] [1, 4] thiazine from monopersulfate

Abstract

The invention provides a method for synergistically preparing 3, 4-dihydro-2H-benzo [b] [1, 4] thiazine through monopersulfate, and belongs to the technical field of heterocyclic compounds. In the presence of a mixed solvent, a 2-N-benzenesulfonyl substituted phenylmethyl sulfide derivative and a halide MX are used as raw materials, and the (E)-2-(halogenated methylene)-4-p-toluenesulfonyl-3, 4-dihydro-2H-benzo [b] [1, 4] thiazine is prepared through catalysis of a catalyst monopersulfate at the reaction temperature of not more than 80 DEG C. The preparation method comprises the following steps of: preparing the (E)-2-(halogenated methylene)-4-p-toluenesulfonyl-3, 4-dihydro-2H-benzo [b] [1, 4] thiazine, the method has the advantages of simple preparation steps, mild reaction conditions, environmental protection, high product yield, high stereoselectivity, simple composition of raw materials and auxiliary materials participating in the reaction, low price, and easy obtaining, and reduces the synthesis cost.

Description

Technical Field

[0001] The present application relates to a method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine in cooperation with monopersulfate, belonging to the technical field of heterocyclic compounds. Background Art

[0002] 1,4-Benzothiazine and its derivatives are an important class of heterocyclic compounds, whose skeletons are widely found in natural products and synthetic drug molecules, and have a broad spectrum of biological activities, such as antibacterial activity, and can be used for anti-diabetes, anti-arrhythmia and anti-tumor, etc. Therefore, the research on its synthesis methods in the fields of synthetic chemistry and medicinal chemistry has attracted widespread attention from scientists.

[0003] Among them, alkenyl halides with defined stereo configurations are important reaction building blocks for the synthesis of complex functional molecules (such as tetrasubstituted alkenes), and are widely used in the construction of CC bonds and CX (X is a heteroatom) bonds. Many classic cross-coupling reactions (such as Heck reaction, Suzuki reaction, etc.) use alkenyl halides as starting materials. It is well known that in the coupling reaction catalyzed by transition metal Pd, the activity order of alkenyl or aryl halides is: iodide> bromide>> chloride. In addition, alkenyl halides also have important applications in the field of medical research, such as thyroid treatment, single photon emission computed tomography, X-ray imaging, etc. Therefore, it is of great significance to develop a green, simple, efficient and stereoselective CX bond construction method.

[0004] At present, the commonly used methods for 1,4-benzothiazine compounds are as follows:

[0005] a) Using aryl halides as starting materials, a tandem cyclization reaction between molecules is carried out under the action of transition metals. For details, see the literature Jiang, et al., Efficient Access to 1,4-Benzothiazine: Palladium-Catalyzed Double CS Bond Formation Using Na2S2O3 as Sulfurating Reagent, Org. Lett. 2013, 15, 2594; Gong, et al., Application of Thio-Ugi Adducts for the Preparation of Benzo[b]thiophene and S-Heterocycle Library via Copper Catalyzed Intramolecular CS Bond Formation, ACS Comb. Sci. 2015, 17, 365; Zhang, et al., Copper-Catalyzed Three-Component Tandem Cyclization for One-Pot Synthesis of 1,4-Benzothiazines, J. Org. Chem. 2016, 81, 8647; Orentas, et al. al.,N-Tosyl-1,5,2,6-dithiadiazocane:AWaste-free Electrophilic Sulfur Reagent for the EfficientSynthesis of Medium-ring S,N-Heterocycles,Chem.Commun.2016,52,4325;

[0006] This method uses aromatic halides as starting materials and usually requires the use of transition metal catalysts such as Pd and Cu. It is not only costly and has poor biocompatibility, but also produces metal residues during the drug production process, which is not in line with the concept of sustainable development chemistry.

[0007] b) Using a derivative of 2-aminothiophenol as a starting material, undergoing an intramolecular nucleophilic substitution reaction, see Matsuoka, et al., Antirheumatic Agents: Novel Methotrexate Derivatives Bearing a Benzoxazine or Benzothiazine Moiety, J. Med. Chem. 1997, 40, 105; Barbe, et al., Synthesis of 4-octyl-2H-1,4-benzo-thiazin-3-ones, Eur. J. Med. Chem. 2003, 38, 769;

[0008] This method uses a derivative of 2-aminothiophenol as a starting material, usually has a short reaction time and good substrate adaptability, but usually requires multiple steps to achieve, and requires the use of a large number of toxic and hazardous reagents, which not only has poor step economy, but also produces a large amount of toxic waste liquid, which is very harmful to both the operator and the environment.

[0009] c) Using thioamide-substituted aromatic amine derivatives as starting materials, an electrochemically promoted intramolecular dehydrogenative coupling reaction is carried out. For details, see Xu, et al., Continuous-Flow Electrosynthesis of Benzofused S-Heterocycles by Dehydrogenative CS Cross-Coupling, Angew. Chem. Int. Ed. 2019, 58, 6650, etc.

[0010]

[0011] This method uses an electrochemically promoted thioamide derivative as a starting material and undergoes an intramolecular dehydrogenation coupling reaction, but it consumes electrical energy and has high requirements for the reaction equipment. Summary of the invention

[0012] In view of this, the present application provides a method for preparing a 3,4-dihydro-2H-benzo[b][1,4]thiazine skeleton in one step by using monopersulfate in conjunction with a halide. In the presence of a mixed solvent, a 2-N-benzenesulfonyl-substituted anisole derivative (I) and a halide MX are used as raw materials, and monopersulfate is used as a catalyst and initiator to react to obtain (E)-2-(halomethylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (II).

[0013] The structural formula of compound (I) is expressed as:

[0014]

[0015] The structural formula of compound (II) is expressed as:

[0016] Here, R is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 4-chlorophenyl, etc. Me-methyl, Ts-benzenesulfonyl.

[0017] The above scheme uses 2-N-benzenesulfonyl substituted anisole derivatives and halides as raw materials, monopersulfate as initiator and catalyst, and synthesizes (E)-2-(halogenated methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine in a simple, efficient, green and highly stereoselective manner. The method for preparing 1,4-benzothiazine compounds by using monopersulfate in conjunction with halides is not only simple in steps, but also can be completed without the reaction temperature exceeding 80°C, and the reaction conditions are mild and green. In addition, the raw materials and auxiliary materials involved in the reaction are simple in composition, cheap and easy to obtain, and the product yield is high, the stereoselectivity is high, and the synthesis cost is reduced.

[0018] Further, as a preference:

[0019] In the halide MX, M is K or Na, and X is a halogen element, such as any one of Br and I, and is preferably sodium iodide (NaI) or potassium iodide (KI) or sodium bromide (NaBr).

[0020] The monopersulfate is potassium monopersulfate

[0021] The catalytic reaction time is 20 to 48 hours. When the molar addition amount of the monopersulfate is 1 to 3 times the molar addition amount of the 2-N-benzenesulfonyl substituted anisole derivative (i.e., the molar ratio of the monopersulfate to the 2-N-benzenesulfonyl substituted anisole derivative (I) is 1 to 3:1), the catalyst can ensure good reaction activity, raw material reaction rate and conversion rate are both above 70%, and the cost can be well controlled in this range. In the experimental process, we found that when the molar addition amount of potassium monopersulfate is 2 times the molar addition amount of the 2-N-benzenesulfonyl substituted anisole derivative (i.e., the molar ratio of the monopersulfate to the 2-N-benzenesulfonyl substituted anisole derivative (I) is 2:1), the catalytic effect is the best, at this time, the reaction speed is fast and the reaction is stable, and the yield of the target product is as high as 72%. In addition, the molar ratio of the monopersulfate to the 2-N-benzenesulfonyl-substituted thioanisole derivative (I) is 1 to 3:1.

[0022] On the basis of the above technical scheme, we have further studied the solvent and determined that the preferred reaction solvent satisfies: when the mixed solvent is a mixture of any one of tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane and water, the reaction effect is better. With the mixed solvent, on the one hand, water helps the solvent of the catalyst, and on the other hand, tetrahydrofuran helps the dissolution of the raw material. Therefore, the solubility problem of the catalyst and the raw material is mainly solved, thereby reducing the occurrence of side reactions, and the yield is improved as a result. The mixed volume ratio of any one of tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane and water is preferably 1:3. In particular, tetrahydrofuran-water (v / v=1:3) has a high yield, so the reaction solvent is preferably tetrahydrofuran-water (v / v=1:3).

[0023] Based on the above technical solution, we have conducted a systematic study on the reaction temperature and determined that the optimal reaction parameters meet the following requirements: In the high reaction temperature range above 60°C, when the catalytic reaction temperature is 80-100°C, the finished product yield can be guaranteed to be around 70%. Too high a temperature does not significantly increase the yield, but on the contrary, it increases energy consumption, which is not conducive to cost control; and when the reaction temperature is too low, such as 25-40°C, the reaction activity is poor, the reaction rate will decrease, and the raw materials cannot be completely converted. Therefore, under comprehensive consideration, the reaction temperature is appropriately controlled at 40-80°C, and the reaction effect is better at 60-80°C.

[0024] The beneficial effects of the present invention are as follows:

[0025] (1) The present invention realizes a one-step reaction to prepare (E)-2-(iodo- or bromo-methylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine by controlling an alcohol solvent and utilizing the catalytic effect of potassium monopersulfate, which provides a new method for preparing such compounds. The method has fewer reaction steps, mild reaction conditions, and simple operation. The raw materials and auxiliary materials involved in the reaction are all cheap and readily available, thereby reducing the synthesis cost.

[0026] (2) The present invention is applicable to a wide range of substrates. In the above process, the catalyst, halide and mixed solvent are all conventional reagents, which are non-toxic and non-corrosive. The reaction is carried out in air. The entire reaction process has no particularly stringent external requirements and has good substrate extensibility. The substituent R on the skeleton structure has good reactivity, including not only hydrogen, alkyl, aryl, and naphthyl. The finished product yield can be controlled at above medium, and can reach up to 82%.

[0027] (3) The (E)-2-(halogenated methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine prepared by the above method can be further derivatized and converted into other functional compounds, which will have great application potential in biomedicine, functional materials and other fields.

[0028] In the above technical scheme, potassium monopersulfate is used as a catalyst and a mixed solvent is used, so that the reaction system can complete the synthesis of (E)-2-(halogenated methylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine at 60°C. The reaction conditions are mild, the raw materials and catalysts are cheap and easy to obtain, the stereostructure of the product is single, and after the reaction is completed, the product is dried and passed through a column to obtain a fine product, and the yield can be guaranteed to be 72-82%. Compared with the conventional preparation method, the catalyst is commercial potassium monopersulfate. It has the advantages of being cheap, easily available, and green. When the halide is cheap sodium iodide, it is non-toxic and non-corrosive. The mixed solvent is a mixture of tetrahydrofuran and water. It can not only greatly reduce the preparation cost of (E)-2-(halomethylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, but also reduce pollution. Therefore, it is easier to industrialize and promote. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 For product A1 1 H spectrum;

[0031] Figure 2 For product A1 13 C spectrum;

[0032] Figure 3 For product A2 1 H spectrum;

[0033] Figure 4 For product A2 13 C spectrum;

[0034] Figure 5 For product A3 1 H spectrum;

[0035] Figure 6 For product A3 13 C spectrum;

[0036] Figure 7 For product A4 1 H spectrum;

[0037] Figure 8 For product A413 C spectrum;

[0038] Fig. 9 For product A5 1 H spectrum;

[0039] Fig.10 For product A5 13 C spectrum;

[0040] Fig.11 For product A6 1 H spectrum;

[0041] Fig.12 For product A6 13 C spectrum. DETAILED DESCRIPTION

[0042] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0043] The analytical instruments and equipment used in this example are: nuclear magnetic resonance instrument, AVANCE DMXⅡⅠ400M (TMS internal standard, Bruker Company).

[0044] The following six representative structures A1, A2, A3, A4, A5 and A6 are prepared, and the details are shown in Examples 1 to 6.

[0045]

[0046] Example 1

[0047] This example is used to prepare product A1, whose chemical name is: (E)-2-(bromo(phenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the preparation process is as follows:

[0048] A 10 mL round-bottom flask was sequentially added with 2-N-benzenesulfonyl-substituted anisole derivative (81.5 mg, 0.2 mmol), potassium monopersulfate (300 mg, 0.4 mmol, the main active ingredient KHSO5 content was about 46%, produced by Inokai Reagent Company), sodium bromide (41.2 mg), and a mixed solvent (2 mL) of tetrahydrofuran and water (v / v=1:3), stirred at 60°C for 24 h, spin-dried, and column-filtered with petroleum ether-ethyl acetate (v / v=5:1) to obtain 68.0 mg of the target compound, recorded as product A1, which was a light yellow solid with a yield of 72% and a raw material conversion rate (I) of 95%. The purity was 98% as measured by HPLC.

[0049] X-Ray diffraction confirmed that the stereo configuration of the product A1 is as follows:

[0050]

[0051] Product structure verification (see Figure 1 , Figure 2 ):

[0052] 1 H NMR (400MHz, CDCl3) δ7.87-7.76(m,2H),7.60-7.51(m,1H),7.45-7.37(m,2H),7.38-7.30(m,6H),7.14-7.01(m,2H),4.84(s,2H),2.46(s,3H).

[0053] 13 C NMR (101MHz, CDCl3) δ143.9,141.2,139.8,137.9,135.9,131.4,130.8,13 0.4,129.6,129.5,129.3,129.3,128.7,128.3,127.7,111.3,56.6,21.6.

[0054] Example 1-1

[0055] The configuration of this embodiment is the same as that of embodiment 1, except that the mixed solvent replaces the solvents shown in Table 1.

[0056] Table 1: Reaction results of different solvents

[0057] Serial number Solvents Yield (%) 1 Tetrahydrofuran 58 2 Chloroform 29 3 1,2-Dichloroethane 23 4 1,4-Dioxane 52 5 Acetonitrile 28 6 N,N-Dimethylformamide 0 7 Ethanol 0 8 2-Methyltetrahydrofuran 50 9 Tetrahydrofuran-water (v / v=1:2) 66 10 Tetrahydrofuran-water (v / v=1:1) 65 11 Tetrahydrofuran-water (v / v=3:1) 65 12 Tetrahydrofuran-water (v / v=2:1) 64 13 1,4-Dioxane-water (v / v=1:3) 68 14 2-Methyltetrahydrofuran-water (v / v=1:3) 70 .

[0058] As can be seen from Table 1, mixed solvents such as tetrahydrofuran-water, 1,4-dioxane-water and 2-methyltetrahydrofuran-water have better reaction effects, especially tetrahydrofuran-water has a high yield, so the reaction solvent is preferably tetrahydrofuran-water, especially when the mixing ratio of tetrahydrofuran to water is 1:3, it is most ideal. When a mixed solvent is used, on the one hand, water helps to dissolve the catalyst, and on the other hand, tetrahydrofuran helps to dissolve the raw material. Therefore, a lower volume ratio of tetrahydrofuran to water is not conducive to improving the reaction yield, and mainly solves the solubility problem of the catalyst and the raw material, thereby reducing the occurrence of side reactions, and as a result, the yield is improved (see Table 1 No. 9, 10, 11, 12 and Example 1).

[0059] In addition, single solvents such as tetrahydrofuran, chloroform, 1,2-dichloroethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, and ethanol were also used for experiments, but the reaction effect was very poor and the yield was very low.

[0060] Example 1-2

[0061] The configuration of this embodiment is the same as that of embodiment 1, except that the reaction temperature of 60°C is replaced by 25°C, 40°C, 80°C, and 100°C, respectively, so that the reaction is carried out at different oil bath temperatures. The results are shown in Table 2.

[0062] Table 2: Reaction results at different reaction temperatures

[0063] Serial number Reaction temperature (℃) Raw material conversion rate (I) % Yield (%) 1 25 20 10 2 40 50 40 3 80 100 73 4 100 100 70

[0064] As can be seen from Table 3: when the catalytic reaction temperature is 80℃ and 100℃, the finished product yield can be guaranteed to be around 70%. Too high a temperature cannot significantly increase the yield, but on the contrary, it increases energy consumption, which is not conducive to cost control; when the reaction temperature is too low, such as 25℃ and 40℃, the reaction activity is poor, the reaction rate will decrease, and the raw materials cannot be completely converted. Therefore, the reaction temperature is preferably controlled at 40-80℃, especially 60-80℃. When it is around 60℃, the comprehensive reaction yield and cost effect are most ideal.

[0065] Examples 1-3

[0066] The configuration of this embodiment is the same as that of embodiment 1, except that the amount of the catalyst potassium monopersulfate was replaced by 2 equiv (in embodiment 1, the amount of the 2-N-benzenesulfonyl-substituted anisyl thioether derivative was 0.2 mmol, the amount of the catalyst was 0.4 mmol, and the corresponding equivalent was 2 equiv) to 0 (i.e., no catalyst was added), 0.5 equiv, 1 equiv, and 3 equiv, respectively, and the experiments were carried out. The results are shown in Table 3.

[0067] Table 3: Reaction results of different amounts of initiators

[0068] Serial number Potassium monopersulfate (x equiv.) Yield (%) 1 0 0 2 0.5 26 3 1 45 4 3 72

[0069] It can be seen from Table 3 that the reaction effect and yield of 1 to 3 times the amount of potassium monopersulfate are both good to excellent. Taking the cost into consideration, the amount of potassium monopersulfate is preferably 2 times the amount of the substance. At this time, the reaction speed is fast and the reaction is stable, and the yield of the target product is as high as 72% (see Example 1).

[0070] From the above parallel cases, it can be seen that in the reaction system of the present application, the molar ratio of MX to the 2-N-benzenesulfonyl-substituted anisole derivative (I) is appropriately controlled at 1 to 3:1, and preferably 2:1; the reaction temperature is 60 to 80°C, and preferably 60°C; the reaction time is appropriately controlled at 24h; the mixed solvent is appropriately selected from a mixture of any one of tetrahydrofuran, 1,4-dioxane, and 2-methyltetrahydrofuran and water, and preferably tetrahydrofuran-water (v / v=1:3).

[0071] The following preferred reaction conditions are used to prepare the remaining products A2, A3, A4, A5, and A6, and the reaction formula is expressed as follows:

[0072]

[0073] Example 2

[0074] This example is used to prepare product A2, whose chemical name is: (E)-2-(bromo(4-methylphenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the preparation process is as follows:

[0075] A 10 mL round-bottom flask was sequentially added with 2-N-benzenesulfonyl-substituted anisole derivative (84.3 mg, 0.2 mmol), potassium monopersulfate (300 mg, 0.4 mmol, the main active ingredient KHSO5 content was about 46%, produced by Inokai Reagent Company), sodium bromide (59.9 mg), and a mixed solvent (2 mL) of tetrahydrofuran and water (v / v=1:3), stirred at 60°C for 24 hours, dried by spin drying, and filtered with petroleum ether-ethyl acetate (v / v=5:1) to obtain 75.8 mg of the target compound as a white solid with a yield of 78%. The purity was 98% as measured by HPLC.

[0076] Product structure verification (see Figure 3 , Figure 4 ):

[0077] 1H NMR (400MHz, CDCl3) δ7.86-7.69(m,2H),7.59-7.48(m,1H),7.43-7.33(m,2H),7.35-7.24 (m,3H),7.15(d,J=7.9Hz,2H),7.01-6.87(m,2H),4.81(s,2H),2.44(s,3H),2.36(s,3H).

[0078] 13 C NMR (101MHz, CDCl3) δ143.8,141.2,138.7,137.9,136.8,135.4,131.4,130. 8,130.4,129.5,129.4,129.2,129.1,129.0,127.7,110.8,56.6,21.6,21.4.

[0079] Example 3

[0080] This example is used to prepare product A3, whose chemical name is: (E)-2-(iodo(4-methylphenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the preparation process is as follows:

[0081] A 10 mL round-bottom flask was added with 2-N-benzenesulfonyl-substituted anisole derivative (84.3 mg, 0.2 mmol), potassium monopersulfate (300 mg, 0.4 mmol, the main active ingredient KHSO5 content was about 46%, produced by Inokai Reagent Company), sodium iodide (59.9 mg), and a mixed solvent (2 mL) of tetrahydrofuran and water (v / v=1:3), stirred at 60°C for 24 hours, dried by spin drying, and filtered through a column with petroleum ether-ethyl acetate (v / v=5:1) to obtain 87.4 mg of the target compound as a white solid with a yield of 82%. The purity was 98% as measured by HPLC.

[0082] Product structure verification (see Figure 5 , Figure 6 ):

[0083] 1 H NMR (400MHz, CDCl3) δ7.78 (dd, J=8.0, 1.5Hz, 1H), 7.58-7.45 (m, 2H), 7.23-7.04 (m, 6H) ,6.93(dd,J=8.0,1.5Hz,1H),6.89-6.74(m,2H),4.74(s,2H),2.42(s,3H),2.35(s,3H).

[0084] 13C NMR (101MHz, CDCl3) δ143.9,138.8,138.6,136.8,134.9,131.1,129.6,129.2 ,129.1,128.4,128.1,127.6,127.2,125.9,125.1,86.2,55.54,21.62,21.36.

[0085] Example 4

[0086] This example is used to prepare product A4, whose chemical name is: (E)-2-(bromo(3,5-dimethylphenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the preparation process is as follows:

[0087] A 10 mL round-bottom flask was sequentially added with 2-N-benzenesulfonyl-substituted anisole derivative (87.1 mg, 0.2 mmol), potassium monopersulfate (300 mg, 0.4 mmol, the main active ingredient KHSO5 content was about 46%, produced by Inokai Reagent Company), sodium bromide (41.2 mg), and a mixed solvent (2 mL) of tetrahydrofuran and water (v / v=1:3), stirred at 60°C for 24 hours, dried by spin drying, and column-filtered with petroleum ether-ethyl acetate (v / v=5:1) to obtain 80.0 mg of the target compound as a colorless oily liquid with a yield of 80%. The purity was 98% as measured by HPLC.

[0088] Product structure verification (see Figure 7 , Figure 8 ):

[0089] 1 H NMR (400MHz, CDCl3) δ7.87-7.77(m,2H),7.53(dd,J=8.1,1.5Hz,1H),7.42-7.34(m,2H),7.35-7 .26(m,3H),6.96(d,J=1.5Hz,1H),6.64(d,J=1.5Hz,2H),4.81(s,2H),2.46(s,3H),2.32(s,3H).

[0090] 13 C NMR (101MHz, CDCl3) δ143.7,141.2,139.6,138.0,137.8,135.4,131.4,130.9,1 30.3,129.6,129.3,129.1,127.8,127.7,126.8,110.5,56.6,30.1,21.7,21.3.

[0091] Example 5

[0092] This example is used to prepare product A5, whose chemical name is: (E)-2-(bromo(4-methoxyphenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the preparation process is as follows:

[0093] A 10 mL round-bottom flask was sequentially added with 2-N-benzenesulfonyl-substituted anisole derivative (87.5 mg, 0.2 mmol), potassium monopersulfate (300 mg, 0.4 mmol, the main active ingredient KHSO5 content was about 46%, produced by Inokai Reagent Company), sodium bromide (41.2 mg), and a mixed solvent (2 mL) of tetrahydrofuran and water (v / v=1:3), stirred at 60°C for 24 hours, dried by spin drying, and column-filtered with petroleum ether-ethyl acetate (v / v=5:1) to obtain 73.3 mg of the target compound as a colorless oily liquid with a yield of 73%. The purity was 98% as measured by HPLC.

[0094] Product structure verification (see Fig. 9 , Fig.10 ):

[0095] 1 H NMR (400MHz, CDCl3) δ7.87-7.72(m,2H),7.52(dd,J=8.2,1.6Hz,1H),7.43-7.34(m,2H),7.3 4-7.24(m,3H),7.08-6.95(m,2H),6.90-6.79(m,2H),4.80(s,2H),3.81(s,3H),2.43(s,3H).

[0096] 13 C NMR (101MHz, CDCl3) δ159.7,143.9,141.2,137.8,135.5,131.8,131.3,130. 8,130.6,130.4,129.5,129.4,129.2,127.7,113.6,110.8,56.7,55.3,21.6.

[0097] Example 6

[0098] This example is used to prepare product A6, whose chemical name is: (E)-2-(bromo(4-chlorophenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the preparation process is as follows:

[0099] A 10 mL round-bottom flask was sequentially added with 2-N-benzenesulfonyl-substituted anisole derivative (88.4 mg, 0.2 mmol), potassium monopersulfate (300 mg, 0.4 mmol, the main active ingredient KHSO5 content is about 46%, produced by Inotech Reagent Company), sodium bromide (41.2 mg), and a mixed solvent (2 mL) of tetrahydrofuran and water (v / v=1:3). The mixture was stirred and reacted at 60 ° C for 24 h, and then dried by spin drying. The mixture was filtered through a column with petroleum ether-ethyl acetate (v / v=5:1) to obtain 81.1 mg of the target compound as a colorless oily liquid with a yield of 80%. The purity was 98% as measured by HPLC.

[0100] Product structure verification (see Fig.11 , Fig.12 ):

[0101] 1 H NMR (400MHz, CDCl3) δ7.85-7.73 (m, 2H), 7.53 (dd, J=7.5, 2.0Hz, 1H), 7.41 (dd, J= 8.0,6.2Hz,2H),7.38-7.22(m,5H),7.12-6.88(m,2H),4.81(s,2H),2.46(s,3H).

[0102] 13 C NMR (101MHz, CDCl3) δ143.9,141.2,138.1,137.9,135.1,134.6,131.3,13 0.8,130.5,129.8,129.7,129.5,129.3,128.6,127.7,111.9,56.6,21.6.

[0103] The reaction substrates of Examples 2 to 6 are different from those of Example 1. Specifically, different substituents are used to conduct the experiments. The results are shown in Table 4.

[0104] Table 4: Comparison of reaction effects with different substituents

[0105] X R Yield (%) Example 1 Br Ph 72 Example 2 Br 4-MePh 78 Example 3 I 4-MePh 82 Example 4 Br <![CDATA[3,5-Me2Ph]]> 80 Example 5 Br 4-MeOPh 73 Example 6 Br 4-ClPh 80 .

[0106] Combining Table 4 with Examples 1 to 6, it can be seen that compared with X=Br and R=Ph in Example 1, when X is unchanged, R can obtain equivalent or higher yields by using 4-MePh, 3,5-Me2Ph, 4-MeOPh, and 4-ClPh (see Examples 2, 4, 5, and 6), indicating that under the same conditions, the reaction activity in this reaction system is 3,5-Me2Ph=4-ClPh>4-MePh>4-MeOPh>Ph; and when R is unchanged, the reaction yield when X=Br will be lower than the reaction activity when X=I, which also confirms that the activity of iodide is indeed better than that of bromide. The above experimental results show that the reaction of this application is carried out in air, the entire reaction process has no particularly harsh external requirements, has good substrate expansibility, and the substituent R on the skeleton structure has good reactivity, and its yield can be guaranteed to be 72 to 82%.

[0107] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate, characterized in that: In the presence of a mixed solvent, a 2-N-benzenesulfonyl substituted anisole derivative and a halide MX are used as raw materials and catalyzed by a catalyst monopersulfate to prepare (E)-2-(halomethylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine, and the reaction temperature does not exceed 80°C; The structural formula of the 2-N-benzenesulfonyl-substituted anisole derivative is expressed as: The structural formula of the (E)-2-(halomethylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine is expressed as: R is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl and 4-chlorophenyl.

2. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 1, characterized in that: In the MX, M is K or Na, and X is a halogen element.

3. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 2, characterized in that: The MX is NaI, KI or NaBr.

4. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 1, characterized in that: The monopersulfate salt is potassium monopersulfate.

5. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 1, characterized in that: The molar ratio of the monopersulfate to the 2-N-benzenesulfonyl-substituted anisole derivative is 1 to 3:

1.

6. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 1, characterized in that: The mixed solvent is a mixture of any one of tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane and water.

7. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 1, characterized in that: The catalytic reaction temperature is 40-80°C.

8. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 1, characterized in that: The catalytic reaction time is 20 to 48 hours.

9. A method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to any one of claims 1 to 8, characterized in that: The molar ratio of MX to the 2-N-benzenesulfonyl-substituted anisole derivative is 2:1, the catalytic reaction temperature is 60° C., the mixed solvent is a mixture of tetrahydrofuran and water, and the volume ratio of tetrahydrofuran to water is 1:

3.

10. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine with monopersulfate according to claim 9, characterized in that: MX is NaBr, R in the 2-N-benzenesulfonyl substituted anisole derivative is phenyl, and the stereostructure of (E)-2-(bromo(phenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine is:

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