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

Abstract

The invention provides a method for synergistically preparing 3, 4-dihydro-2H-benzo [b] [1, 4] thiazine-1-oxide through monopersulfate, and belongs to the technical field of heterocyclic compounds. In the presence of an alcohol solvent, a 2-N-benzenesulfonyl substituted phenylmethyl sulfide derivative and a halide MX are used as raw materials, and the (R, E)-2-(halogenated methylene)-4-p-toluenesulfonyl-3, 4-dihydro-2H-benzo [b] [1, 4] thiazine-1-oxide with a determined spatial configuration is prepared through a catalytic reaction of a catalyst monopersulfate. 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-1-oxide in cooperation with monopersulfate, belonging to the technical field of heterocyclic compounds. Background Art

[0002] Derivatives of 1,4-Benzothiazine 1-oxide 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, 1,4-benzothiazine-1-oxide compounds are mainly prepared by a two-step reaction, first preparing a precursor 1,4-benzothiazine compound, and then oxidizing the precursor 1,4-benzothiazine compound with a suitable oxidant. The commonly used methods for synthesizing precursor 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:A Waste-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 3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide in cooperation with monopersulfate, in the presence of an alcohol solvent, using a 2-N-benzenesulfonyl-substituted anisole derivative (I) and a halide MX as raw materials, catalyzed by a catalyst monopersulfate, to prepare (R,E)-2-(halomethylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide (II) with a defined stereo configuration.

[0013]

[0014] Here, R is any one of hydrogen (H), aryl (Ar), alkyl, 1-naphthyl (1-nai), etc. Me-methyl, Ts-benzenesulfonyl.

[0015] The above scheme uses 2-N-benzenesulfonyl substituted anisole derivatives and halides as raw materials, and monopersulfate as an initiator and catalyst to synthesize (R,E)-2-(halogenated methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide in a simple, efficient, green and highly stereoselective manner. The monopersulfate synergistic preparation method not only has simple steps, mild reaction conditions, and is green and environmentally friendly, but also the raw materials and auxiliary materials involved in the reaction are simple in composition, cheap and easy to obtain, the product yield is high, the stereoselectivity is high, and the synthesis cost is reduced.

[0016] Further, as a preference:

[0017] 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 sodium bromide (NaBr).

[0018] The monopersulfate is potassium monopersulfate

[0019] 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 80%, 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 70%. In addition, the molar ratio of the monopersulfate to the 2-N-benzenesulfonyl substituted anisole derivative (I) is 1 to 3:1.

[0020] Based on the above technical solution, we further studied the solvent and determined that it is preferred to use any one of ethanol, methanol and isopropanol, so that potassium monopersulfate can fully contact with the raw material, and effectively control the reaction speed and reaction direction, thereby ensuring the yield of the finished product. In particular, when ethanol is used, the control effect on the conversion rate and reaction direction is the best.

[0021] 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 within the range of 50-60%. 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°C.

[0022] The beneficial effects of the present invention are as follows:

[0023] (1) The present invention realizes a one-step reaction to prepare (R, E)-2-(iodo or bromomethylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide by controlling an alcohol solvent and using the catalytic effect of potassium monopersulfate, which provides a new method for preparing such compounds. The method has fewer reaction steps, mild reaction conditions, simple operation, and the raw and auxiliary materials involved in the reaction are cheap and easily available, thereby reducing the synthesis cost.

[0024] (2) The present invention is applicable to a wide range of substrates. In the above process, the catalyst, halide and alcohol solvent are all conventional reagents, which are non-toxic and non-corrosive. The reaction is carried out in the 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 75%.

[0025] (3) The (R,E)-2-(halomethylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide 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.

[0026] In the above technical scheme, potassium monopersulfate is used as an initiator to effectively improve the activity of the raw materials in an alcohol solvent, and the synthesis of (R, E)-2-(halogenated methylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide can be completed under relatively mild conditions of about 60°C. The raw materials and initiators are cheap and easy to obtain, and the stereostructure of the product is single. After the reaction is completed, the product is dried by rotation and passed through a column to obtain a fine product, and the yield can be guaranteed to be (65-75)%. Compared with the conventional preparation method, the initiator is commercial potassium monopersulfate, which has the advantages of being cheap, easy to obtain, and green, and the halogenation reagent is cheap sodium iodide, which is non-toxic and non-corrosive. These can not only greatly reduce the preparation cost of (R, E)-2-(halogenated methylene)-4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide, but also reduce pollution, so it is easier to industrialize and promote. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] 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.

[0028] Figure 1 For product A1 1 H spectrum;

[0029] Figure 2 For product A1 13 C spectrum;

[0030] Figure 3 For product A2 1 H spectrum;

[0031] Figure 4 For product A2 13 C spectrum;

[0032] Figure 5 For product A3 1 H spectrum;

[0033] Figure 6 For product A3 13 C spectrum;

[0034] Figure 7 For product A4 1 H spectrum;

[0035] Figure 8 For product A4 13 C spectrum;

[0036] Fig. 9 For product A5 1 H spectrum;

[0037] Fig.10 For product A5 13 C spectrum;

[0038] Fig.11 For product A6 1 H spectrum;

[0039] Fig.12 For product A6 13 C spectrum. DETAILED DESCRIPTION

[0040] 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.

[0041] The analytical instruments and equipment used in this example are: nuclear magnetic resonance instrument, AVANCE DMXⅡⅠ400M (TMS internal standard, Bruker Company).

[0042] The following six representative structures A1, A2, A3, A4, A5 and A6 are prepared below, and the details are shown in Examples 1 to 6.

[0043]

[0044] Example 1

[0045] This example is used to prepare product A1, whose chemical name is: (R,E)-2-(iodo(phenyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide, and the preparation process is as follows:

[0046] A 10 mL round-bottom flask was 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 iodide (59.9 mg), and ethanol (2 mL) in sequence, stirred at 60°C for 24 h, spin-dried, and column-filtered with petroleum ether-ethyl acetate (v / v=2:1) ​​to obtain 74.9 mg of the target compound, recorded as product A1, which was a light yellow solid, with a yield of 70%, and a raw material conversion rate (I) of 95%. The purity was 98% as measured by HPLC.

[0047] X-Ray diffraction confirmed that the stereo configuration of the product A1 is as follows:

[0048]

[0049] Product structure verification (see Figure 1 , Figure 2 ):

[0050] 1 H NMR (400MHz, CDCl3) δ8.09 (dd, J=8.3, 1.1Hz, 1H), 7.66-7.49 (m, 4H), 7.43-7.28 (m, 4H), 7.22 (d ,J=8.3Hz,2H),7.07-6.89(m,2H),5.34(d,J=15.6Hz,1H),4.75(d,J=15.6Hz,1H),2.40(s,3H).

[0051] 13 C NMR (101MHz, CDCl3) δ144.6,142.4,140.4,135.6,135.2,133.6,132.9,13 0.8,129.9,129.7,128.6,128.2,127.6,126.8,126.7,115.4,50.7,21.6.

[0052] Example 1-1

[0053] The configuration of this embodiment is the same as that of embodiment 1, except that ethanol is replaced by tetrahydrofuran, chloroform, 1,2-dichloroethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, methanol, isopropanol and water, respectively. The results are shown in Table 1.

[0054] Table 1: Reaction results of different solvents

[0055]

[0056]

[0057] As can be seen from Table 1, alcohol solvents such as ethanol, methanol and isopropanol have better reaction effects, especially ethanol has a high yield, so ethanol is preferably used as the reaction solvent. The use of ethanol mainly solves the solubility problem of the initiator and the raw material, thereby reducing the occurrence of side reactions, and as a result, the yield is improved.

[0058] In addition, experiments were also conducted using non-alcohol solvents such as tetrahydrofuran, chloroform, 1,2-dichloroethane, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide, but the reaction effect was very poor and the yield was very low.

[0059] Example 1-2

[0060] 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.

[0061] Table 2: Reaction results at different reaction temperatures

[0062] Serial number Reaction temperature (℃) Raw material conversion rate (I) % Yield (%) 1 25 20 15 2 40 50 42 3 80 100 60 4 100 100 52

[0063] As can be seen from Table 2: after the temperature exceeds 60°C, the conversion rate of the raw material exceeds 95%, and reaches 100% after 80°C. When the catalytic reaction temperature is 80°C and 100°C, the finished product yield can also be guaranteed to be in the range of 50-60%. Too high a temperature cannot significantly increase the yield, but on the contrary, it also increases energy consumption, which is not conducive to cost control; and when the reaction temperature is too low, such as 25°C and 40°C, the reaction activity is poor, the reaction rate will decrease, and the raw material cannot be completely converted. Therefore, under comprehensive consideration, the reaction temperature is preferably controlled at 40-80°C, especially 60-80°C, and the reaction effect is most ideal when it is around 60°C.

[0064] Examples 1-3

[0065] 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.

[0066] Table 3: Reaction results of different amounts of initiators

[0067]

[0068]

[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 70% (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 solvent is appropriately selected from alcohol solvents represented by ethanol, methanol and isopropanol, and preferably ethanol.

[0071] The following preferred reaction conditions are used to prepare the remaining products A2, A3, A4, and A5, 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: (R,E)-2-(iodo(1-naphthyl)methylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide, and the preparation process is as follows:

[0075] A 10 mL round-bottom flask was added with 2-N-benzenesulfonyl-substituted anisole derivative (91.5 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 iodide (59.9 mg), and ethanol (2 mL) in sequence, stirred at 60 ° C for 24 hours, dried by spin drying, and column-filtered with petroleum ether-ethyl acetate (v / v=2:1) ​​to obtain 87.8 mg of the target compound as a white solid with a yield of 75%. The purity was 99% as measured by HPLC.

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

[0077] 1H NMR (400MHz, CDCl3) δ7.91-7.84(m,1H),7.82(d,J=8.2Hz,1H),7.78(dd,J=8.2,1.5Hz,1H),7 .75-7.68(m,1H),7.66-7.59(m,2H),7.56-7.47(m,2H),7.37(dd,J=8.2,7.0Hz,1H),7.27(d,J =7.0Hz,2H),7.18(td,J=7.5,1.5Hz,1H),7.09(td,J=7.6,1.5Hz,1H),6.89(dd,J=7.5,1.5Hz, 1H), 6.82 (dd, J=7.5, 1.5Hz, 1H), 5.34 (d, J=16.6Hz, 1H), 4.50 (d, J=16.6Hz, 1H), 2.46 (s, 3H).

[0078] 13 C NMR (101MHz, CDCl3) δ143.9,138.2,137.1,134.9,134.5,134.0,129.6,129.4,129.2,128.9,1 28.5,128.2,127.6,127.2,127.1,126.5,126.4,126.3,126.0,125.4,124.8,82.1,55.2,21.6.

[0079] Example 3

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

[0081] A 10 mL round-bottom flask was added with 2-N-benzenesulfonyl-substituted anisole derivative (91.5 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 iodide (59.9 mg), and ethanol (2 mL) in sequence, stirred at 60 ° C for 24 hours, spin-dried, and column-filtered with petroleum ether-ethyl acetate (v / v=2:1) ​​to obtain 66.1 mg of the target compound as a colorless oily liquid with a yield of 72%. The purity was 98% as measured by HPLC.

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

[0083] 1H NMR (400MHz, CDCl3) δ7.79-7.66(m,1H),7.61-7.52(m,2H),7.51-7.47(m,1H),7.45(d,J=8.3Hz,2H),7.22(d, J=8.3Hz,2H),6.96(t,J=2.9Hz,1H),4.91(dd,J=17.7,2.9Hz,1H),4.26(dd,J=17.7,2.9Hz,1H),2.39(s,3H).

[0084] 13 C NMR (101MHz, CDCl3) δ150.1,144.9,139.4,135.0,133.0,131.5,130.1,128.9,128.6,127.1,123.3,78.5,50.5,21.7.

[0085] Example 4

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

[0087] A 10 mL round-bottom flask was added with 2-N-benzenesulfonyl-substituted anisole derivative (91.5 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 ethanol (2 mL) in sequence, stirred at 60 ° C for 24 hours, spin-dried, and column-filtered with petroleum ether-ethyl acetate (v / v=2:1) ​​to obtain 75.3 mg of the target compound as a white solid with a yield of 70%. The purity was 98% as measured by HPLC.

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

[0089] 1 H NMR (400MHz, CDCl3) δ7.95-7.80(m,4H),7.74-7.64(m,1H),7.57(dd,J=7.7,1.4Hz,1H),7.55-7.39(m,5H),7.36 (dd,J=7.2,2.8Hz,3H),7.03(dd,J=7.2,1.4Hz,1H),5.07(d,J=19.1Hz,1H),4.76(d,J=19.1Hz,1H),2.48(s,3H).

[0090] 13 C NMR (101MHz, CDCl3) δ144.0,141.4,137.9,137.4,136.2,133.7,131.1,130.8,130.1,129.9,12 9.7,129.4,129.1,129.0,128.6,127.8,126.7,126.6,126.2,125.3,124.9,114.5,56.2,21.7.

[0091] Example 5

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

[0093] A 10 mL round-bottom flask was added with 2-N-benzenesulfonyl-substituted anisole derivative (91.5 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 ethanol (2 mL) in sequence, stirred at 60 ° C for 24 hours, spin-dried, and column-filtered with petroleum ether-ethyl acetate (v / v=2:1) ​​to obtain 53.6 mg of the target compound as a colorless oily liquid with a yield of 65%. The purity was 98% as measured by HPLC.

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

[0095] 1 H NMR (400MHz, CDCl3) δ7.74(dd,J=7.4,1.3Hz,1H),7.61-7.54(m,2H),7.50(dd,J=7.4,1.3Hz,1H),7.45(d,J=8.3Hz,2H) ,7.23(d,J=8.2Hz,2H),6.71(t,J=2.5Hz,1H),4.96(dd,J=17.8,2.5Hz,1H),4.35(dd,J=17.8,2.5Hz,1H),2.40(s,3H).

[0096] 13 C NMR (101MHz, CDCl3) δ146.1,144.9,139.1,134.9,133.0,131.6,130.1,128.9,128.5,127.1,123.7,107.6,46.5,21.7.

[0097] Example 6

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

[0099] A 10 mL round-bottom flask was 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 (59.9 mg), and ethanol (2 mL) in sequence, stirred at 60°C for 24 h, spin-dried, and column-filtered with petroleum ether-ethyl acetate (v / v=2:1) ​​to obtain 54.2 mg of the target compound, recorded as product A6, which was a light yellow solid, with a yield of 71% and a raw material conversion rate (I) of 98%. The purity was 98% as measured by HPLC.

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

[0101] 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).

[0102] 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.

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

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

[0105] X R Yield (%) Example 1 I Ph 70 Example 2 I 1-nai 75 Example 3 I H 72 Example 4 Br H 65 Example 5 Br 1-nai 70 Example 6 Br Ph 71 .

[0106] Combining Table 4 with Examples 1 to 6, it can be seen that compared with X=I and R=Ph in Example 1, when X is unchanged, R can obtain equivalent or higher yields by using 1-nai and H (see Examples 2 and 3), indicating that under the same conditions, the reaction activity in this reaction system is 1-nai>H>Ph, which is also confirmed when X takes Br (see Examples 4, 5, and 6); 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 whole reaction process has no particularly harsh external requirements, has good substrate expansibility, and the substituent R on the skeleton structure has good reactivity, not only hydrogen, alkyl, aryl, naphthyl, but also the finished product yield can be controlled above medium, up to 75%.

[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-1-oxide by using hydrogen monopersulfate, characterized in that: In the presence of an alcohol solvent, 2-N-benzenesulfonyl substituted anisole derivative and halide MX are used as raw materials and the reaction is catalyzed by monopersulfate to prepare (R,E)-2-(halomethylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide with a determined stereo configuration. The structural formula of the 2-N-benzenesulfonyl-substituted anisole derivative is expressed as: The structural formula of (R,E)-2-(halomethylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide is expressed as: R is any one of hydrogen, phenyl, alkyl, and naphthyl.

2. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide by using 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-1-oxide by using 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-1-oxide by using 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-1-oxide by using 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-1-oxide by using monopersulfate according to claim 1, characterized in that: The alcohol solvent is any one of ethanol, methanol and isopropanol.

7. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide by using 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-1-oxide by using hydrogen monopersulfate according to any one of claims 1 to 7, 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., and the alcohol solvent is ethanol.

9. The method for preparing 3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide by using hydrogen monopersulfate according to claim 8, characterized in that: MX is NaI, R in the structure of the 2-N-benzenesulfonyl substituted anisole derivative is hydrogen, and the stereo configuration structure of (R,E)-2-(halomethylene)-4-p-toluenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-1-oxide is:

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