Six-membered sultam derivative as well as electrochemical synthesis method and application thereof

Abstract

The invention provides a six-membered sultam derivative as well as an electrochemical synthesis method and application thereof, and a 2-isoallylbenzenesulfonamide derivative and a hydroxyl-containing compound are electrified and reacted in an electrolyte to obtain the six-membered sultam derivative. The electrolyte comprises 2, 2, 6, 6-tetramethylpiperidine and an electrolyte tetrabutylammonium tetrafluoroborate; compared with the prior art, the sultam derivative can be obtained through reaction under the electrochemical condition, no oxidizing agent or reducing agent is needed in the reaction, no metal catalyst or high temperature is needed, synthesis steps are simple, side reactions are few, the yield of the target product is high, and the method can be used for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a six-membered sulfolactam derivative and an electrochemical synthesis method and application thereof. BACKGROUND

[0002] Sulfolactam compounds are concerned in the field of drug research due to their unique biological activity. The stability of their cyclic structure and diverse structure-activity relationship provide a new direction for the design of antibacterial drugs. The currently reported methods for synthesizing sulfolactam compounds mainly include the following:

[0003] In 2021, Fan's group reported a Rh(III)-catalyzed [4+1] spirocyclization reaction of arylsulfonamides with imines. In 2022, Barrera et al. studied the enantioselective transamino halogenation of unsaturated medium-sized cyclic phenylsulfonamides using chiral acid and phase transfer catalysis. In 2023, Niu's group reported a cobalt-catalyzed enantioselective C-H / N-H ring experimental scheme of arylsulfonamides with alkenes or alkynes. In 2024, Ryu's group established a gold(I)-catalyzed intramolecular dehydrative amination method, which can efficiently synthesize various cyclic sulfonamide compounds under mild conditions. The above preparation methods mostly use noble metal catalysts or have high reaction temperatures, which are not conducive to industrial promotion due to high cost.

[0004] In the prior art, on May 24, 2022, a Chinese patent with publication number CN 114525527 A disclosed an electrochemical synthesis method of sulfolactam derivatives. 2-isoallyl benzene sulfonamide derivatives and iodide were reacted in a mixed solvent by passing electricity, and then separated and purified to obtain sulfolactam derivatives. Although this method does not require an oxidizing agent and a reducing agent, and does not need to add a metal catalyst and high temperature, it only prepares five-membered sulfolactam derivatives.

[0005] Six-membered cyclic structures have unique conformational stability and spatial adaptability in organic chemistry. Compared with other ring systems, they have low bond angle tension and more balanced intramolecular interactions. However, the prior art lacks research on the preparation of six-membered sulfolactam compounds.

[0006] Therefore, it is necessary to provide a green preparation method for synthesizing six-membered sulfolactam derivatives. SUMMARY

[0007] The present application aims to provide a six-membered sulfolactam derivative and an electrochemical synthesis method thereof, which is prepared by reacting a cheap hydroxyl-containing compound with a 2-isoallyl benzene sulfonamide derivative in a common solvent under electrochemical conditions, and the synthesis method does not need an oxidant and a reducing agent, does not need to add a metal catalyst, has simple synthesis steps, simple experimental operation, reaction in line with green chemistry standards, high popularization value and is suitable for industrial production.

[0008] The present application also provides an application of the six-membered sulfolactam derivative to the preparation of antibacterial drugs, especially drugs for inhibiting Escherichia coli.

[0009] The specific technical scheme of the present application is as follows:

[0010] The present application provides an electrochemical synthesis method of a six-membered sulfolactam derivative, which specifically comprises:

[0011] The 2-isoallyl benzene sulfonamide derivative and the hydroxyl-containing compound are subjected to an electric reaction in an electrolyte to obtain the six-membered sulfolactam derivative.

[0012] The molar ratio of the 2-isoallyl benzene sulfonamide derivative to the hydroxyl-containing compound is 1:20-200.

[0013] The 2-isoallyl benzene sulfonamide derivative has the following structural formula: wherein, R 2 is a benzene ring with a substituent, a benzyl group or an isopropyl group, preferably -C6H5, 4-CH3C6H4-, 3,4-(CH3)2C6H4-, 4-NO2C6H4-, 4- t BuC6H4-, Bn-, CH(CH3)2- or 4-ClC6H4-.

[0014] The hydroxyl-containing compound is selected from at least one of H2O, an alcohol compound and a carboxylic acid compound; preferably, the alcohol compound is selected from methanol, ethanol or isopropyl alcohol; and the carboxylic acid compound is selected from formic acid or acetic acid.

[0015] The electrolyte comprises an additive and an electrolyte;

[0016] The molar ratio of the electrolyte to the 2-isoallyl benzene sulfonamide derivative is 0.3:1.

[0017] The additive is used in an amount of 5% of the molar amount of the 2-isoallyl benzene sulfonamide derivative.

[0018] The solvent of the electrolyte is acetonitrile, ethyl acetate, acetone or dimethyl sulfoxide; preferably acetonitrile.

[0019] The 2-isoallyl benzene sulfonamide derivative and the solvent are used in a ratio of 0.05-0.1 mol / L; preferably 0.075 mol / L.

[0020] The additive is sodium iodide or 2,2,6,6-tetramethylpiperidine TEMPO, preferably 2,2,6,6-tetramethylpiperidine;

[0021] The electrolyte is tetrabutylammonium tetrafluoroborate, lithium perchlorate, tetrabutylammonium hexafluoroborate or sodium carbonate, preferably tetrabutylammonium tetrafluoroborate;

[0022] The electrode used in the electrolysis reaction is a carbon-carbon electrode, a carbon-platinum electrode, a carbon-nickel electrode or a nickel-nickel electrode, preferably a combination of a carbon electrode and a foamed nickel electrode;

[0023] The temperature condition of the electrolysis reaction is that the current is 10-15 mA under the condition of 60-80℃, and the reaction time is 1.5-3 h; preferably, the current is 10 mA or 15 mA; and the reaction time is 1.5 h, 2 h or 3 h.

[0024] The electrolysis reaction process does not need to be isolated from air and can be carried out in the presence of air; that is, it can be carried out in an air atmosphere.

[0025] The mixture obtained after the electrolysis reaction is subjected to extraction, drying and vacuum concentration in sequence to obtain a crude product, and then the crude product is purified by column chromatography; the extractant used in the extraction is ethyl acetate; the drying agent used in the drying is anhydrous sodium sulfate; and the developing agent used in the column chromatography is obtained by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1.

[0026] The application provides a six-membered sulfolactam derivative, which is prepared by using the electrochemical synthesis method of the six-membered sulfolactam derivative.

[0027] Among them, R 1 is an alkyl, a fatty alcohol, a carboxyl or an acyl, preferably -CH3, -CH2CH3, -CH(CH3)2 or -COCH3.

[0028] The application provides the application of the six-membered sulfolactam derivative, which is used for preparing an antibacterial drug, especially a drug for inhibiting Escherichia coli.

[0029] The synthetic method provided by the present application overcomes many defects in the prior art in synthesizing sulfamidate derivatives, and provides a synthetic method of six-membered sulfamidate derivatives, which can obtain the six-membered sulfamidate derivatives by electrically reacting a cheap hydroxyl-containing compound such as at least one of (H2O, an alcohol compound, a carboxylic acid compound) and a 2-isoallyl benzene sulfonamide derivative in a common solvent.

[0030] Compared with the prior art, the present application has the following advantages: (1) no excessive oxidizing agent or reducing agent is used, and cost is saved; (2) no metal catalyst such as palladium and iron is used, and cost is saved; (3) the synthetic method is efficient, has a wide range of use, and is suitable for reactions of various substrates. The method is performed in an air atmosphere, has low cost, does not use an oxidizing agent or a reducing agent, and does not need a metal catalyst. The synthetic steps of the present application are simple, the experimental operation is simple, the reaction meets the green chemistry standard, and the present application has high popularization value. (4) The six-membered sulfamidate derivative prepared by the present application has lower ring tension and is more stable, and can be used to inhibit Escherichia coli. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 is a 1H NMR chart of the product prepared in Example 1 1 is a 1H NMR chart of the product prepared in Example 1

[0032] Figure 2 is a 1H NMR chart of the product prepared in Example 1 13 is a 1H NMR chart of the product prepared in Example 1

[0033] Figure 3 is a 1H NMR chart of the product prepared in Example 2 1 is a 1H NMR chart of the product prepared in Example 2

[0034] Figure 4 is a 1H NMR chart of the product prepared in Example 2 13 is a 1H NMR chart of the product prepared in Example 2

[0035] Figure 5 is a 1H NMR chart of the product prepared in Example 3 1 is a 1H NMR chart of the product prepared in Example 3

[0036] Figure 6 is a 1H NMR chart of the product prepared in Example 3 13 is a 1H NMR chart of the product prepared in Example 3

[0037] Figure 7 is a 1H NMR chart of the product prepared in Example 4 1 is a 1H NMR chart of the product prepared in Example 4

[0038] Figure 8 is a 1H NMR chart of the product prepared in Example 4 13 is a 1H NMR chart of the product prepared in Example 4

[0039] Figure 9 is a 1H NMR chart of the product prepared in Example 5

[0040] Figure 10 is the product prepared in Example 5 13 H NMR chart;

[0041] Figure 11 is the product prepared in Example 6 1 H NMR chart;

[0042] Figure 12 is the product prepared in Example 6 13 H NMR chart;

[0043] Figure 13 is the product prepared in Example 7 1 H NMR chart;

[0044] Figure 14 is the product prepared in Example 7 13 H NMR chart;

[0045] Figure 15 is the product prepared in Example 8 1 H NMR chart;

[0046] Figure 16 is the product prepared in Example 8 13 H NMR chart;

[0047] Figure 17 is the product prepared in Example 9 1 H NMR chart;

[0048] Figure 18 is the product prepared in Example 9 13 H NMR chart;

[0049] Figure 19 is the product prepared in Example 10 1 H NMR chart;

[0050] Figure 20 is the product prepared in Example 10 13 H NMR chart;

[0051] Figure 21 is the product prepared in Example 11 1 H NMR chart;

[0052] Figure 22 is the product prepared in Example 11 13 H NMR chart;

[0053] Figure 23 is the product prepared in Example 12 1 H NMR chart;

[0054] Figure 24 is the product prepared in Example 12 13 C NMR chart;

[0055] Figure 25 is the product prepared in Example 12 19 F NMR chart;

[0056] Figure 26 is the single crystal structure schematic diagram of the product prepared in Example 12

[0057] Figure 27 is the mechanism chart prepared in Example 1 of the application

[0058] Figure 28 is the antibacterial experiment, the left side is blank control group and the right side is experimental group DETAILED DESCRIPTION

[0059] In order to make the purpose, technical scheme and advantages of the embodiments of the application clearer, the technical scheme in the embodiments of the application will be described clearly and completely below in combination with the embodiments of the application. Obviously, the described embodiments are part of the embodiments of the application, rather than all the embodiments of the application. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the application.

[0060] The test materials and reagents used in the following embodiments, unless otherwise specified, can be obtained from commercial channels.

[0061] Unless otherwise specified in the embodiments, the technology or conditions can be carried out according to the technology or conditions described in the literature in the art or according to the product instructions.

[0062] Culture medium used in the application:

[0063] Nutrient Broth Medium (NB) | Qingdao Haibo | CN120054-250g

[0064] Nutrient Agar Medium (NA) | Qingdao Haibo | CN230275-250g

[0065] Nutrient Broth Medium (NB): Proteose peptone 10g; Beef infusion powder 3g; Sodium chloride 5g; pH 7.2±0.2 (25℃). Weigh 33g of culture medium, heat and dissolve in 1L of sterile water, after dispensing, sterilize at 121℃ for 15-20min.

[0066] Nutrient Agar Medium (NA): Proteose peptone 10 g; beef extract 3 g; sodium chloride 5 g; agar 15 g; pH 7.3 ± 0.1 (25 °C). Weigh 33 g of the medium, dissolve in 1 L of sterilized water, and sterilize at 121 °C for 15-20 min after dispensing.

[0067] The medium used was LB medium.

[0068] Example 1

[0069] An electrochemical synthesis method of a six-membered sulfolactam derivative, specifically the synthesis of 4-methoxy-4-methyl-2-phenyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (the structural formula is shown as formula (2)), includes the following steps:

[0070] (1) Take 0.3 mmol of N-phenyl-2-isopropenyl benzene sulfonamide (the structural formula is shown as formula (1) below) and 2 mL of methanol, and place them in a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine, and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of 15 mA at 60 °C in an air atmosphere for 2.5 h;

[0071] (2) The mixture obtained after the electrolysis reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white solid;

[0072]

[0073] The reaction equation of Example 1 is as follows:

[0074]

[0075] The preparation mechanism of Example 1 is shown in Figure 23 TEMPO is first oxidized at the anode through a single electron transfer process to generate a TEMPO cation intermediate, N-phenyl-2-isopropenyl benzene sulfonamide A is subjected to the action of methoxy anion to generate nitrogen anion B, then nitrogen anion B reacts with the TEMPO cation intermediate to generate radical intermediate C. Intermediate C attacks the double bond to form carbon radical D, then carbon radical is further oxidized to generate carbon cation E, and then carbon cation E combines with methoxy anion (methanol is reduced at the cathode to generate methoxy anion and H2) to generate the final product F. At the cathode, methanol is reduced to generate methoxy anion and H2, completing the electrochemical cycle.

[0076] Use 1The prepared product was characterized by 1H NMR, and the results are as follows: Figure 1 As shown. The chemical shifts are as follows: 1 H NMR(400MHz, CDCl3)δ7.91(dd,J=8.0,1.5Hz,1H),7.63–7.58(m,2H),7.52–7.47(m,1H),7.43–7.38( m,4H),7.37–7.31(m,1H),4.46(d,J=13.6Hz,1H),3.88(d,J=14.0Hz,1H),3.19(s,3H),1.63(s,3H).

[0077] use 13 The prepared product was characterized by C NMR, and the results are as follows: Figure 2 As shown. The chemical shifts are as follows: 13 C NMR (126MHz, CDCl3) δ139.3,138.7,138.1,132.8,129.5,128.8,128.0,127.8,127.5,123.4,74.7,57.8,52.1,28.9.HRMS(ESI): Calcd for C 16 H 18 NO3S[M+H] + 304.1002, found 304.1001.

[0078] As can be seen from the above results, the method described in this invention can successfully prepare 4-methoxy-4-methyl-2-phenyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide, and the calculated yield is 76%.

[0079] The product of Example 1 (sample 1) was used as a drug sample for the antibacterial experiment. The specific steps were as follows:

[0080] (1) Preparation of bacterial working solution:

[0081] Strain activation: *Escherichia coli* was used as the test bacterium for in vitro antibacterial testing. The glycerol tubes of the bacterial strain stored at -80℃ were removed, thawed at room temperature, and 100 μL of the bacterial suspension was streaked into prepared solid culture medium. After single colonies grew, they were inoculated into liquid culture medium and incubated overnight at 37℃. Once the bacteria reached the logarithmic growth phase, the bacterial suspension was streaked again. This activation process was repeated three times. The logarithmic growth phase bacterial suspension was then stored at 4℃ for later use.

[0082] Preparation of bacterial working solution: Centrifuge the activated bacterial solution at 4000 rpm for 10 min to allow the bacterial cells to precipitate to the bottom of the centrifuge tube, and discard the supernatant. Resuspend the bacterial cells in sterile PBS, dilute to 10⁸ CFU / mL, and store at 4℃ for later use.

[0083] (2) Sample sterilization

[0084] The sample was sterilized by ultraviolet irradiation for 2 hours and stored at a concentration of 10 mg / mL;

[0085] (3) Antimicrobial test

[0086] The activated bacteria solution was inoculated into a freshly prepared liquid medium at a volume percentage of 1% (1 mL system), and the sample was added to the above liquid medium. It was placed in a 37°C incubator and cultured at 180 rpm overnight. The next day, the medium was shaken and a suitable amount of bacteria solution was gradient diluted and plated. The solid culture after gradient dilution was incubated at 37°C overnight, and after clear single colonies were grown, the plate count was taken. The number of colonies on each plate was counted, and the inhibition rate was calculated by comparing with the blank control (inhibition rate = (blank control - experimental group) / blank control). The blank control was the blank control without sample (pure bacteria).

[0087] According to the test results, it is found that sample 1 has a certain antibacterial effect on E. coli, and the inhibition rate can reach 50%.

[0088] Example 2

[0089] An electrochemical synthesis method of a six-membered sulfilactam derivative, specifically the synthesis of 4-ethoxy-4-methyl-2-phenyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (the structural formula is shown as formula (2)), comprising the following steps:

[0090] (1) Take 0.3 mmol of N-phenyl-2-isopropyl benzene sulfonamide (the structural formula is shown as formula (1)) and 2 mL of ethanol, and place them in a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 2,2,6,6-tetramethylpiperidine 0.015 mmol and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of 10 mA at 60°C in an air atmosphere for 2 h;

[0091] (2) The mixture obtained after the electrolysis reaction was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (developing agent: mixed by volume ratio of petroleum ether: ethyl acetate = 6:1) to obtain a white solid;

[0092]

[0093] Use 1 The prepared product was characterized by H NMR, and the results are shown in Figure 3 The chemical shifts are as follows: 1H NMR (400 MHz, CDC13) δ 7.78 (d, J = 8.0 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.38 - 7.34 (m, 1H), 7.33 - 7.26 (m, 4H), 7.23 - 7.19 (m, 1H), 4.37 (d, J = 14.0 Hz, 1H), 3.76 (d, J = 14.0 Hz, 1H), 3.41 (dq, J = 8.8, 6.8 Hz, 1H), 3.11 (dq, J = 8.8, 6.8 Hz, 1H), 1.53 (s, 3H), 1.01 (t, J = 6.8 Hz, 3H).

[0094] Using 13 The product prepared was characterized by1H NMR, and the results are shown in Figure 4 The chemical shifts are as follows: 13 C NMR (101 MHz, CDC13) δ 139.4, 139.2, 137.8, 132.7, 129.4, 128.6, 127.9, 127.6, 127.4, 123.2, 74.5, 59.7, 58.1, 29.3, 15.9. HRMS (ESI): Calcd for C 17 H 20 NO3S[M+H] + 318.1158, found 318.1161.

[0095] From the above results, it can be seen that the method described in the present application can successfully prepare 4-ethoxy-4-methyl-2-phenyl-3,4-dihydro-2H- benzo[e][l,2]thiazine 1,1-dioxide, and the calculated yield is 73%.

[0096] Example 3

[0097] A method for electrochemical synthesis of a six-membered sulfolactam derivative, in particular synthesis of 4-isopropoxy-4-methyl-2-phenyl-3,4-dihydro-2H-benzo[e][l,2]thiazine- 1,1-dioxide (structural formula as shown in formula (2)), comprising the following steps:

[0098] (1) Take 0.3 mmol of N-phenyl-2-isopropyl benzene sulfonamide (structural formula as shown in formula (1)) and 2 mL of isopropyl alcohol, and place them in a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine, and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of 15 mA at 80°C under air atmosphere for 2 h;

[0099] (2) The mixture obtained after the power-on reaction was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (developing agent: a mixture of petroleum ether: ethyl acetate = 6: 1 by volume) to obtain a white oily liquid;

[0100]

[0101] Using 1 The prepared product was characterized by H NMR, and the results are shown in Figure 5 The chemical shifts are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.70-7.68 (m, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.43-7.40 (m, 4H), 7.37-7.32 (m, 1H), 4.49 (d, J = 13.6 Hz, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.86-3.79 (m, 1H), 1.64 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H).

[0102] Using 13 The prepared product was characterized by C NMR, and the results are shown in Figure 6 The chemical shifts are as follows: 13 C NMR (101 MHz, CDCl3) δ 140.2, 139.3, 137.7, 132.5, 129.5, 128.7, 128.4, 128.1, 127.6, 123.4, 75.1, 67.1, 59.3, 29.5, 25.4, 24.4. HRMS (ESI): Calcd for C 18 H 22 NO3S [M+H] + 332.1315, found 332.1313.

[0103] From the above results, it can be seen that the method described in the present application can successfully prepare 4-isopropoxy-4-methyl-2-phenyl-3,4-dihydro-2H-benzo[e][1,2]thiazine-1,1-dioxide, and the calculated yield is 72%.

[0104] Example 4

[0105] An electrochemical synthesis method of a six-membered sulfolactam derivative, in particular, a synthesis of 4-methoxy-4-methyl-2-(p-tolyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine-1,1-dioxide (structural formula as shown in formula (2)), comprising the following steps:

[0106] (1) Take 0.3 mmol of N-(4-methylphenyl)-2-isopropyl benzene sulfonamide (structural formula as shown in formula (1)) and 2 mL of methanol into a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of 15 mA at 60°C in an air atmosphere for 3 h;

[0107] (2) The mixture obtained after the electrochemical reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white liquid;

[0108]

[0109] Using 1 H NMR is used to characterize the prepared product, and the results are shown in Figure 7 The chemical shifts are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 7.8, 1.2 Hz, 1H), 7.63-7.57 (m, 2H), 7.50-7.45 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 14.0 Hz, 1H), 3.84 (d, J = 14.0 Hz, 1H), 3.18 (s, 3H), 2.35 (s, 3H), 1.62 (s, 3H).

[0110] Using 13 C NMR is used to characterize the prepared product, and the results are shown in Figure 8 The chemical shifts are as follows: 13 C NMR (101 MHz, CDCl3) δ 138.7, 138.1, 138.1, 136.5, 132.7, 130.1, 128.7, 127.7, 127.4, 123.4, 74.7, 57.8, 52.0, 28.9, 21.1. Calcd for C 17 H 20 NO3S[M+H] + 318.1158, found 318.1163.

[0111] From the above results, it can be seen that the method according to the present application can successfully prepare 4-methoxy-4-methyl-2-(p-tolyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine-1,1-dioxide, with a calculated yield of 68%.

[0112] Example 5

[0113] A method for electrochemical synthesis of a six-membered sulfolactam derivative, in particular synthesis of 2-(3,4-dimethylphenyl)-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine-1,1-dioxide (structural formula as shown in formula (2)), comprises the following steps:

[0114] (1) 0.3 mmol of N-(3,4-dimethylphenyl)-2-isopropylidenebenzenesulfonamide (structural formula as shown in formula (1)) and 2 mL of methanol are placed in a reaction tube equipped with a carbon electrode and a nickel electrode, 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine and 0.09 mmol of tetrabutylammonium tetrafluoroborate are added, and the mixture is stirred at 60°C under an air atmosphere under the condition of 15 mA for 1.5 h;

[0115] (2) The mixture obtained after the electrolysis reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white oily liquid;

[0116]

[0117] Using 1 The product prepared is characterized by H NMR, and the results are shown in Figure 9 The chemical shifts are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 8.0, 1.2 Hz, 1H), 7.64-7.57 (m, 2H), 7.51-7.47 (m, 1H), 7.20-7.13 (m, 3H), 4.43 (d, J = 13.6 Hz, 1H), 3.82 (d, J = 13.6, 1H), 3.19 (s, 3H), 2.27 (d, J = 2.4 Hz, 6H), 1.64 (s, 3H).

[0118] Using 13 The product prepared is characterized by C NMR, and the results are shown in Figure 10 The chemical shifts are as follows: 13C NMR (101 MHz, CDC13) δ 138.8, 138.3, 138.0, 136.9, 136.7, 132.7, 130.6, 128.8, 128.7, 127.8, 124.9, 123.4, 74.8, 57.9, 52.1, 29.1, 19.9, 19.5. HRMS (ESI): Calcd for C 18 H 22 NO3S[M+H] + 332.1315, found 332.1311.

[0119] From the above results, it can be seen that the method of the present application can successfully prepare 2-(3,4-dimethylphenyl)-4-methoxy-4-methyl-3,4-dihydro-2H- benzo[e][l,2]thiazine-l,l-dioxide, and the calculated yield is 67%.

[0120] Example 6

[0121] An electrochemical synthesis method of a six-membered sulfolactam derivative, in particular, a synthesis of 4-methoxy-4-methyl-2-(4-nitrophenyl)-3,4-dihydro-2H- benzo[e][l,2]thiazine-l,l-dioxide (structural formula as shown in formula (2)), comprises the following steps:

[0122] (1) 0.3 mmol of N-(4-nitrophenyl)-2-isopropylidenebenzenesulfonamide (structural formula as shown in formula (1)) and 2 mL of methanol are placed in a reaction tube equipped with a carbon electrode and a nickel electrode, then 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine and 0.09 mmol of tetrabutylammonium tetrafluoroborate are added, and the mixture is stirred in an air atmosphere under the condition of heating at 60°C at 15 mA for 2 h;

[0123] (2) The mixture obtained after the electrochemical reaction is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent obtained by mixing petroleum ether: ethyl acetate = 6: 1 by volume) to obtain a yellow solid;

[0124]

[0125] Using 1 The product prepared is characterized by H NMR, and the results are shown in Figure 11 The chemical shifts are as follows: 1H NMR (400 MHz, CDC13) δ 8.27 (d, J = 9.2 Hz, 2H), 7.92 (dd, J = 8.0, 1.2 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.63 - 7.53 (m, 4H), 4.47 (d, J = 14.0 Hz, 1H), 4.06 (d, J = 14.0 Hz, 1H), 3.19 (s, 3H), 1.64 (s, 3H).

[0126] Using 13 The product prepared was characterized by1H NMR, and the results are shown in Figure 12 The chemical shifts are as follows: 13 C NMR (101 MHz, CDC13) δ 146.2, 145.4, 138.3, 137.4, 133.2, 129.2, 128.1, 126.8, 124.9, 123.7, 74.2, 57.6, 51.9, 28.1. HRMS (ESI): Calcd for C 16 H 17 N2O5S [M+H] + 349.0853, found 349.0850.

[0127] From the above results, it can be seen that the method described in the present application can successfully prepare 4-methoxy-4-methyl-2-(4-nitrophenyl)-3,4-dihydro-2H- benzo[e][l,2]thiazine 1,1-dioxide, and the calculated yield is 77%.

[0128] Example 7

[0129] An electrochemical synthesis method of a six-membered sulfolactam derivative, specifically the synthesis of 2-(4-(tert-butyl)phenyl)-4-methoxy-4-methyl-3,4-dihydro-2H- benzo[e][l,2]thiazine 1,1-dioxide (structural formula as shown in formula (2)), comprises the following steps:

[0130] (1) Take 0.3 mmol of N-(4-(tert-butyl)phenyl)-2-isopropyl benzene sulfonamide (structural formula as shown in formula (1)), and 2 mL of methanol are placed in a reaction tube equipped with a carbon electrode and a nickel electrode, then 4 mL of acetonitrile, 2,2,6,6-tetramethylpiperidine 0.015 mmol and 0.09 mmol of tetrabutylammonium tetrafluoroborate are added, and the reaction is stirred in an air atmosphere at 60°C under the condition of heating at 15 mA for 2 h;

[0131] (2) The mixture obtained after the power-on reaction was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (developing agent: mixed by volume ratio of petroleum ether: ethyl acetate = 6:1) to obtain a white oily liquid;

[0132]

[0133] Using 1 The prepared product was characterized by H NMR, and the results are shown in Figure 13 The chemical shifts are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.49 (m, 1H), 7.44-7.41 (m, 2H), 7.35-7.32 (m, 2H), 4.45 (d, J = 14.0 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 3.20 (s, 3H), 1.64 (s, 3H), 1.33 (s, 9H).

[0134] Using 13 The prepared product was characterized by C NMR, and the results are shown in Figure 14 The chemical shifts are as follows: 13 C NMR (126 MHz, CDCl3) δ 151.2, 138.8, 138.2, 136.4, 132.8, 128.8, 127.8, 127.1, 126.5, 123.6, 74.8, 57.8, 52.2, 34.8, 31.4, 29.1. HRMS (ESI): Calcd for C 20 H 26 NO3S[M+H] + 360.1628, found 360.1625.

[0135] From the above results, it can be seen that the method described in the present application can successfully prepare 2-(4-(tert-butyl)phenyl)-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide, and the calculated yield is 71%.

[0136] Example 8

[0137] An electrochemical synthesis method of a six-membered sulfolactam derivative, specifically the synthesis of 2-benzyl-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (structural formula as shown in formula (2)), comprising the following steps:

[0138] (1) Take 0.3 mmol of N-benzyl-2-isopropyl benzene sulfonamide (structure as shown in formula (1)) and 2 mL of methanol in a reaction tube equipped with a carbon electrode, a nickel electrode, then add 4 mL of acetonitrile, 2,2,6,6-tetramethylpiperidine 0.015 mmol and 0.09 mmol of tetrabutylammonium tetrafluoroborate, heat at 60°C under the condition of 10 mA, and stir the reaction under air atmosphere for 2 h;

[0139] (2) The mixture obtained after the electrochemical reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent is obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white oily liquid;

[0140]

[0141] Use 1 The prepared product is characterized by H NMR, and the results are shown in Figure 15 The chemical shift is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 7.6, 1.2 Hz, 1H), 7.60-7.58 (m, 1H), 7.53-7.47 (m, 2H), 7.42-7.33 (m, 5H), 4.66 (d, J = 14.0 Hz, 1H), 4.27 (d, J = 14.0 Hz, 1H), 3.85 (d, J = 14.4 Hz, 1H), 3.37 (d, J = 14.4 Hz, 1H), 3.05 (s, 3H), 1.39 (s, 3H).

[0142] Use 13 The prepared product is characterized by C NMR, and the results are shown in Figure 16 The chemical shift is as follows: 13 C NMR (101 MHz, CDCl3) δ 139.1, 136.9, 135.2, 132.7, 129.3, 128.8, 128.8, 128.3, 127.8, 123.6, 73.7, 51.8, 51.4, 50.5, 28.2. HRMS (ESI): Calcd for C 17 H 20 NO3S[M+H] + 318.1158, found 318.1154.

[0143] From the above results, it can be seen that the method described in the present application can successfully prepare 2-benzyl-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide, and the calculated yield is 60%.

[0144] Example 9

[0145] A method for electrochemical synthesis of a six-membered sulfolactam derivative, specifically 2-isopropyl-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (structure shown as Formula (2)), comprising the following steps:

[0146] (1) Take 0.3 mmol of N-isopropyl-2-isopropenyl benzene sulfonamide (structure shown as Formula (1)) and 2 mL of methanol in a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of 15 mA at 60°C in an air atmosphere for 1.5 h;

[0147] (2) The mixture obtained after the electrochemical reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white oily liquid;

[0148]

[0149] Using 1 The prepared product was characterized by H NMR, and the results are shown in Figure 17 The chemical shifts are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.0, 1.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.51-7.49 (m, 1H), 7.47-7.42 (m, 1H), 4.57-4.46 (m, 1H), 3.95 (d, J = 14.0 Hz, 1H), 3.25 (d, J = 14.0 Hz, 1H), 3.17 (s, 3H), 1.56 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H).

[0150] Using 13 The prepared product was characterized by C NMR, and the results are shown in Figure 18 The chemical shifts are as follows: 13 C NMR (101 MHz, CDCl3) δ 138.4, 138.3, 132.4, 128.6, 127.3, 122.9, 75.0, 51.9, 47.0, 45.9, 29.3, 20.8, 20.2. HRMS (ESI): Calcd for C 13H 20 NO3S[M+H] + 270.1158, found 270.1154.

[0151] From the above results, it can be seen that the method of the present application can successfully prepare 2-isopropyl-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide, and the calculated yield is 62%.

[0152] Example 10

[0153] An electrochemical synthesis method of a six-membered sulfolactam derivative, in particular, a synthesis method of 2-(4-chlorophenyl)-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine-1,1-dioxide (the structural formula is shown as formula (2)) comprises the following steps:

[0154] (1) 0.3 mmol of N-(4-chlorophenyl)-2-isopropyl benzene sulfonamide (the structural formula is shown as formula (1)) and 2 mL of methanol are placed in a reaction tube provided with a carbon electrode and a nickel electrode, then 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine and 0.09 mmol of tetrabutylammonium tetrafluoroborate are added, and the reaction is stirred in an air atmosphere under the condition of heating at 60°C at 15 mA for 2 h;

[0155] (2) The mixture obtained after the electrolysis reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent: mixed by volume ratio of petroleum ether: ethyl acetate = 6:1) to obtain a white solid;

[0156]

[0157] Using 1 H NMR is used to characterize the prepared product, and the results are shown in Figure 19 The chemical shifts are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.53-7.49 (m, 1H), 7.40-7.34 (m, 4H), 4.41 (d, J = 14.0 Hz, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.18 (s, 3H), 1.63 (s, 3H).

[0158] Using 13 C NMR is used to characterize the prepared product, and the results are shown in Figure 20 The chemical shifts are as follows: 13C NMR (101 MHz, CDC13) δ 138.6, 137.8, 137.8, 133.9, 132.9, 129.7, 128.9, 128.8, 127.9, 123.5, 74.6, 57.7, 52.0, 28.8. HRMS (ESI): Calcd for C 16 H 17 ClNO3S[M+H] + 338.0612, found338.0609.

[0159] From the above results, it can be seen that the method of the present application can successfully prepare 2-(4-chlorophenyl)-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine-1,1-dioxide, and the calculated yield is 82%.

[0160] Example 11

[0161] An electrochemical synthesis method of a six-membered sulfolactam derivative, in particular, a synthesis of 4-methyl-1,1-dioxide-2-phenyl-3,4-dihydro-2H-benzo[e][1,2]thiazine-4-yl acetate (the structural formula is shown as formula (2)), comprising the following steps:

[0162] (1) Take 0.3 mmol of N-phenyl-2-isopropyl benzene sulfonamide (the structural formula is shown as formula (1)), and 2 mL of acetic acid in a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 2,2,6,6-tetramethylpiperidine 0.015 mmol and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of 15 mA at 60°C under air atmosphere for 3 h;

[0163] (2) The mixture obtained after the electrochemical reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent is obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white solid;

[0164]

[0165] Using 1 H NMR was used to characterize the prepared product, and the results are shown in Figure 21 The chemical shifts are as follows: 1H NMR (400 MHz, CDC13) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.54 - 7.50 (m, 1H), 7.42 - 7.35 (m, 4H), 7.34 - 7.30 (m, 1H), 4.89 (d, J = 14.0 Hz, 1H), 4.29 (d, J = 14.0 Hz, 1H), 1.97 (s, 3H), 1.92 (s, 3H).

[0166] Using 13 C NMR was used to characterize the product prepared, and the results are shown in Figure 22 Chemical shifts are as follows: 13 C NMR (101 MHz, CDC13) δ 169.9, 139.6, 138.9, 136.6, 132.8, 129.6, 129.2, 128.0, 127.6, 127.1, 123.8, 78.1, 57.3, 26.5, 22.1.

[0167] From the above results, it can be seen that the method described in the present application can successfully prepare 4-methyl-1,1-dioxide-2-phenyl-3,4-dihydro-2H- benzo[e][1,2]thiazine-4-yl acetate, with a calculated yield of 69%.

[0168] Example 12

[0169] An electrochemical synthesis method of a six-membered sulfolactam derivative, specifically the synthesis of 2-(4-fluorophenyl)-4-methoxy-4-methyl-3,4-dihydro-2H- benzo[e][1,2]thiazine 1,1-dioxide (structural formula as shown in formula (2)), includes the following steps:

[0170] (1) Take 0.3 mmol of N-(4-fluorophenyl)-2-isopropenyl benzene sulfonamide (structural formula as shown in formula (1)), and 2 mL of methanol, and place them in a reaction tube equipped with a carbon electrode and a nickel electrode, then add 4 mL of acetonitrile, 0.015 mmol of 2,2,6,6-tetramethylpiperidine, and 0.09 mmol of tetrabutylammonium tetrafluoroborate, and stir the reaction under the condition of heating at 60°C and air atmosphere at 15 mA for 2 h;

[0171] (2) The mixture obtained after the electrochemical reaction is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (developing agent obtained by mixing petroleum ether: ethyl acetate = 6:1 by volume) to obtain a white solid;

[0172]

[0173] Using1 H NMR was used to characterize the prepared product, and the results are shown in Figure 23 The chemical shifts are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.91 (dd, J = 6.4, 1.2 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.53 - 7.50 (m, 1H), 7.42 - 7.38 (m, 2H), 7.13 - 7.08 (m, 2H), 4.40 (d, J = 11.2 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.19 (s, 3H), 1.64 (s, 3H).

[0174] Using 13 C NMR was used to characterize the prepared product, and the results are shown in Figure 24 The chemical shifts are as follows: 13 C NMR (101 MHz, CDCl3) δ 162.2 (d, J C-F = 249.5 Hz), 138.7, 137.9, 135.1 (d, J C-F = 3.0 Hz), 132.9, 129.6 (d, J C-F = 8.1 Hz), 128.9, 127.9, 123.6, 116.5 (d, J C-F = 23.2 Hz), 74.7, 57.9, 52.1, 28.9.

[0175] Using 19 F NMR was used to characterize the prepared product, and the results are shown in Figure 25 The chemical shifts are as follows: 19 F NMR (471 MHz, CDCl3) δ -113.04. HRMS (ESI): Calcd for C 16 H 17 FNO3S [M + H] + 322.0908, found 322.0905.

[0176] The prepared product was characterized by using single crystal diffraction test, and the single crystal structure is shown in Figure 26 .

[0177] From the above results, it can be seen that the method described in the present application can successfully prepare 2-(4-fluorophenyl)-4-methoxy-4-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide, and the calculated yield is 76%.

[0178] Comparative Example 1

[0179] The procedure of Example 1 was followed except that the 2-isoallylbenzenesulfonamide derivative starting material was replaced with a 2-isoallylbenzenesulfonamide derivative having the structure The reaction equation is as follows:

[0180]

[0181] It was found through the reaction that the starting material in Comparative Example 1 had a large steric hindrance and the reaction effect was not good, and the target product could not be obtained.

[0182] Comparative Example 2

[0183] The procedure of Example 1 was followed except that the 2-isoallylbenzenesulfonamide derivative starting material was replaced with a 2-isoallylbenzenesulfonamide derivative having the structure The reaction equation is as follows:

[0184]

[0185] In Comparative Example 2, the methoxy group in the para position was more easily oxidized to a hydroxyl group, and the olefin and the methanol did not participate in the reaction.

[0186] The above description of the embodiments is to facilitate the understanding and use of the present application by those of ordinary skill in the art. Those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without having to undergo creative labor. Therefore, the present application is not limited to the above-described embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present application without departing from the scope of the present application should be within the scope of protection of the present application.

Claims

1. An electrochemical synthesis method for a hexa-sulfonamide derivative, characterized in that, The electrochemical synthesis method of the hexa-sulfonamide derivative is as follows: A 2-isoallylbenzenesulfonamide derivative and a hydroxyl-containing compound are reacted by electrolysis in an electrolyte to obtain a hexa-sulcinolamide derivative; the electrolyte includes an additive; the additive is sodium iodide or 2,2,6,6-tetramethylpiperidine.

2. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 1 or 2, characterized in that, The molar ratio of the 2-isoallylbenzenesulfonamide derivative and the hydroxyl-containing compound is 1:20-200.

3. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 1 or 2, characterized in that, The structural formula of the 2-isoallylbenzenesulfonamide derivative is: Among them, R 2 It is a benzene ring with a substituent, benzyl, or isopropyl.

4. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 1 or 2, characterized in that, The hydroxyl-containing compound is selected from at least one of H2O, alcohols, and carboxylic acids.

5. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 1 or 2, characterized in that, The electrolyte also includes an electrolyte; the electrolyte is tetrabutylammonium tetrafluoroborate, lithium perchlorate, tetrabutylammonium hexafluoroborate, or sodium carbonate.

6. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 5, characterized in that, The molar ratio of the electrolyte to the 2-isoallylbenzenesulfonamide derivative is 0.3:

1.

7. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 1 or 2, characterized in that, The amount of the additive used is 5% of the molar amount of the 2-isoallylbenzenesulfonamide derivative.

8. The electrochemical synthesis method of the hexa-sulfonamide derivative according to claim 1 or 2, characterized in that, The temperature conditions for the electrochemical reaction are: 60-80℃, current of 10mA-15mA, and reaction time of 1.5-3h.

9. A hexabenzenesulfonamide derivative, prepared by the electrochemical synthesis method of the hexabenzenesulfonamide derivative according to any one of claims 1-8, wherein the structural formula of the hexabenzenesulfonamide derivative is: in, R 1 It can be an alkyl group, a fatty alcohol, a carboxyl group, or an acyl group.

10. An application of the hexasulfonamide derivative of claim 9 for the preparation of an antibacterial drug.

Images