A piperazine-containing seven-membered cyclic sulfonamide derivative and an electrochemical synthesis method thereof

Abstract

This invention discloses a piperazine-containing seven-membered cyclic sulfonamide derivative and its electrochemical synthesis method. The method employs an electrochemical oxidation process, using electrons as a clean oxidant, to achieve a dehydrogenation cross-coupling reaction between the seven-membered cyclic sulfonamide and piperazine compounds, synthesizing a series of piperazine-modified seven-membered cyclic sulfonamide derivatives with anti-inflammatory activity. This synthetic method has significant advantages in green chemistry, requiring no noble metal catalysts, stoichiometric oxidants, or strong bases. The reaction conditions are mild and the process is easily controlled. Furthermore, this invention achieves Csp... 2 The direct oxidative cross-dehydrogenation coupling between -H and N-H constructs a C-N bond in one step, which is highly atom-economical and avoids the drawbacks of substrate prefunctionalization and multi-step reactions in traditional synthesis, thus improving the synthesis efficiency.

Description

Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, and particularly relates to a piperazine-containing seven-membered cyclic sulfonamide derivative and its electrochemical synthesis method. Background Technology

[0002] Cyclic sulfonamides are an important class of nitrogen-containing heterocyclic compounds with diverse biological and pharmacological activities, such as antibacterial, antitumor, antidepressant, and antioxidant activities. Among them, seven-membered cyclic sulfonamides... N Sulfonamides have attracted particular attention, with clinically approved antidepressants such as tianeptine demonstrating their therapeutic value. Given the diverse medicinal potential of these compounds, the development of efficient and universal synthetic methods to construct these seven-membered ring derivatives has garnered significant research interest in recent years. Recent advances include strategies such as 1,3-dipolar cycloaddition, transition metal-catalyzed cyclization, and organocatalytic asymmetric reactions, achieving efficient construction of complex sulfonamide skeletons. Furthermore, studies have developed visible light-driven, quinine ring-mediated, and chiral arylthiol-catalyzed racemic deracemation reactions for the synthesis of highly enantioselective cyclic sulfonamide compounds. Despite these advancements, existing seven-membered ring... N The synthesis and modification strategies of sulfonyl imides still often face limitations such as complex operation, reliance on noble metal catalysts, or multi-step reactions. Therefore, the development of seven-membered ring... N There remains an urgent need for efficient synthetic methods for sulfonamide derivatives.

[0003] Electrochemical synthesis, as a green and efficient method, uses clean electrons as redox agents to achieve the construction of complex molecules by generating highly reactive intermediates through the oxidation or reduction of compounds on the electrode surface. Currently, the electrochemical modification of seven-membered ring sulfonamides has not been fully studied. Piperazines are a versatile tool in medicinal chemistry, greatly contributing to the development of efficient and synthetic drugs by enhancing binding, improving pharmacokinetics (solubility, permeability), and providing flexible modification sites. Summary of the Invention

[0004] The purpose of this invention is to solve the problems of multiple steps and harsh reaction conditions in the synthesis of seven-membered cyclic sulfonamide derivatives. It provides a piperazine-containing seven-membered cyclic sulfonamide derivative and its electrochemical synthesis method. This method employs an electrochemical oxidation process, using electrons as a clean oxidant, to achieve a dehydrogenation cross-coupling reaction between the seven-membered cyclic sulfonamide and piperazine compounds, synthesizing a series of piperazine-modified seven-membered cyclic sulfonamide derivatives with anti-inflammatory activity. This synthetic method has significant advantages in green chemistry, requiring no noble metal catalysts, stoichiometric oxidants, or strong bases. The reaction conditions are mild and the process is easily controlled. Furthermore, this invention achieves Csp... 2The direct oxidative cross-dehydrogenation coupling between -H and NH bonds constructs a CN bond in one step, which is highly atom-economical and avoids the drawbacks of substrate prefunctionalization and multi-step reactions in traditional synthesis, thus improving the synthesis efficiency.

[0005] This invention proposes an oxidative cross-coupling reaction of a seven-membered cyclic sulfonamide with piperazine for the electrochemical synthesis of piperazine-containing seven-membered cyclic sulfonamide derivatives. This process is not only highly efficient but also highly selective. The reaction exhibits several advantages: (a) no expensive transition metal catalysts or equivalent bases are involved; (b) electrons are the sole oxidant, eliminating the need for stoichiometric oxidants; (c) the reaction conditions are mild, and the substrate adaptability is broad; (d) hydrogen is the only byproduct, resulting in high atom economy; and (e) the synthesized piperazine-containing seven-membered cyclic sulfonamide compounds possess highly efficient anti-inflammatory activity.

[0006] The technical solution of the present invention is as follows:

[0007] A piperazine-containing seven-membered cyclic sulfonamide derivative, which has a seven-membered cyclic sulfonamide as its parent structure, and its Csp 2 Different piperazine-based compound skeletons are introduced at the -H position. The general chemical structural formula of the piperazine-containing seven-membered cyclic sulfonamide derivatives is as follows:

[0008] .

[0009] Among them, piperazine compounds Selected from: N -Methylpiperazine, N -Ethylpiperazine, N -Isopropylpiperazine, N -Cyclopropylpiperazine, N -Cyclohexylpiperazine, 1-(cyclopropylmethyl)piperazine, benzyl-1-piperazine carbonate N -Ethyl piperazine carboxylate, N - Acetylpiperazine, 2-(piperazin-1-yl)pyrimidine, N -Phenylacetazine, 1-(4-bromophenyl)piperazine, 1-(4-fluorophenyl)piperazine, 3-(piperazin-1-yl)benzo[d]isothiazolium, N -piperazine, 1-(oxetane-3-yl)piperazine, 4-methanesulfonylpiperazine, 4-methanesulfonylphenylpiperazine N Any one of the following: ethyl piperazine, 7-chloro-4-(-1-piperazinyl)quinoline, 1-methyl-2-piperazinone, 1-(2-tetrahydrofuranoyl)piperazine, 4-(4-fluoro-3-(piperazin-1-carbonyl)benzyl)phthalazin-1-(2H)-one, and ciprofloxacin.

[0010] Where R1 and R2 represent different substituents in the structure of piperazine compounds, such as when the piperazine compound isN When the piperazine is 1-methyl-2-piperazine, R1 is methyl and R2 is hydrogen; when the piperazine compound is 1-methyl-2-piperazinone, R1 is methyl and R2 is ketone.

[0011] The piperazine-containing seven-membered cyclic sulfonamide derivatives are selected from the following structural formulas:

[0012] .

[0013] The present invention also provides an electrochemical synthesis method for the piperazine-containing seven-membered cyclic sulfonamide derivative, comprising the following steps: in an electrolytic cell, an anode and a cathode are set up, and a seven-membered cyclic sulfonamide, a piperazine compound, an electrolyte and a solvent are added sequentially, and the reaction is carried out under constant current conditions. After the reaction is completed, the reaction solution is collected to obtain the piperazine-containing seven-membered cyclic sulfonamide derivative.

[0014] The structural formula of the seven-membered cyclic sulfonamide is: .

[0015] Preferably, the molar ratio of the seven-membered cyclic sulfonamide, piperazine compound, and electrolyte is 3:2:2, the electrolyte is potassium iodide, and the solvent is acetonitrile.

[0016] Preferably, the anode is a carbon rod, the cathode is a platinum sheet, the constant current is 2-4 mA, and the reaction time is 15-30 h. More preferably, the constant current is 3 mA, and the reaction time is 20 h.

[0017] Preferably, in the above electrochemical synthesis method, after the reaction is completed, the reaction solution is concentrated and purified by column chromatography to obtain a seven-membered cyclic sulfonamide derivative containing piperazine. The column chromatography conditions are: petroleum ether / ethyl acetate = 1 / 2, volume ratio.

[0018] The present invention also provides the use of the piperazine-containing seven-membered cyclic sulfonamide derivative in the preparation of anti-inflammatory drugs.

[0019] The present invention also provides a pharmaceutical formulation comprising the piperazine-containing seven-membered cyclic sulfonamide derivative, and one or more pharmaceutically acceptable carriers or excipients.

[0020] The beneficial effects of this invention are:

[0021] 1. The piperazine-containing seven-membered cyclic sulfonamide derivative obtained in this invention has a good anti-inflammatory effect and can be used to prepare anti-inflammatory drugs.

[0022] 2. This invention uses electrochemical oxidation, utilizing clean electrons as oxidizing agents, to achieve the oxidative cross-dehydrogenation coupling reaction of seven-membered cyclic sulfonamides and piperazines in the absence of metals, external oxidants, and equivalent bases, thereby constructing a piperazine-containing seven-membered cyclic sulfonamide derivative in one step.

[0023] 3. This invention solves the problems of traditional synthesis of seven-membered cyclic sulfonamide active molecules, such as multiple steps, harsh reaction conditions, difficult synthetic routes, and the need for pre-functional group activation of substrates. At the same time, it can avoid the use of a large amount of expensive transition metal catalysts and equivalent oxidizing agents in the synthesis process. Most importantly, this method can provide ideas and methodological references for the green and inexpensive synthesis of piperazine derivatives under mild conditions. Attached Figure Description

[0024] Figure 1 This is the general chemical structural formula of the piperazine-containing seven-membered cyclic sulfonamide derivative of the present invention;

[0025] Figure 2 This describes the reaction mechanism of the electrochemical synthesis in this invention. Detailed Implementation

[0026] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Unless otherwise specified, all reagents involved in the embodiments of this invention are commercially available products and can be purchased through commercial channels.

[0028] The general structural formula of the piperazine-containing seven-membered cyclic sulfonamide derivative of this invention is shown in the figure. Figure 1 The electrochemical reaction mechanism (taking compound 1 as an example) is shown in [reference needed]. Figure 2 Specifically, the process involves using a seven-membered cyclic sulfonamide and a piperazine compound as starting materials, clean electrons as the oxidant, and potassium iodide as the electrolyte. At the anode, iodine anions undergo oxidation to generate iodine molecules (I2). This electrochemically generated I2 then reacts with the piperazine substrate (2a) to generate intermediate A. Intermediate A undergoes NI bond cleavage to generate an imine radical cation intermediate B. Intermediate B further adds to the C=C double bond of the olefin substrate, the seven-membered cyclic sulfonamide (1a), to form intermediate C. Subsequently, intermediate C undergoes single-electron anodic oxidation followed by proton elimination to obtain the target product—a piperazine-containing seven-membered cyclic sulfonamide derivative (3a). Simultaneously at the cathode, protons (H+) in the reaction medium... + It is reduced to produce hydrogen gas.

[0029] I. Electrochemical Synthesis of Compounds

[0030] Example 1: Synthesis of Compound 1

[0031]

[0032] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N 1-Methylpiperazine (0.5 mmol, 50.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0033] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 1) with a separation yield of 95%.

[0034] 1 H NMR (400 MHz, CDCl3) d 8.11 (d, J = 8.0 Hz, 1H), 7.67-7.60 (m, 4H),7.54-7.44 (m, 3H), 3.99-3.83 (m, 2H), 3.57-3.52 (m, 1H), 3.26-3.21 (m, 1H),2.49-2.38 (m, 3H), 2.26 (s, 4H).

[0035] 13 C NMR (101 MHz, CDCl3) δ 165.24, 144.04, 139.46, 135.47, 132.12,131.57, 131.04, 129.93, 129.78, 129.12, 128.48, 127.91, 125.86, 55.22, 54.21, 49.70, 45.66, 45.56.

[0036] HRMS (ESI) calcd for C 18 H 19 N3O2S: 342.1271 (M+H + ), found: 342.1274.

[0037] Example 2 Synthesis of Compound 2

[0038]

[0039] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially.N -Ethylpiperazine (0.5 mmol, 57.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0040] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 2) with a separation yield of 83%.

[0041] 1 H NMR (400 MHz, CDCl3) d 8.11 (d, J = 8.0 Hz, 1H), 7.67-7.62 (m, 4H),7.55-7.45 (m, 3H), 4.02-3.83 (m, 2H), 3.59-3.54 (m, 1H), 3.28-3.23 (m, 1H),2.56-2.42 (m, 5H), 2.35-2.30 (m, 1H), 2.26 (t, J = 8.0 Hz, 3H).

[0042] 13 C NMR (101 MHz, CDCl3) δ 160.35, 139.37, 134.81, 130.73, 127.28,126.78, 126.33, 125.24, 124.94, 124.37, 123.76, 123.09, 121.23, 48.35, 47.24,47.19, 44.99, 40.90, 7.12.

[0043] HRMS (ESI) calcd for C 19 H 21 N3O2S: 356.1427 (M+H + ), found: 356.1430.

[0044] Example 3 Synthesis of Compound 3

[0045]

[0046] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N- Isopropylpiperazine (0.5 mmol, 64.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0047] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 3) with a separation yield of 72%.

[0048] 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 8.0 Hz, 1H), 7.68-7.60 (m, 4H),7.55-7.47 (m, 3H), 4.03-3.98 (m, 1H), 3.88-3.83 (m, 1H), 3.60-3.55 (m, 1H),3.29-3.25 (m, 1H), 2.80-2.75 (m, 1H), 2.63 (s, 3H), 2.46-2.40 (m, 1H),1.02(d, J = 4.0 Hz, 6H).

[0049] 13 C NMR (101 MHz, CDCl3) δ 165.07, 143.95, 139.43, 135.46, 132.18,131.59, 131.03, 129.87, 129.82, 129.21, 128.52, 127.94, 125.81, 54.87, 49.61,48.90, 47.84, 45.45, 18.20, 18.18.

[0050] HRMS (ESI) calcd for C 20 H 23 N3O2S: 370.1584 (M+H + ), found: 370.1577.

[0051] Example 4 Synthesis of compound 4

[0052]

[0053] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially.N - Cyclopropylpiperazine (0.5 mmol, 63.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0054] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 4) with a separation yield of 55%.

[0055] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.68-7.62 (m, 4H), 7.55-7.46 (m, 3H), 3.97-3.79 (m, 2H), 3.52-3.47 (m, 1H), 3.21-3.17 (m, 1H), 2.68-2.61 (m, 3H), 2.49-2.43 (m, 1H), 1.63 (s, 1H), 0.46-0.40 (m, 4H).

[0056] 13 C NMR (101 MHz, CDCl3) δ 165.13, 144.11, 139.52, 135.50, 132.05,131.53, 131.07, 130.03, 129.70, 129.13, 128.50, 127.85, 125.95, 53.51, 52.46,49.75, 45.66, 38.00, 5.94, 5.91.

[0057] HRMS (ESI) calcd for C 20 H 21 N3O2S: 368.1427 (M+H) + ), found: 368.1430.

[0058] Example 5: Synthesis of Compound 5

[0059]

[0060] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. NCyclohexylpiperazine (0.5 mmol, 84.1 mg) and potassium iodide electrolyte (0.5 mmol, 83 mg) were purged with argon three times, then acetonitrile was added, and the reaction was carried out under a constant current of 3 mA for 20 h.

[0061] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 5) with a separation yield of 73%.

[0062] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.67-7.61 (m, 4H), 7.55-7.44 (m, 3H), 4.04-3.82 (m, 2H), 3.57-3.52 (m, 1H), 3.22-3.19 (m, 1H), 2.62-2.57 (m, 3H), 2.44-2.39 (m, 1H), 2.29-2.24 (m, 1H), 1.79-1.76 (m, 4H), 1.32-1.06 (m, 5H), 0.94-0.86 (m, 1H).

[0063] 13 C NMR (101 MHz, CDCl3)δ 164.90, 144.15, 139.55, 135.50, 131.97,131.46, 131.05, 130.03, 129.66, 129.17, 128.48, 127.78, 125.97, 63.36, 50.21,49.47, 48.37, 46.09, 28.84 (d, J = 3.0 Hz), 26.12, 25.67.

[0064] HRMS (ESI) calcd for C 23 H 27 N3O2S: 410.1897 (M+H + ), found: 410.1891.

[0065] Example 6 Synthesis of Compound 6

[0066]

[0067] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 1-(cyclopropylmethyl)piperazine (0.5 mmol, 70.1 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0068] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 6) with a separation yield of 46%.

[0069] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.67-7.62 (m, 4H),7.55-7.45 (m, 3H), 4.02-3.86 (m, 2H), 3.61-3.55 (m, 1H), 3.29-3.25 (m, 1H),2.64-2.53 (m, 3H), 2.43-2.38 (m, 1H), 2.26 (d, J = 8.0 Hz, 2H), 0.88-0.79 (m,1H), 0. 51(d, J = 8.0 Hz, 2H), 0.08 (d, J = 8.0 Hz, 2H).

[0070] 13 C NMR (101 MHz, CDCl3) δ 165.09, 144.10, 139.54, 135.48, 132.04,131.53, 131.08, 129.98, 129.70, 129.14, 128.51, 127.87, 125.97, 63.13, 53.38,52.38, 49.69, 45.57, 8.10, 3.94, 3.88.

[0071] HRMS (ESI) calcd for C 21 H 23 N3O2S: 382.1584 (M+H + ), found: 382.1581.

[0072] Example 7 Synthesis of Compound 7

[0073]

[0074] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), benzyl-1-piperazine carbonate (0.5 mmol, 110.1 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0075] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 7) with a separation yield of 91%.

[0076] 1 H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 7.66-7.62 (m, 4H), 7.56-7.44 (m, 3H), 7.32 (s, 5H), 5.11 (s, 2H), 3.88-3.84 (m, 2H), 3.59-3.48(m, 4H), 3.33-3.22 (m, 2H).

[0077] 13 C NMR (101 MHz, CDCl3) δ 165.77, 154.99, 143.90, 139.62, 136.15,135.33, 132.26, 131.83, 131.20, 129.80, 129.72, 129.02, 128.66, 128.60,128.30, 128.06, 126.08, 67.63, 49.47, 45.54, 44.09, 42.96.

[0078] HRMS (ESI) calcd for C 25 H 23 N3O4S: 462.1482 (M+H + ), found: 462.1489.

[0079] Example 8 Synthesis of Compound 8

[0080]

[0081] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N - Ethyl piperazine carboxylate (0.5 mmol, 79.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under a constant current of 3 mA for 20 h;

[0082] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 8) with a separation yield of 89%.

[0083] 1 H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.0 Hz, 1H), 768-7.64 (m, 4H), 7.53-7.50 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 4.16-4.11 (m, 2H), 3.90-3.87 (m,2H), 3.56-3.49 (m, 4H), 3.29-3.22 (m, 2H), 1.26-1.18 (m, 3H).

[0084] 13 C NMR (101 MHz, CDCl3) δ 166.21, 155.21, 143.94, 139.65, 135.34,132.21, 131.80, 131.20, 129.76, 128.99, 128.64, 128.03, 126.11, 61.92, 49.52,45.56, 43.95, 42.87, 14.59.

[0085] HRMS (ESI) calcd for C 20 H 21 N3O4S: 400.1326 (M+H + ), found: 400.1320.

[0086] Example 9 Synthesis of Compound 9

[0087]

[0088] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N Acetylpiperazine (0.5 mmol, 64.1 mg) and potassium iodide electrolyte (0.5 mmol, 83 mg) were purged with argon three times, then acetonitrile was added, and the reaction was carried out under a constant current of 3 mA for 20 h.

[0089] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 9) with a separation yield of 72%.

[0090] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.68-7.64 (m, 4H),7.58-7.47 (m, 3H), 3.98-3.87 (m, 2H), 3.70-3.51 (m, 4H), 3.35-3.24 (m, 2H),2.10-2.04 (m, 3H).

[0091] 13 C NMR (101 MHz, CDCl3) δ 171.02, 166.77, 145.71, 139.65, 135.33,133.18, 131.94, 131.25, 129.89, 139.75, 129.04, 128.67, 128.14, 126.16,49.49, 45.69, 45.13, 41.63, 21.34.

[0092] HRMS (ESI) calcd for C 19 H 20 N3O3S: 370.1220 (M+H + ), found: 370.1214.

[0093] Example 10 Synthesis of Compound 10

[0094]

[0095] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 2-(piperazin-1-yl)pyrimidine (0.5 mmol, 82.1 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0096] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 10) with a separation yield of 93%.

[0097] 1 H NMR (400 MHz, CDCl3) d 8.29 (d, J = 4.0 Hz, 2H), 8.13 (d, J = 8.0 Hz,1H), 7.69-7.62 (m, 4H), 7.52 (t, J = 8.0 Hz, 3H), 6.54 (t, J = 4.0 Hz, 1H), 4.01-3.85 (m, 5H), 3.65-3.58 (m, 2H), 3.36-3.27 (m, 1H).

[0098] 13 C NMR (101 MHz, CDCl3) δ 165.60, 161.29, 157.80, 144.00, 139.56,135.45, 132.19, 131.74, 131.15, 129.93, 129.83, 129.13, 128.57, 128.03,125.95, 110.89, 49.52, 45.67, 44.09, 42.90.

[0099] HRMS (ESI) calcd for C 21 H 19 N5O2S: 406.1332 (M+H + ), found: 406.1336.

[0100] Example 11 Synthesis of Compound 11

[0101]

[0102] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N -Phenylacetazine (0.5 mmol, 81.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0103] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 11) with a separation yield of 95%.

[0104] 1 H NMR (400 MHz, CDCl3) d 7.93 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz,1H), 7.77-7.71 (m, 4H),7.62 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 2H), 6.95-6.88 (m, 2H), 6.79 (t, J = 8.0 Hz, 1H), 4.04-3.97 (m, 1H), 3.86-3.80 (m, 1H), 3.66-3.61 (m, 1H), 3.32-3.23 (m, 4H), 2.99-2.95 (m, 1H).

[0105] 13 C NMR (101 MHz, CDCl3)δ164.92, 150.62, 144.14, 139.13, 135.63,132.98, 132.07, 131.21, 130.82, 130.11, 129.94, 129.48, 129.15, 128.49,125.16, 119.88, 116.12, 49.43, 48.78, 47.95. 45.09.

[0106] HRMS (ESI) calcd for C 23 H 21 N3O2S: 404.1427 (M+H + ), found: 404.1419.

[0107] Example 12 Synthesis of compound 12

[0108]

[0109] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 1-(4-bromophenyl)piperazine (0.5 mmol, 120.1 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0110] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 12) with a separation yield of 92%.

[0111] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.66-7.62 (m, 4H), 7.56-7.50 (m, 3H), 7.39-7.26 (m, 2H), 6.73 (d, J = 8.0 Hz, 2H), 4.11-3.99 (m,2H), 3.71-3.67 (m, 1H), 3.43-3.37 (m, 1H), 3.21-3.14 (m, 3H), 2.99-293 (m,1H).

[0112] 13 C NMR (101 MHz, CDCl3)δ 165.45, 149.33, 143.95, 139.63, 135.39,132.23, 132.08, 131.77, 131.18, 129.80, 129.77, 129.15, 128.64, 128.02,126.03, 118.13, 113.03, 49.72, 49.46, 48.61, 45.44.

[0113] HRMS (ESI) calcd for C 23 H 20 BrN3O2S: 482.0532 (M+H +), found: 482.0537.

[0114] Example 13 Synthesis of Compound 13

[0115]

[0116] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 1-(4-fluorophenyl)piperazine (0.5 mmol, 210.6 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0117] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 13) with a separation yield of 95%.

[0118] 1 H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 7.67-7.63 (m, 4H), 7.55-7.51 (m, 3H), 6.96-6.92 (m, 2H), 6.84-6.82 (m, 2H), 4.08-4.00 (m, 2H), 3.76-3.66 (m, 1H), 3.46-3.38 (m, 1H), 3.15-3.06 (m, 3H), 2.92-2.85 (m, 1H).

[0119] 13 C NMR (101 MHz, CDCl3) δ 165.41, 157.13 (d, J = 8.0 Hz), 146.94,143.96, 140.19, 135.86, 132.25, 131.75, 131.15, 129.85, 129.81, 129.20,128.60, 128.04, 126.38, 118.57 (d, J = 8.1Hz), 115.76 (d, J = 22.2 Hz), 50.92, 49.86, 49.70, 45.60.

[0120] HRMS (ESI) calcd for C 23 H 20 FN3O2S: 422.1333 (M+H + ), found: 422.1337.

[0121] Example 14 Synthesis of compound 14

[0122]

[0123] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 3-(piperazin-1-yl)benzo[d]isothiazol (0.5 mmol, 109.6 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0124] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 14) with a separation yield of 78%.

[0125] 1 H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.0 Hz, 2H),

[0126] 7.69-7.63 (m, 4H), 7.56-7.46 (m, 4H), 7.36 (t, J = 8.0 Hz, 1H), 4.12(d, J = 8.0 Hz, 2H), 3.81-3.76 (m, 1H), 3.60-3.55 (m, 3H), 3.50-3.45 (m, 1H), 3.36-3.32 (m, 1H).

[0127] 13C NMR (101 MHz, CDCl3) δ 165.61, 162.89, 152.86, 143.98, 139.63,135.43, 132.25, 131.76, 131.15, 129.85, 129.83, 129.18, 128.62, 128.05,127.92, 127.61, 126.00, 124.37, 123.51, 120.71, 50.05, 49.79, 49.52, 45.44.

[0128] HRMS (ESI) calcd for C 24 H 20 N4O2S2: 461.1100 (M+H + ), found: 461.1102.

[0129] Example 15 Synthesis of Compound 15

[0130]

[0131] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N - Piperazine (0.5 mmol, 230.1 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0132] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 15) with a separation yield of 72%.

[0133] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J= 8.0 Hz, 1H), 7.69-7.60 (m, 4H), 7.56-7.44 (m, 3H), 6.80 (s, 1H), 6.73-6.67 (m, 2H), 5.93 (s, 2H), 4.00-3.84(m, 2H), 3.55-3.50 (m, 1H), 3.41 (s, 2H), 3.26-3.21 (m, 1H), 2.53-2.42 (m, 3H), 2.29-2.26 (m, 1H).

[0134] 13 C NMR (101 MHz, CDCl3) δ 165.16, 147.81, 147.02, 144.05, 139.51,135.46, 132.09, 131.55, 131.07, 129.94, 129.72, 129.12, 128.54, 127.86,125.97, 122.43, 109.42, 108.01, 101.02, 62.11, 52.92, 52.06, 49.59, 45.49,30.44.

[0135] HRMS (ESI) calcd for C 25 H 23 N3O4S: 462.1482 (M+H + ), found: 462.1472.

[0136] Example 16 Synthesis of Compound 16

[0137]

[0138] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 1-(oxetane-3-yl)piperazine (0.5 mmol, 71.1 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0139] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 16) with a separation yield of 93%.

[0140] 1H NMR (400 MHz, CDCl3) d 8.10 (d, J = 8.0 Hz, 1H), 7.68-7.60 (m, 4H),7.53 (t, J = 8.0 Hz, 1H), 7.49-7.43 (m, 2H), 4.63-4.51 (m, 4H), 3.99-3.84 (m,2H), 3.59-3.53 (m, 1H), 3.49-3.44 (m, 1H), 3.28-3.22 (m, 1H), 2.37-2.32 (m,3H),2.16 (t, J = 8.0 Hz, 1H).

[0141] 13 C NMR (101 MHz, CDCl3) δ 165.28, 143.93, 139.44, 135.43, 132.22,131.65, 131.06, 129.85, 129.78, 129.13, 128.55, 127.96, 125.83, 75.13, 75.11,58.64, 49.82, 49.47, 48.86, 45.29.

[0142] HRMS (ESI) calcd for C 20 H 21 N3O3S: 384.1376 (M+H + ), found: 384.1377.

[0143] Example 17 Synthesis of Compound 17

[0144]

[0145] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 4-methanesulfonylpiperazine (0.5 mmol, 202.1 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0146] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 17) with a separation yield of 33%.

[0147] 1 H NMR (400 MHz, CDCl3) d 7.91 (d, J = 4.0 Hz, 1H), 7.85 (d, J = 8.0 Hz,1H), 7.78-7.71 (m, 4H), 7.64-7.58 (m, 2H), 4.07-4.02 (m, 1H), 3.75-3.70 (m,1H), 3.62-3.56 (m, 1H), 3.30-3.26 (m, 4H), 3.11-3.05 (m, 1H), 2.89 (s, 3H).

[0148] 13 C NMR (101 MHz, CDCl3) δ 165.20, 144.01, 139.23, 135.61, 133.07,132.20, 131.32, 130.88, 129.96, 129.86, 129.20, 128.50, 125.23, 49.12, 45.66, 45.06, 44.99, 34.83.

[0149] HRMS (ESI) calcd for C 18 H 19 N3O4S2: 406.0890 (M+H + ), found: 406.0891.

[0150] Example 18 Synthesis of Compound 18

[0151]

[0152] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 4-methanesulfonylphenylpiperazine (0.5 mmol, 240.5 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0153] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 18) with a separation yield of 25%.

[0154] 1H NMR (400 MHz, CDCl3) d 7.91 (d, J = 4.0 Hz, 1H), 7.85 (d, J = 8.0 Hz,1H), 7.76-7.74 (m, 4H), 7.69 (d, J = 12.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 2H), 7.00(d, J = 8.0 Hz, 2H), 4.05-3.99 (m, 1H), 3.81-3.70 (m, 2H), 3.57-3.47 (m, 3H), 3.32-3.26 (m, 2H), 3.03 (s, 3H).

[0155] 13 C NMR (101 MHz, DMSO) δ 164.99, 153.39, 144.11, 139.16, 135.66,132.97, 132.11, 131.25, 130.89, 130.08, 129.98, 129.16, 129.05, 128.43,125.18, 113.81, 48.81, 46.77, 45.63, 45.31, 44.68.

[0156] HRMS (ESI) calcd for C 24 H 23 N3O4S2: 482.12O3 (M+H) + ), found: 481.1211.

[0157] Example 19 Synthesis of Compound 19

[0158]

[0159] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. A seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg) was added sequentially. N - Ethyl piperazine (0.5 mmol, 206.5 mg), potassium iodide electrolyte (0.5 mmol, 83 mg), after argon purging 3 times, acetonitrile was added, and the reaction was carried out under constant current of 3 mA for 20 h;

[0160] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 19) with a separation yield of 84%.

[0161] 1 H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 7.68-7.61 (m, 4H), 7.56-7.45 (m, 3H), 4.15 (q, J = 8.0 Hz, 2H), 4.05-3.99 (m, 1H), 3.92-3.86 (m,1H), 3.61-3.55 (m, 1H), 3.31-3.25 (m, 1H), 3.23 (s, 2H), 2.69-2.64 (m, 3H),2.49-2.44 (m, 1H), 1.24 (t, J = 8.0 Hz, 3H).

[0162] 13 C NMR (101 MHz, CDCl3) δ 169.80, 165.20, 143.94, 139.47, 135.40,132.12, 131.59, 131.06, 129.78, 129.76, 129.09, 128.50, 127.89, 125.88,60.81, 58.55, 52.83, 51.88, 49.60, 45.47, 14.17.

[0163] HRMS (ESI) calcd for C 21 H 23 N3O4S: 414.1482 (M+H + ), found: 414.1495.

[0164] Example 20 Synthesis of Compound 20

[0165]

[0166] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 7-chloro-4-(-1-piperazinyl)quinoline (0.5 mmol, 244 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After purging with argon gas three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0167] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 20) with a separation yield of 43%.

[0168] 1 H NMR (400 MHz, CDCl3) d 8.72 (d, J = 4.0 Hz, 1H), 8.16 (d, J = 8.0 Hz,1H), 8.04 (s, 1H), 7.87 (d, J = 12.0 Hz, 1H), 7.69-7.65 (m, 4H), 7.58-7.54 (m,3H), 7.43 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 4.0 Hz, 1H), 4.26-4.23 (m, 2H), 3.86-3.81 (m, 1H), 3.57-3.50 (m, 1H), 3.28-3.21 (m, 3H), 3.04-2.97 (m, 1H).

[0169] 13 C NMR (101 MHz, CDCl3) δ 165.76, 155.75, 151.89, 150.11, 143.95,139.76, 135.38, 135.31, 132.28, 131.86, 131.26, 129.79, 129.72, 129.15,129.13, 128.71, 128.07, 126.81, 126.17, 124.51, 121.64, 109.44, 52.56, 51.34,49.83, 45.57.

[0170] HRMS (ESI) calcd for C 26 H 21ClN4O2S: 489.1147 (M+H + ), found: 489.1157.

[0171] Example 21 Synthesis of compound 21

[0172]

[0173] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 1-methyl-2-piperazinone (0.5 mmol, 177.5 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0174] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 21) with a separation yield of 74%.

[0175] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.71-7.66 (m, 4H), 7.58-7.49 (m, 3H), 4.68-4.62 (m, 1H), 4.20-1.15 (m, 1H), 3.90-3.86 (m, 1H), 3.70-3.63 (m, 1H), 3.51-3.43 (m, 1H), 3.32-3.27 (m, 1H), 2.91 (s, 3H).

[0176] 13 C NMR (101 MHz, CDCl3) δ 165.00, 163.79, 143.48, 138.76, 135.39,132.37, 132.26, 131.29, 130.31, 129.34, 129.03, 128.70, 128.27, 125.46,55.38, 46.60, 42.85, 35.28.

[0177] HRMS (ESI) calcd for C 18 H 17 N3O3S: 356.1063 (M+H) +), found: 356.1059.

[0178] Example 22 Synthesis of compound 22

[0179]

[0180] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 1-(2-tetrahydrofuranoyl)piperazine (0.5 mmol, 212.5 mg), and electrolyte potassium iodide (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0181] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 22) with a separation yield of 46%.

[0182] 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.68-7.64 (m, 4H), 7.58-7.46 (m, 3H), 4.60-4.44 (m, 1H), 4.12 (q, J = 8.0 Hz, 1H), 3.92-.379 (m,4H), 3.63-3.45 (m, 3H), 3.26-3.14 (m, 2H), 2.35-2.21 (m, 1H), 2.12-1.83 (m,3H).

[0183] 13 C NMR (101 MHz, CDCl3) δ 171.06, 165.78, 145.64, 140.24, 136.50,132.29, 131.87, 131.23, 130.30, 129.60, 129.04, 128.67, 128.09, 126.06,74.45, 69.20, 49.59, 45.73, 44.45, 42.39, 29.70, 25.75.

[0184] HRMS (ESI) calcd for C 22 H 23 N3O4S: 426.1482 (M+H)+ ), found: 426.1481.

[0185] Example 23 Synthesis of compound 23

[0186]

[0187] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazine-1-(2H)-one (0.5 mmol, 303.6 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After purging with argon gas three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0188] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 23) with a separation yield of 56%.

[0189] 1 H NMR (400 MHz, CDCl3) d 11.5 (s, 1H), 8.44 (t, J = 8.0 Hz, 1H), 8.12 (t, J = 8.0 Hz, 1H),7.76-7.61 (m, 7H),7.55-7.43 (m, 3H),7.35-7.27 (m, 2H),7.06-6.92 (m, 1H),4.28-4.23 (m, 2H),3.89-3.58 (m, 4H),3.51-3.22 (m, 4H).

[0190] 13 C NMR (101 MHz, CDCl3) δ 165.88, 165.72, 165.31, 165.01, 160.95,157.21 (d, J = 289.9 Hz), 145.6, 143.75 (d, J = 3.0 Hz), 139.56(d, J = 9.1Hz), 135.28 (d, J = 7.1 Hz), 134.52 (d, J= 4.0 Hz), 133.75, 132.41, 131.97, 131.69,131.22, 129.98, 129.51, 129.12, 128.69, 128.20, 127.08, 126.01, 125.04,123.20, 123.17 (d, J = 30.3 Hz), 116.14, 116.03 (d, J = 44.4 Hz), 48.68, 47.17, 45.86, 42.32, 38.18.

[0191] HRMS (ESI) calcd for C 33 H 26 FN5O4S: 608.1762 (M+H + ), found: 608.1769.

[0192] Example 24 Synthesis of compound 24

[0193]

[0194] (1) In a 25 mL three-necked reaction tube equipped with a stir bar and dried, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Seven-membered cyclic sulfonamide (0.75 mmol, 182.2 mg), ciprofloxacin (0.5 mmol, 155.6 mg), and potassium iodide electrolyte (0.5 mmol, 83 mg) were added in sequence. After argon gas was purged three times, acetonitrile was added and the reaction was carried out under a constant current of 3 mA for 20 h.

[0195] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the pure piperazine-containing seven-membered cyclic sulfonamide derivative (compound 25) with a separation yield of 50%.

[0196] 1 H NMR (400 MHz, CDCl3) δ15.12 (s, 1H), 8.64-8.61 (m, 1H), 7.92 (d, J =8.0 Hz, 1H), 7.89-7.82 (m, 2H), 7.79-7.75 (m, 4H), 7.65-7.58 (m, 2H), 7.49 (d, J= 8.0 Hz, 1H),4.07-3.98 (m, 2H), 3.82-3.71 (m, 2H), 3.62-3.40 (m,4H), 3.23-3.18(m, 1H), 1.35-1.30 (m, 2H), 1.25-1.14 (m, 2H).

[0197] 13 C NMR (101 MHz, CDCl3) δ 176.75, 166.32, 164.99, 153.59 (d, J = 263.6Hz), 148.43, 144.76 (d, J = 10.1 Hz), 144.09, 139.51, 139.24, 135.65, 132.99,132.12, 131.28, 130.85, 129.99, 129.16, 128.47, 125.20, 119.17 (d, J = 8.1 Hz), 111.44 (d, J = 23.2 Hz), 107.57, 107.19, 106.84, 49.61, 49.18, 48.97, 48.64,45.24, 36.82, 8.07.

[0198] HRMS (ESI) calcd for C 30 H 25 FN4O5S: 573.16O2 (M+H + ), found: 573.1614.

[0199] II. Anti-inflammatory activity experiments of the compounds

[0200] (I) Experimental Methods

[0201] 1. Cell Culture and Passaging

[0202] RAW264.7 mouse macrophage cell line was cultured in DMEM high-glucose medium containing 10% fetal bovine serum and 1% penicillin-streptomycin, and incubated at 37°C, 5% CO2, and saturated humidity. Cells were passaged every 2-3 days at a passage ratio of 1:3.

[0203] 2. Effect of the compound on RAW264.7 cell viability determined by CCK-8 assay

[0204] The effect of piperazine-containing seven-membered cyclic sulfonamide derivatives on the viability of RAW264.7 cells was evaluated using the CCK-8 assay. A blank control group and one treatment group with a concentration gradient (40 μmol / L) were set up in 96-well plates, with four replicates for each group. RAW264.7 cells in logarithmic growth phase were inoculated at 5 × 10⁻⁶ cells / well. 5 Cells were seeded at a density of 100 μL / well and cultured for 24 h until adherence. The culture medium was then discarded. The drug-treated group was treated with a medium containing 40 μmol / L of a piperazine-containing seven-membered cyclic sulfonamide derivative, while the blank control group was treated with a medium (100 μL / well for both groups). After 36 h of culture at 37℃ and 5% CO2, a 10% CCK-8 solution was prepared, the supernatant was discarded, and 100 μL of CCK-8 solution was added to each well for further incubation for 40 min. OD values ​​were measured at 450 nm using a microplate reader, and cell viability was calculated using the formula: Cell viability (%) = (OD of drug-treated group / OD of blank control group) × 100%.

[0205] The experimental results are shown in Table 1. Most of the piperazine-containing seven-membered cyclic sulfonamide derivatives of this invention did not show cytotoxicity under the condition of 40 μmol / L. Among them, compounds 10, 19, and 23 showed a certain degree of damage to cells and can be used as drugs by reducing the dosage.

[0206] Table 1. CCK-8 assay for the viability of derivatives in 40 μmol / L RAW264.7 cells.

[0207]

[0208] 3. NO reagent kit was used to detect the inhibitory effect of compounds on the inflammatory factor NO in LPS-stimulated RAW264.7 cells.

[0209] An LPS-induced inflammation model was used in RAW264.7 cells, with dexamethasone (40 μmol / L) as a positive control, to evaluate the inhibitory effect of a piperazine-containing seven-membered cyclic sulfonamide derivative (40 μmol / L) on NO production. Logarithmic growth phase cells were cultured at 3 × 10⁻⁶ cells per cell line. 6 Inoculated at a density of [number] cells / mL in 24-well plates, and after 24 h of culture, the plates adhered to the plates. A blank control group, a model control group, a positive control group (dexamethasone), and a drug-treated group (each with 3 replicates) were set up. Pretreatment with the corresponding drug or culture medium was performed for 2 h. Except for the blank control group, all other groups were added with LPS solution at a final concentration of 100 ng / mL, and cultured for another 36 h. The supernatant was collected, and the NO concentration was determined according to the NO kit instructions. The NO formation rate was calculated using the formula: NO formation rate (%) = (NO concentration in the drug-treated group or the positive control group or the blank control group / NO concentration in the model control group) × 100%.

[0210] The experimental results are shown in Table 2. The piperazine-containing seven-membered cyclic sulfonamide derivatives exhibited different NO inhibition effects under the condition of 40 μmol / L. Among them, compounds 7, 12, 13, 14, 15, 20, and 23 had NO generation rates below 65%, and showed better NO inhibition effects compared to the glucocorticoid drug dexamethasone.

[0211] Table 2. Inhibition effect of derivatives on NO at 40 μmol / L

[0212]

[0213] 4. RT-qPCR was used to determine the levels of the compound on the inflammatory cytokines TNF-α (tumor necrosis factor), IL-1β (interleukin-1β), and IL-6 (interleukin-6) in LPS-stimulated RAW264.7 cells.

[0214] Using an LPS-induced RAW264.7 cell inflammation model, the effects of compounds 7, 12, 13, 14, 15, 20, and 23 at a concentration of 40 μmol / L on the expression of inflammatory cytokine mRNA were investigated. Logarithmically growing cells were cultured at a concentration of 3 × 10⁻⁶ cells / year. 6 Cells were seeded at a density of 0.5 mL / well in 24-well plates. After 24 h of culture and adherence, blank control, model control, and drug-treated groups were set up. Each group was pretreated with 0.5 mL of the corresponding drug or culture medium for 2 h. Except for the blank control group, all other groups were added with LPS solution at a final concentration of 100 ng / mL and cultured for another 36 h. Cells were collected, and total RNA was extracted using the SteadyPure kit. After purity was tested using NanoDrop 2000 (A260 / A280 = 1.8-2.0), cDNA was obtained by reverse transcription using the 5X Evo M-MLV kit (stored at -20 ℃). qPCR was performed using SYBR Green Pro taq HS premixed reagent: the reaction system contained 10 μL of 2×Premix, 0.4 μL each of forward and reverse primers (10 μM), 2 μL of cDNA, and ddH2O to a final volume of 20 μL; the reaction program was 95 ℃ for 30 s (pre-denaturation), followed by 40 cycles of 95 ℃ for 5 s and 60 ℃ for 30 s, and the melting curve was analyzed.

[0215] The relative expression levels of the target genes were calculated using the 2^(-ΔΔCt) method, with β-actin as an internal reference. The experimental results are shown in Tables 3 and 4. For the inflammatory factor IL-6, compounds 12, 13, 14, and 15 significantly downregulated its level compared to the model control group, exhibiting significant inhibitory effects. For the inflammatory factor IL-1β, compounds 7, 12, 13, 14, 15, and 20 significantly downregulated its level compared to the model control group, exhibiting significant inhibitory effects. For the inflammatory factor TNF-α, compounds 12, 14, and 15 significantly downregulated its level compared to the model control group, exhibiting significant inhibitory effects.

[0216] Table 3. Effects of compounds 7, 13, 14, 15, 20, and 23 at a concentration of 40 μmol / L on LPS-induced IL-6, IL-1β, and TNF-α levels in RAW 264.7 cells (X±s, n=3).

[0217]

[0218] Table 4. Effects of compound 12 at a concentration of 40 μmol / L on LPS-induced IL-6, IL-1β, and TNF-α levels in RAW 264.7 cells (X±s, n=3)

[0219]

[0220] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of a piperazine-containing seven-membered cyclic sulfonamide derivative for the preparation of an anti-inflammatory medicament, characterized in that: The piperazine-containing seven-membered cyclic sulfonamide derivative is selected from the following structural formula: 。 2. Use according to claim 1, characterized in that: The electrochemical synthesis method of the piperazine-containing seven-membered cyclic sulfonamide derivative comprises the following steps: in an electrolytic cell, an anode and a cathode are arranged, a seven-membered cyclic sulfonamide, a piperazine compound, an electrolyte and a solvent are sequentially added, and a reaction is carried out under a constant current condition; and after the reaction is completed, a reaction solution is collected to obtain the piperazine-containing seven-membered cyclic sulfonamide derivative. The structural formula of the seven-membered cyclic sulfamide is: ; The electrolyte is potassium iodide, and the solvent is acetonitrile. The molar ratio of the seven-membered cyclic sulfonamide, the piperazine compound and the electrolyte is 3:2:

2.

3. Use according to claim 2, characterized in that: The anode is a carbon rod, the cathode is a platinum sheet, the constant current is 2-4 mA, and the reaction time is 15-30 h.

4. Use according to claim 2, characterized in that: The electrochemical synthesis method further comprises: the reaction solution is concentrated and purified by column chromatography to obtain the piperazine-containing seven-membered cyclic sulfonamide derivative, and the column chromatography condition is that the volume ratio of petroleum ether to ethyl acetate is 1 / 2.

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