A selenium-containing sulindac derivative and an electrochemical synthesis method thereof

Abstract

The application discloses a selenium-containing sulindac acid derivative and an electrochemical synthesis method thereof. The method adopts an electrochemical oxidation technology, uses clean and massless electrons as an oxidant, starts a reaction through a carboxylic acid with a low oxidation potential of sulindac acid as a free radical source, realizes the dual functional group activation of sulindac acid, a traditional non-steroidal anti-inflammatory drug (NSAIDs), and a diselenide compound, and constructs a selenium-containing sulindac acid derivative with anti-inflammatory activity and multi-functional groups in one step. The synthesis method has the characteristics of green chemistry, avoids the use of expensive transition metal catalysts, excessive oxidants and strong alkalis, solves the problems of pre-functionalization of a substrate and multi-step reactions in traditional synthesis, and provides a synthesis path with mild conditions and controllable reaction process. The compound has good anti-inflammatory activity, and the anti-inflammatory activity of the original drug is greatly improved after modification.

Description

Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, and particularly relates to a selenium-containing sulinic acid derivative and its electrochemical synthesis method. Background Technology

[0002] Sulindac, a classic nonsteroidal anti-inflammatory drug (NSAID), exerts its anti-inflammatory effects primarily by inhibiting cyclooxygenase (COX) activity and blocking prostaglandin synthesis. Unlike traditional NSAIDs, this drug has attracted considerable attention due to its unique multi-target activity. Current research is exploring its potential value in cancer prevention, metabolic regulation, and neuroprotection. Sulindac is a prodrug that is reductively metabolized in vivo to a highly reactive sulfide, and can also be oxidized to a sulfone with increased hydrophilicity but significantly reduced activity. While its chiral sulfoxide group can reduce the lipophilicity of the parent nucleus and improve solubility, commercially available formulations are racemic. The reversible cycle between methyl sulfide and methyl sulfoxide leads to instability of the chiral center, making it difficult to accurately study the chiral effect at this site in vivo. Notably, the oxidation to sulfone is irreversible, and the inhibitory activity of this hydrophilic product on COX is significantly weakened. Therefore, the synthesis and modification of sulindac's structure to enhance its activity has long been a focus of medicinal chemists.

[0003] Currently, significant progress has been made in structural modification of sulindac at different reaction sites, resulting in the synthesis of a series of sulindac derivatives exhibiting excellent biological activity. The research primarily focuses on two strategies. The first involves the dehydration condensation reaction of the carboxyl group of sulindac with amines and alcohols using condensing reagents to construct amides and esters. The second involves the reconstruction of sulindac derivatives using aldehydes with different substitutions and the indanate skeleton. However, these activation processes often require the participation of metal reagents, equivalent oxidants, and bases, and their limited substrate scope, stringent reaction conditions, and numerous byproducts remain challenges. Particularly noteworthy is the presence of multiple olefinic structural units within the sulindac molecule, making it a highly attractive candidate substrate for derivatization research. However, direct derivatization of the olefinic skeleton of sulindac to construct sulindac derivatives is currently lacking, hindering the further clinical application of sulindac compounds.

[0004] Organic electrochemical synthesis utilizes inexpensive, readily available, and intrinsically safe electrons as redox reagents. It achieves efficient conversion by generating active intermediates through reactions of compounds on electrode surfaces, overcoming the limitations of traditional synthesis reactions that require expensive transition metal catalysts and equivalent amounts of redox reagents. Furthermore, electrochemistry offers a wide-range tunable redox potential, allowing for excellent control over reaction selectivity. Currently, our understanding of the electrochemical modification of sulindac to construct derivatives is relatively limited and requires further investigation. Summary of the Invention

[0005] The purpose of this invention is to provide a selenium-containing sulindac derivative and its electrochemical synthesis method, which exhibits anti-inflammatory effects. This invention also provides a green, mild, and efficient modular electrochemical oxidation method that can efficiently and selectively construct bifunctionalized sulindac derivatives in one step, solving the problems of multiple synthesis steps and harsh reaction conditions associated with sulindac derivative synthesis. This provides a conceptual and methodological reference for the research and development of green and inexpensive synthesis of sulindac derivatives.

[0006] This invention proposes a method for the bifunctionalization of sulindac's five-membered ring skeleton into olefins for the electrochemical synthesis of selenium-containing sulindac derivatives. This process is not only highly efficient but also highly selective. The reaction exhibits several significant advantages: (a) it can be carried out without the use of metal catalysts or bases; (b) electrons act as the sole oxidant, thus avoiding the need for stoichiometric oxidants; (c) the reaction conditions are mild, requiring no high temperatures, and it is compatible with a variety of substrates; (d) it achieves extremely high chemoselectivity in the construction of sulindac derivatives with lactone rings; and (e) the synthesized compounds, at the same dosage, show superior NO inhibition rates and regulatory abilities on inflammatory factors IL-6 and IL-1β compared to the sulindac raw material.

[0007] The technical solution of the present invention is as follows:

[0008] A selenium-containing sulinic acid derivative, with sulinic acid as the parent structure, undergoes esterification and selenization reactions on an olefin with its five-membered ring. The general chemical structural formula of the selenium-containing sulinic acid derivative is as follows:

[0009] ,

[0010] Wherein, R is selected from any one of C1 to C3 alkyl, phenyl, and substituted phenyl, and the substituent in the substituted phenyl is any one of alkyl, halogen, haloalkanes, C1 to C6 alkyl, C1 to C3 alkylthio, and cyano.

[0011] Preferably, R is selected from any one of: phenyl, p-iodophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-tolyl, m-tolyl, ethyl, p-isopropylphenyl, 3,4-dimethylphenyl, o-bromophenyl, m-chlorophenyl, methyl, m-fluorophenyl, p-chlorophenyl, p-ethylphenyl, o-fluorophenyl, 2,4,6-trimethylphenyl, o-tolyl, p-cyanophenyl, o-methylthiophenyl, m-methylthiophenyl, and p-methylthiophenyl.

[0012] Specifically, the selenium-containing sulinic acid derivative is selected from the following structural formulas:

[0014] This invention also provides an electrochemical synthesis method for a selenium-containing sulinic acid derivative. The method uses sulinic acid and diselenoether compounds as starting materials, clean electrons as the oxidant, and tetrabutylammonium tetrafluoroborate as the electrolyte. Under electrochemical conditions, firstly, the diselenoether compound is anolyxolized to generate a radical cation intermediate (A). This intermediate undergoes cleavage to produce a selenium-centered radical (B) and a selenium cation (C). The selenium cation (C) is then reduced at the cathode to regenerate the diselenoether compound for subsequent catalytic cycling. Simultaneously, sulinic acid is oxidized at the anode to form a carbon-centered radical intermediate (D). This intermediate (D) undergoes an intramolecular radical cyclization reaction to generate a carbon radical intermediate (E). Finally, the selenium-centered radical (B) and the carbon radical intermediate (E) undergo a radical-radical cross-coupling reaction to obtain the target product.

[0015] The specific steps of the electrochemical synthesis method are as follows: In an electrolytic cell, the anode and cathode are set up, and sulinic acid, diselenide compounds, electrolyte and solvent are added in sequence. The reaction is carried out under constant current conditions. After the reaction is completed, the reaction solution is collected to obtain a selenium-containing sulinic acid derivative.

[0016] Preferably, the molar ratio of sulindac, diselenyl ether compound, and electrolyte is 1:1:1, the electrolyte is tetrabutylammonium tetrafluoroborate, and the solvent is acetonitrile.

[0017] The structural formula of the sulindac drug is: ;

[0018] The general chemical structural formula of the diselenide compounds is: RSeSeR, where R represents different substituents in the structure of the diselenide compounds and is consistent with the general chemical structural formula of the above-mentioned selenium-containing sulinic acid derivatives. For example, when the diselenide compound is a diphenyl diselenide, R is phenyl.

[0019] Preferably, the diselenide compounds are selected from: diphenyldiselenide, 1,2-di-p-iodophenyldiselenide, 1,2-di-p-bromophenyldiselenide, 1,2-di-p-trifluoromethylphenyldiselenide, 1,2-di-p-tolyldiselenide, 1,2-di-m-tolyldiselenide, diethyldiselenide, 1,2-di-p-isopropylphenyldiselenide, 1,2-bis(3,4-xylyl)diselenide, 1,2-di-o-bromophenyldiselenide, 1,2-di-m-chlorophenyldiselenide, 1,2-dimethyldiselenide, 1,2-di-m-fluorophenyldiselenide, 1,2-di-p-chlorophenyldiselenide, 1,2-di-p-ethylphenyldiselenide, 1,2-di-o-fluorophenyldiselenide, 1,2-di(2,4-dichlorophenyldiselenide) Any one of 4,6-trimethylyl)diselenoether, 1,2-di-o-methylyldiselenoether, 1,2-di-p-cyanophenyldiselenoether, 1,2-di-o-methylthiophenyldiselenoether, 1,2-di-m-methylthiophenyldiselenoether, and 1,2-di-p-methylthiophenyldiselenoether.

[0020] Preferably, the anode is a carbon rod and the cathode is a platinum sheet.

[0021] Preferably, the constant current is 12-15 mA and the reaction time is 6.5-12 h. More preferably, the constant current is 15 mA and the reaction time is 6.5 h.

[0022] 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 selenium-containing sulinic acid derivative. The column chromatography conditions are: petroleum ether / ethyl acetate = 5 / 1, volume ratio.

[0023] The present invention also provides the application of the selenium-containing sulindac derivative in the preparation of anti-inflammatory drugs.

[0024] The present invention also provides a pharmaceutical formulation comprising the said selenium-containing sulindac derivative, and one or more pharmaceutically acceptable carriers or excipients.

[0025] The beneficial effects of this invention are:

[0026] 1. The selenium-containing sulindac derivative obtained in this invention has significant anti-inflammatory effects. Under the same dosage, the NO inhibition rate of the synthesized compound and its ability to regulate inflammatory factors IL-6 and IL-1β are superior to those of sulindac raw material.

[0027] 2. This invention uses electrochemical oxidation, utilizing clean electrons as oxidizing agents, to achieve for the first time the activation of the bifunctional group of the five-membered ring olefin skeleton of sulinic acid in the absence of metals, external oxidants, and equivalent bases, thereby constructing a series of selenized five-membered ring lactone compounds with high selectivity and efficiency.

[0028] 3. This invention solves the problems of traditional synthesis of sulindac active molecules, such as multiple steps, harsh reaction conditions, difficult synthesis 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 control the site selectivity of the reaction under mild conditions, providing ideas and methodological references for the green and inexpensive synthesis of selenium-containing sulindac derivatives.

[0029] 4. The synthesis method of the present invention achieves highly efficient site-selective activation of the sulinic acid olefin skeleton through free radical / free radical cross-coupling, which not only improves the synthesis efficiency, but also significantly enhances the application potential and industrial application value of the method. Attached Figure Description

[0030] Figure 1 The general chemical structural formula of the selenized sulinac derivatives prepared in this invention is shown below.

[0031] Figure 2 The reaction mechanism of the electrochemical synthesis of this invention is described. Detailed Implementation

[0032] 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.

[0033] Unless otherwise specified, all reagents involved in the embodiments of this invention are commercially available products and can be purchased through commercial channels.

[0034] This invention discloses a method for synthesizing a selenium-containing sulindac derivative, the reaction mechanism of which is described below. Figure 2 The general structural formula of the selenium-containing sulindac derivative obtained is shown in [reference needed]. Figure 1 .

[0035] I. Electrochemical Synthesis of Compounds

[0036] Example 1: Synthesis of Compound 1

[0037]

[0038] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), diphenyldiselenoether (0.3 mmol, 93.6 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0039] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 1) with a separation yield of 92%.

[0040] 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 8.4 Hz,1H), 7.40-7.15 (m,5H) 7.10 (d, J = 8.3 Hz, 2H), 6.93 (s, 1H), 6.90-6.73 (m,2H), 3.42 (d, J = 7.8 Hz, 2H), 2.78 (s, 3H), 2.01 (s, 3H).

[0041] 13 C NMR (101 MHz, DMSO- d 6) δ 172.97, 163.11 (d, J = 247.5 Hz), 148.94(d, J = 8.4 Hz), 146.34 (d, J = 2.6 Hz), 139.21 (d, J = 142.9 Hz), 137.54, 133.12(d, J = 2.6 Hz), 131.32, 129.95 (d, J = 5.8 Hz), 129.37, 129.16 (d, J = 2.2 Hz),128.34, 126.72, 125.80, 125.63 (d, J = 9.3 Hz), 124.37 (d, J = 4.4 Hz), 116.39 (d,J = 23.2 Hz), 113.43, 96.89, 58.38 (d, J = 2.2 Hz), 43.51 (d, J = 5.5 Hz), 21.31.

[0042] 19 F NMR (376 MHz, DMSO- d 6) δ -110.04.

[0043] HRMS (ESI) calcd for C 26 H 21 FO3SSe: 513.0433 (M+H + ), found: 513.0430.

[0044] Example 2: Synthesis of Compound 2

[0045]

[0046] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-iodophenyl diselenyl ether (0.3 mmol, 169.2 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0047] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 2) with a separation yield of 69%.

[0048] 1 H NMR (400 MHz, CDCl3) δ7.69-7.49(m,5H),7.06-6.75(m,7H),3.46-3.40(m,2H), 2.79(d, J = 3.9 Hz, 3H), 1.97(s, 3H).

[0049] 13 C NMR (101 MHz, CDCl3) δ 177.59, 167.94 (d, J = 248.0 Hz), 153.57 (d, J = 8.4 Hz), 151.11 (d,J = 4.7 Hz), 144.25, 143.79 (d, J = 110.09 Hz), 143.18 (d, J =8.5 Hz), 142.85, 138.02 (d, J = 20.5 Hz), 133.88 (d, J = 2.9 Hz), 131.44, 130.42 (d, J = 9.3 Hz), 129.93 (d, J = 2.2 Hz), 129.24, 121.38 (d, J = 23.3 Hz), 118.08(d, J = 23.1 Hz), 102.53 (d, J = 3.8 Hz), 101.56, 63.28 (d, J = 2.3 Hz), 48.40 (d, J = 16.1 Hz), 43.72, 25.89.

[0050] 19 F NMR (376 MHz, CDCl3) δ -104.86 (d, J = 7.8 Hz).

[0051] HRMS (ESI) calcd for C 26 H 20 FIO3SSe: 638.9400 (M+H + ), found: 638.9464.

[0052] Example 3: Synthesis of Compound 3

[0053]

[0054] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-bromophenyl diselenyl ether (0.3 mmol, 140.4 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0055] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 3) with a separation yield of 88%.

[0056] 1 H NMR (400 MHz, DMSO- d 6) δ 7.65 (d, J = 8.2 Hz, 2H), 7.58-7.52 (m,1H),7.38 (d, J = 8.6 Hz, 2H), 7.13-6.77(m,7H), 3.43 (d, J = 7.2 Hz, 2H), 2.78 (s, 3H), 1.99 (s, 3H).

[0057] 13 C NMR (101 MHz, DMSO- d 6) δ 172.84, 163.19 (d, J = 247.9 Hz), 148.76(d, J = 8.6 Hz), 146.42 (d, J = 4.0 Hz), 139.67, 139.58, 138.40 (d, J = 4.6 Hz), 133.15 (d, J = 2.5 Hz), 133.11 (d, J = 64.2 Hz), 132.25, 129.09 (d, J = 2.6 Hz), 126.76, 125.68 (d, J = 9.2 Hz), 124.52 (d, J = 48.6 Hz), 124.40 (d, J = 4.5 Hz), 116.65 (d, J = 23.4 Hz), 113.36 (d, J = 23.4 Hz), 96.81, 58.59 (d, J = 2.1 Hz), 43.62 (d, J = 12.2 Hz), 39.01, 21.17.

[0058] 19 F NMR (376 MHz, DMSO- d6) δ -104.83.

[0059] HRMS (ESI) calcd for C 26 H 20 FBrO3SSe: 590.9539 (M+H + ), found: 590.9538.

[0060] Example 4: Synthesis of Compound 4

[0061]

[0062] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-trifluoromethylphenyl diselenyl ether (0.3 mmol, 135.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0063] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 4) with a separation yield of 39%.

[0064] 1 H NMR (400 MHz, DMSO- d 6) δ 7.63-7.39 (m, 7H), 7.08 - 6.77 (m, 5H), 3.56-3.38 (m, 2H), 2.77 (d, J = 3.4 Hz, 3H), 2.02 (s, 3H).

[0065] 13 C NMR (101 MHz, CDCl3) δ 171.61, 163.51 (d, J = 252.3 Hz), 147.74 (dd, J = 8.0, 2.8 Hz), 145.57 (d, J = 5.2 Hz), 139.80 (d, J = 3.3 Hz), 138.59 (d, J =11.5 Hz), 137.56, 132.80 (t, J = 2.6 Hz), 131.60 (dd,J = 32.7, 5.2 Hz), 130.01,128.87 (d, J = 5.6 Hz), 126.21, 126.11, 125.50 (d, J = 3.7 Hz), 124.02 (d, J = 5.2Hz), 116.66 (d, J = 23.0 Hz), 112.26 (d, J = 23.0 Hz), 96.43 (d, J = 1.9 Hz),58.28, 53.48, 43.80 (d, J = 5.9 Hz), 40.01, 21.65.

[0066] 19 F NMR (376 MHz, CDCl3) δ -62.81, -108.43.

[0067] HRMS (ESI) calcd for C 27 H 20 F4O3SSe: 581.0307 (M+H + ), found: 581.0302.

[0068] Example 5: Synthesis of Compound 5

[0069]

[0070] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-tolyl diselenide (0.3 mmol, 98.1 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 12 mA for 12 h.

[0071] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 5) with a separation yield of 81%.

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J= 8.2 Hz, 2H), 7.15-6.94 (m, 7H), 6.86-6.63 (m, 3H), 3.18-3.01 (m, 2H), 2.77 (s, 3H), 2.33 (s, 3H), 1.99 (s, 3H).

[0073] 13 C NMR (101 MHz, CDCl3) δ 172.23, 163.42 (d, J = 251.2 Hz), 148.46 (d, J = 7.8 Hz), 145.27 (d, J = 8.5 Hz), 140.37 (d, J = 4.8 Hz), 139.95, 139.09 (d, J =8.9 Hz), 137.40, 132.66 (d, J = 3.0 Hz), 129.74, 129.18 (d, J = 3.3 Hz), 126.01(d, J = 8.9 Hz), 125.54, 123.86 (d, J = 3.0 Hz), 122.08, 116.16 (d, J = 22.7 Hz), 112.25 (d, J = 23.0 Hz), 96.71 (d, J = 3.0 Hz), 57.42, 43.87 (d, J = 11.5 Hz), 40.40 (d, J = 5.9 Hz), 21.52, 21.27.

[0074] 19 F NMR (376 MHz, CDCl3) δ -109.12.

[0075] HRMS (ESI) calcd for C 27 H 23 FO3SSe: 527.0590 (M+H + ), found: 527.0595.

[0076] Example 6: Synthesis of Compound 6

[0077]

[0078] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-m-tolyl diselenide (0.3 mmol, 98.1 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0079] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 6) with a separation yield of 76%.

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.18-7.01 (m, 6H), 6.97 (s, 1H), 6.86-6.77 (m, 1H), 6.74 (s, 1H), 6.72-6.62 (m, 1H), 3.17-3.00(m, 2H), 2.77 (d, J = 5.3 Hz, 3H), 2.17 (s, 3H), 1.99 (s, 3H).

[0081] 13 C NMR (101 MHz, CDCl3) δ 172.19, 163.40 (d, J = 250.8 Hz), 148.42 (dd, J = 8.0, 2.8 Hz), 145.21 (d, J = 7.1 Hz), 140.30 (d, J = 4.5 Hz), 139.02 (d, J = 6.3Hz), 138.84, 137.92, 134.35, 132.71 (d, J = 2.6 Hz), 130.29, 129.15 (d, J = 2.2Hz), 128.75, 125.94 (dd, J = 8.9, 4.5 Hz), 125.72 (d, J = 2.6 Hz), 125.37, 123.84 (d,J = 3.3 Hz), 116.05 (d, J = 22.7 Hz), 112.35 (d, J = 21.2 Hz), 96.72 (d, J = 2.2Hz), 57.49, 43.84 (d, J = 9.7 Hz), 40.40 (d, J = 4.1 Hz), 21.60, 21.17.

[0082] 19 F NMR (376 MHz, CDCl3) δ -109.25.

[0083] HRMS (ESI) calcd for C 27 H 23 FO3SSe: 527.0590 (M+H + ), found: 527.0592.

[0084] Example 7: Synthesis of Compound 7

[0085]

[0086] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), diethyl diselenide (0.3 mmol, 65.4 mg), and the electrolyte tetrabutyltetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0087] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 7) with a separation yield of 61%.

[0088] 1 H NMR (400 MHz, DMSO- d 6) δ 7.68 (dd, J = 69.2, 8.2 Hz, 4H), 7.51 (d, J=8.9 Hz, 1H), 7.17-6.97 (m, 3H), 3.35-3.21 (m, 2H), 2.81 (s, 3H), 2.39-2.13(m, 2H), 1.89 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H).

[0089] 13 C NMR (101 MHz, DMSO- d 6) δ 173.25, 163.42 (d, J = 247.8 Hz), 149.84(d, J = 8.5 Hz), 146.57 (d, J = 2.6 Hz), 140.38 (d, J = 3.3 Hz), 138.69 (d, J = 3.3Hz), 132.71 (d, J = 2.6 Hz), 129.29, 126.99, 126.02 (d, J = 8.9 Hz), 124.72, 116.62 (d, J = 23.0 Hz), 113.10 (d, J = 23.4 Hz), 96.89, 54.45, 43.67, 43.63, 21.38, 18.16, 15.40.

[0090] 19 F NMR (376 MHz, DMSO- d 6) δ -109.55.

[0091] HRMS (ESI) calcd for C 22 H 21 FO3SSe: 465.0433 (M+H + ), found: 465.0440.

[0092] Example 8: Synthesis of Compound 8

[0093]

[0094] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-isopropylphenyl diselenyl ether (0.3 mmol, 104.7 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0095] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 8) with a separation yield of 69%.

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 5.1 Hz, 2H), 7.22-6.61 (m, 10H), 3.16-3.01 (m, 2H), 2.91-2.82 (m, 1H), 2.76 (d, J = 5.0 Hz, 3H), 1.99 (s, 3H), 1.21 (d, J = 7.0 Hz, 6H).

[0097] 13 C NMR (101 MHz, CDCl3) δ 172.27, 163.41 (d, J = 251.2 Hz), 150.83,148.49 (d, J = 7.8 Hz), 145.32 (d, J = 7.8 Hz), 140.40 (d, J = 3.7 Hz), 139.12 (d, J = 8.5 Hz), 137.46 (d, J = 2.6 Hz), 132.58 (d, J = 2.6 Hz), 129.14 (d, J = 3.3 Hz), 127.13, 125.89 (dd, J = 8.7, 3.5 Hz), 125.54, 123.89, 122.51, 116.09 (d, J =23.0), 112.32 (d, J= 22.7 Hz), 96.74, 57.39, 43.89 (d, J = 11.1 Hz), 40.58 (d, J = 4.1 Hz), 33.85, 23.85 (dd, J = 21.0, 3.2 Hz), 21.59.

[0098] 19 F NMR (376 MHz, CDCl3) δ -109.15.

[0099] HRMS (ESI) calcd for C 29 H 27 FO3SSe: 555.0903 (M+H + ), found: 555.0909.

[0100] Example 9: Synthesis of Compound 9

[0101]

[0102] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-bis(3,4-xylyl)diselenes (0.3 mmol, 102.3 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0103] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 9) with a separation yield of 62%.

[0104] 1 H NMR (400 MHz, CDCl3) δ 7.60-7.50 (d, J = 10.6 Hz, 2H), 7.16-6.98 (m,4H), 6.97-6.63 (m, 5H), 3.15-2.99(m, 2H), 2.77 (d, J = 5.4 Hz, 3H), 2.23(s, 3H), 2.07(s, 3H), 1.98(s, 3H).

[0105] 13C NMR (101 MHz, CDCl3) δ 172.35, 163.42 (d, J = 251.2 Hz), 148.63 (d, J = 10.4 Hz), 145.20 (d, J = 8.5 Hz), 140.36 (d, J = 4.5 Hz), 139.12 (d, J = 8.5 Hz), 138.30, 137.99 (d, J = 107.4 Hz) 134.86, 132.72 (d, J = 3.0 Hz), 130.13, 129.12 (d, J = 3.0 Hz), 125.87 (d, J = 8.9Hz), 125.51, 123.84 (d, J = 2.6 Hz), 122.27,116.02 (d, J = 20.8 Hz), 112.36 (d, J = 23.0 Hz), 96.77 (d, J = 2.6 Hz), 57.32,43.86 (d, J = 12.3 Hz), 40.34 (d, J = 5.6 Hz), 21.51, 19.57 (d, J = 6.7 Hz).

[0106] 19 F NMR (376 MHz, CDCl3) δ -109.33.

[0107] HRMS (ESI) calcd for C 28 H 25 FO3SSe: 541.0746 (M+H + ), found: 541.0756.

[0108] Example 10: Synthesis of Compound 10

[0109]

[0110] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-o-bromophenyl diselenyl ether (0.3 mmol, 140.4 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0111] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 10) with a separation yield of 57%.

[0112] 1 H NMR (400 MHz, CDCl3) δ 8.12-6.50 (m, 12H), 3.18 (s, 2H), 2.76 (s, 3H), 2.00 (s, 3H).

[0113] 13 C NMR (101 MHz, CDCl3) δ 172.18, 163.13 (d, J = 251.5 Hz), 147.63 (d, J = 8.2 Hz), 145.41 (d, J = 5.2 Hz), 140.07 (d, J = 3.0 Hz), 139.22, 138.92 (d, J =5.2 Hz), 133.48, 132.58 (d, J = 3.0 Hz), 131.86, 131.25, 129.27, 129.19 (d, J =2.6 Hz), 127.64, 126.28, 126.07 (dd, J = 8.7, 2.8 Hz), 124.04 (d, J = 3.0 Hz), 116.34 (d, J = 23.0 Hz), 112.49 (d, J = 23.8 Hz), 96.88, 58.88, 43.82 (d, J = 7.4Hz), 41.29 (d, J = 4.1 Hz), 21.25.

[0114] 19 F NMR (376 MHz, CDCl3) δ -109.01.

[0115] HRMS (ESI) calcd for C 26 H 20 BrFO3SSe: 590.9539 (M+H + ), found: 590.9589.

[0116] Example 11 Synthesis of compound 11

[0117]

[0118] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-dichlorophenyl diselenoether (0.3 mmol, 114.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0119] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 11) with a separation yield of 56%.

[0120] 1 H NMR (400 MHz, DMSO- d 6) δ 7.71-7.40 (m, 4H), 7.31-6.79 (m, 8H), 3.45(d, J = 12.8 Hz, 2H), 2.79 (s, 3H), 2.00 (s, 3H).

[0121] 13 C NMR (101 MHz, DMSO- d 6) δ 172.82, 163.22 (d, J = 248.2 Hz), 148.59(d, J = 8.9 Hz), 146.47 (d, J = 3.0 Hz), 139.71, 138.39 (d, J = 3.0 Hz), 136.32 (d, J = 30.5 Hz), 133.37, 133.18 (d,J = 2.6 Hz), 130.97, 129.95, 129.11, 127.51,127.04, 125.69 (d, J = 8.5 Hz), 124.37, 116.63 (d, J = 23.4 Hz), 113.44 (d, J =23.0 Hz), 96.81, 58.91, 55.37, 43.55 (d, J = 6.3 Hz), 39.18, 21.38.

[0122] 19 F NMR (376 MHz, DMSO- d 6) δ -109.78.

[0123] HRMS (ESI) calcd for C 26 H 20 ClFO3SSe: 547.0044 (M+H + ), found: 547.0039.

[0124] Example 12: Synthesis of Compound 12

[0125]

[0126] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-dimethyldiselenoether (0.3 mmol, 57 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0127] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 12) with a separation yield of 53%.

[0128] 1 H NMR (400 MHz, DMSO- d 6) δ 7.89-6.92 (m, 8H), 2.84 (s, 3H), 2.55 (s, 2H), 1.93 (s, 3H), 1.74 (s, 3H).

[0129] 13C NMR (101 MHz, DMSO- d 6) δ 173.30, 163.45 (d, J = 247.8 Hz), 149.49(d, J = 8.2 Hz), 146.52 (d, J = 2.6 Hz), 140.40 (d, J = 3.0 Hz), 138.74 (d, J = 3.0Hz), 132.88 (d, J = 2.6 Hz), 129.32, 126.88, 125.87 (d, J = 8.9 Hz), 124.71, 116.60 (d, J = 23.4 Hz), 112.94 (d, J = 23.8 Hz), 96.71, 53.47 (d, J = 2.6 Hz), 43.62 (d, J = 4.1 Hz), 39.90, 21.03, 4.37.

[0130] 19 F NMR (376 MHz, DMSO- d 6) δ -109.70.

[0131] HRMS (ESI) calcd for C 21 H 19 FO3SSe: 451.0277 (M+H + ), found: 451.0283.

[0132] Example 13: Synthesis of Compound 13

[0133]

[0134] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-m-fluorophenyl diselenyl ether (0.3 mmol, 105.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0135] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 12) with a separation yield of 81%.

[0136] 1 H NMR (400 MHz, DMSO- d 6) δ 7.73 (s, 2H), 7.55 (s, 1H), 7.46-6.36 (m,9H), 2.84 (s, 3H), 2.56 (s, 3H), 2.06 (s, 2H).

[0137] 13 C NMR (101 MHz, DMSO- d 6) δ 172.85, δ 162.39 (dd, J = 248.2, 153.5 Hz), 148.61 (d, J = 8.2 Hz), 146.45, 139.77, 138.46, 133.74, 133.12, 131.07 (d, J =8.2 Hz), 129.05, 127.35 (d, J = 5.9 Hz), 126.98, 125.69 (d, J = 9.3 Hz), 124.59, 124.43 (d, J = 4.1 Hz), 123.89 (d, J = 21.6 Hz), 116.81 (dd, J = 48.7, 22.3 Hz), 113.44 (d, J = 23.4 Hz), 96.83, 58.87, 43.52 (d, J = 5.9 Hz), 21.37.

[0138] 19 F NMR (376 MHz, DMSO- d 6) δ -109.87, -112.03.

[0139] HRMS (ESI) calcd for C 26 H 20 F2O3SSe: 531.0339 (M+H + ), found: 531.0337.

[0140] Example 14 Synthesis of compound 14

[0141]

[0142] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-dichlorophenyldiselenoether (0.3 mmol, 114.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0143] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 14) with a separation yield of 73%.

[0144] 1 H NMR (400 MHz, CDCl3) δ 7.65-7.58 (m, 2 H), 7.18-6.67 (m, 10 H), 3.23-2.97 (m, 2 H), 2.77 (s, 3H), 1.98 (s, 3H).

[0145] 13 C NMR (101 MHz, CDCl3) δ 171.80, 163.48 (d, J = 251.9 Hz), 147.96 (d, J = 7.8 Hz), 145.48 (d, J = 6.3 Hz), 140.01, 138.77 (d, J = 9.3 Hz), 138.62, 136.44 (d, J = 3.3 Hz), 132.82 (d, J = 3.3 Hz), 129.11, 129.05 (d, J = 4.5 Hz), 126.21(d), 126.16 (d, J = 2.2 Hz), 125.90 (d, J = 2.2 Hz), 124.10, 123.62 (d, J = 3.7Hz), 116.49 (d, J = 23.4 Hz), 112.22 (d,J = 23.0 Hz), 96.49, 43.84 (d, J = 8.9Hz), 40.05 (d, J = 4.1 Hz), 21.59.

[0146] 19 F NMR (376 MHz, CDCl3) δ -108.57.

[0147] HRMS (ESI) calcd for C 26 H 20 ClFO3SSe: 547.0044 (M+H + ), found: 547.0044.

[0148] Example 15: Synthesis of Compound 15

[0149]

[0150] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-ethylphenyl diselenyl ether (0.3 mmol, 101.2 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 12 mA for 12 h.

[0151] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 15) with a separation yield of 62%.

[0152] 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz, 2H), 7.10-6.87 (m, 7H), 6.76-6.54 (m, 3H), 3.08-2.92 (m, 2H), 2.68 (d, J = 4.9 Hz, 3H), 2.58-2.47 (m,2H), 1.90 (s, 3H), 1.15-1.06 (m, 3H).

[0153] 13 C NMR (101 MHz, CDCl3) δ 172.28, 163.38 (d, J= 251.2 Hz), 148.47 (d, J = 7.8 Hz), 146.15, 145.22 (d, J = 8.2 Hz), 140.31 (d, J = 4.1 Hz), 139.05 (d, J =7.8 Hz), 137.44, 132.63 (d, J = 2.6 Hz), 129.15 (d, J = 3.7 Hz), 128.53, 125.92 (dd, J = 8.5, 3.7 Hz), 125.57, 123.85 (d, J = 2.6 Hz), 122.32 (d, J = 1.9 Hz), 116.09 (d, J = 25.3 Hz), 112.30 (d, J = 23.0 Hz), 96.73, 57.40, 43.84 (d, J = 11.5Hz), 40.39 (d, J = 5.2 Hz), 28.54, 21.54, 15.40.

[0154] 19 F NMR (376 MHz, CDCl3) δ -109.11.

[0155] HRMS (ESI) calcd for C 28 H 25 FO3SSe: 541.0746 (M+H + ), found: 541.0755.

[0156] Example 16: Synthesis of Compound 16

[0157]

[0158] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-o-fluorophenyl diselenyl ether (0.3 mmol, 105.0 mg), and the electrolyte tetrabutyltetrafluoroborate ammonium (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0159] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 16) with a separation yield of 59%.

[0160] 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, 2H), 7.42-7.12 (m, 4H), 7.08-6.76 (m, 5H), 6.65 (d, J = 8.2 Hz, 1H), 3.23-3.03 (m, 2H), 2.77 (s, 3H), 2.03 (s, 3H).

[0161] 13 C NMR (101 MHz, CDCl3) δ 172.05, 164.77-161.58 (m), 147.67 (dd, J =8.2, 3.3 Hz), 145.31 (d, J = 6.7 Hz), 139.87, 139.78, 138.94 (d, J = 6.7 Hz),132.56, 132.48, 129.18 (d, J = 2.2 Hz), 126.08, 125.99 (d, J = 5.2 Hz), 124.57(d, J = 3.7 Hz), 123.94 (d, J = 3.7 Hz), 116.02 (dd, J = 49.2, 24.0 Hz), 112.60 (dd, J = 44.8, 22.5 Hz), 96.87 (d, J = 2.2 Hz), 58.34, 43.82 (d, J = 8.9 Hz), 40.53(d, J = 3.7 Hz), 29.67, 21.14.

[0162] 19 F NMR (376 MHz, CDCl3) δ -97.93, -109.11.

[0163] HRMS (ESI) calcd for C26 H 20 F2O3SSe: 531.0339 (M+H + ), found: 531.0332.

[0164] Example 17 Synthesis of Compound 17

[0165]

[0166] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-bis(2,4,6-trimethylyl)diselenes (0.3 mmol, 105.9 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0167] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 17) with a separation yield of 49%.

[0168] 1 H NMR (400 MHz, CDCl3) δ 7.68-7.36 (m, 4H), 6.97-6.76 (m, 4H), 6.57(s, 1H), 5.67 (s, 1H), 3.42-3.28 (m, 2H), 2.71 (s, 3H), 2.21(s,3H), 2.13(s,6H), 1.94(s,3H).

[0169] 13 C NMR (101 MHz, CDCl3) δ 173.05, δ 162.45 (d, J = 250.8 Hz), 147.83(d, J = 8.2 Hz), 145.40 (d, J = 5.2 Hz), 144.93, 140.39, 140.33 (d, J = 3.3 Hz), 139.25 (d, J = 6.3 Hz), 131.84, 129.24 (d, J = 3.3 Hz), 128.96, 126.34, 125.84 (d, J= 11.1 Hz), 124.99, 124.18, 115.48 (d, J = 23.0 Hz), 112.26 (d, J = 23.8 Hz).96.95, 56.65, 44.00, 29.70, 24.42, 21.04, 19.49.

[0170] 19 F NMR (376 MHz, CDCl3) δ -110.44.

[0171] HRMS (ESI) calcd for C 29 H 27 FO3SSe: 555.0903 (M+H + ), found: 555.0911.

[0172] Example 18: Synthesis of Compound 18

[0173]

[0174] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-o-tolyl diselenide (0.3 mmol, 98.1 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 12 mA for 12 h.

[0175] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 18) with a separation yield of 83%.

[0176] 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.9 Hz,1H), 7.10-6.73 (m, 9H), 3.38 (s, 2H), 2.78 (s, 3H), 2.27 (s, 3H), 1.99 (s,3H).

[0177] 13 C NMR (101 MHz, DMSO- d6) δ 173.14, δ 162.70 (d, J = 247.5 Hz), 148.80(d, J = 8.5 Hz), 146.50 (d, J = 3.0 Hz), 143.24, 139.28 (d, J = 140.8 Hz), 138.97,132.84 (d, J = 2.6 Hz), 130.57, 130.37, 129.24, 127.51, 127.03, 126.72, 125.67(d, J = 8.5 Hz), 124.54 (d, J = 3.7 Hz), 116.16 (d, J = 23.4 Hz), 113.12 (d, J = 23.4Hz), 97.03, 58.46, 43.58 (d, J = 5.2 Hz), 23.34, 20.69.

[0178] 19 F NMR (376 MHz, DMSO- d 6) δ -110.05.

[0179] HRMS (ESI) calcd for C 27 H 23 FO3SSe: 527.0590 (M+H + ), found: 527.0597.

[0180] Example 19: Synthesis of Compound 19

[0181]

[0182] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-cyanophenyl diselenyl ether (0.3 mmol, 109.2 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 15 mA for 6.5 h.

[0183] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 19) with a separation yield of 43%.

[0184] 1 H NMR (400 MHz, DMSO- d 6) δ 7.67 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.9 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.33-7.21 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06(s, 1H), 6.97 (s, 1H), 6.92 (t, J = 8.7 Hz, 1H), 6.86-6.82 (m, 1H), 3.58-3.38(m, 2H), 2.79 (s, 3H), 2.00 (s, 3H).

[0185] 13 C NMR (101 MHz, DMSO- d 6) δ 172.81, 163.22 (d, J = 248.2 Hz), 148.60(d, J = 8.2 Hz), 146.49 (d, J = 3.3 Hz), 139.70, 138.38 (d, J = 2.6 Hz), 136.33 (d, J = 29.7 Hz), 133.36, 133.18 (d, J = 2.6 Hz), 130.98, 129.96, 129.09 (d, J = 2.2Hz), 127.51, 127.04, 125.68 (d, J = 8.5 Hz), 124.38 (d, J = 3.0 Hz), 116.63 (d, J =23.0 Hz), 113.45 (d, J = 23.8 Hz), 96.81, 58.90 (d, J = 2.6 Hz), 43.54 (d,J = 6.3Hz), 39.16, 21.38.

[0186] 19 F NMR (376 MHz, DMSO- d 6) δ -109.82.

[0187] HRMS (ESI) calcd for C 27 H 20 FNO3SSe: 538.0386 (M+H + ), found: 538.0389.

[0188] Example 20: Synthesis of Compound 20

[0189]

[0190] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-o-methylthiophenyl diselenyl ether (0.3 mmol, 121.8 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 12 mA for 12 h.

[0191] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 20) with a separation yield of 91%.

[0192] 1 H NMR (400 MHz, DMSO- d 6)δ 7.79 – 7.67 (m, 2H), 7.45 – 7.30 (m, 3H), 7.22 – 7.01 (m, 4H), 6.98 – 6.79 (m, 3H), 3.58 – 3.37 (m, 2H), 2.80 (s, 3H), 2.32 (s, 3H), 2.06 (s, 3H).

[0193] 13 C NMR (101 MHz, DMSO- d 6)δ 173.09, 162.63 (d, J = 247.1 Hz), 148.17 (d, J= 8.5 Hz), 146.54, 146.44 (d, J = 2.6 Hz), 139.89, 138.84, 138.63 (d, J = 2.6Hz), 133.13 (d, J = 2.6 Hz), 130.97, 129.28, 127.06, 125.51 (d, J = 8.9 Hz),124.73, 124.54, 116.31 (d, J = 23.4 Hz), 113.45 (d, J = 23.8 Hz), 97.22, 59.03, 43.58, 40.47, 21.04, 15.87.

[0194] 19 F NMR (376 MHz, DMSO- d 6) δ-110.59.

[0195] HRMS (ESI) calcd for C 27 H 23 FNO3S2Se: 559.0311 (M+H + ), found: 559.0311.

[0196] Example 21 Synthesis of compound 21

[0197]

[0198] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-m-methylthiophenyl diselenyl ether (0.3 mmol, 121.8 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 12 mA for 12 h.

[0199] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 21) with a separation yield of 89%.

[0200] 1 H NMR (400 MHz, DMSO- d6)δ 7.82 – 7.50 (m, 4H), 7.32 – 6.78 (m, 8H), 3.43 (d, J = 7.5 Hz, 2H), 2.79 (s, 3H), 2.30 (s, 3H), 2.00 (s, 3H).

[0201] 13 C NMR (101 MHz, DMSO- d 6)δ 172.89, 163.21 (d, J = 247.5 Hz), δ148.94(d, J = 8.2 Hz), 146.40 (d, J = 3.3 Hz), 139.85, 139.58, 138.43 (d, J = 3.7 Hz), 133.81 (d, J = 13.0 Hz), 133.24 (d, J = 2.6 Hz), 129.72, 129.17, 127.48, 126.81,126.40, 125.75, 125.65, 124.30, 116.51 (d, J = 23.4 Hz), 113.38 (d, J = 23.4 Hz), 96.87, 58.51 (d, J = 2.2 Hz), 43.56 (d, J = 5.9 Hz).39.25, 21.29, 14.84.

[0202] 19 F NMR (376 MHz, DMSO- d 6) δ -110.04.

[0203] HRMS (ESI) calcd for C 27 H 23 FNO3S2Se: 559.0311 (M+H + ), found: 559.0303.

[0204] Example 22 Synthesis of compound 22

[0205]

[0206] (1) In a 21 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. Sulinic acid (0.3 mmol, 106.9 mg), 1,2-di-p-methylthiophenyl diselenyl ether (0.3 mmol, 121.8 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 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 12 mA for 12 h.

[0207] (2) After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulinic acid derivative (compound 22) with a separation yield of 92%.

[0208] 1 H NMR (400 MHz, DMSO- d 6) δ 7.78 – 7.51 (m, 4H), 7.12 – 6.99 (m, 5H), 6.96 – 6.84 (m, 2H), 6.84 – 6.75 (m, 1H), 3.39 (s, 2H), 2.77 (s, 3H), 2.40(d, J = 5.1 Hz, 3H), 1.98 (s, 3H).

[0209] 13 C NMR (101 MHz, DMSO- d 6) δ 172.94, δ 163.17 (d, J = 247.5 Hz), 149.06 (d, J = 8.5 Hz), 146.41, 141.45, 139.83, 138.45, 137.91, 133.19 (d, J = 2.6 Hz),132.82, 130.41, 129.16, 125.93, 125.65 (d, J = 8.5 Hz), 124.56 (d, J = 3.0 Hz),124.31, 120.98, 116.46 (d, J = 23.0 Hz), 113.27 (d, J = 23.0 Hz), 96.89, 58.41, 43.54, 39.06, 21.20, 14.63.

[0210] 19F NMR (376 MHz, DMSO- d 6) δ -109.73.

[0211] HRMS (ESI) calcd for C 27 H 23 FNO3S2Se: 559.0311 (M+H + ), found: 559.0318.

[0212] II. Anti-inflammatory activity experiments of the compounds

[0213] (I) Experimental Methods

[0214] 1. Cell Culture and Passaging

[0215] RAW264.7 mouse macrophage cell line was cultured in DMEM high-glucose complete medium containing 20% ​​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.

[0216] 2. Effect of the compound on RAW264.7 cell viability determined by CCK-8 assay

[0217] The effect of selenium-containing sulindac derivatives on the viability of RAW264.7 cells was evaluated using the CCK-8 assay. A normal control group, a sulindac group, and a concentration gradient (20 μmol / L) of the drug were included in 96-well plates, with three 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 medium containing 20 μmol / L selenium-containing sulindac derivative, the sulindac group with medium containing 20 μmol / L sulindac, and the normal group with 1% serum-containing medium (100 μL / well for all groups). After culturing at 37℃ and 5% CO2 for 24 h, 10 μL of CCK-8 solution was added to each well for an additional 4 h of incubation. 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 or sulindac group / OD of normal group) × 100%.

[0218] The experimental results are shown in Table 1, indicating that most selenium-containing sulindac derivatives did not exhibit cytotoxicity under the condition of 20 μmol / L. Among them, compounds 4, 7, and 12 showed some degree of cell damage and could be used as drugs by reducing the dosage.

[0219] Table 1. Evaluation of the viability of selenium-containing sulindac derivatives in 20 μmol / L RAW264.7 cells using the CCK-8 assay.

[0220]

[0221] 3. NO assay kit was used to detect and determine the inhibitory effect of the compound on the inflammatory factor NO in LPS (lipopolysaccharide)-stimulated RAW264.7 cells.

[0222] An LPS-induced inflammation model was used in RAW264.7 cells. Sulindac (20 μmol / L) was used as a positive control to evaluate the inhibitory effect of a selenium-containing sulindac derivative (20 μmol / L) on NO production. Logarithmic growth phase RAW264.7 cells were cultured at 3 × 10⁻⁶ cells per cell line. 5 Inoculated at a density of 100 cells / mL into 12-well plates and cultured for 24 h until adherence was achieved. Then, control groups, model groups, sulindac groups, and drug-treated groups (containing selenium-sulindac derivatives) were established (each with 3 replicates). The culture medium was discarded, and each group was pretreated with 500 μL of the corresponding drug or culture medium for 2 h. Except for the control group, all other groups were treated with LPS solution at a final concentration of 100 ng / mL and cultured for another 18 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 sulindac group or normal group / NO concentration in the model group) × 100%.

[0223] The experimental results are shown in Table 2. The selenium-containing sulindac derivatives significantly improved the NO inhibition effect of the active pharmaceutical ingredient sulindac under the condition of 20 μmol / L. Compounds 4, 7, and 12 have trace amounts of toxicity, which may have inhibited the NO generation rate.

[0224] Table 2. Inhibition effect of selenium-containing sulindac derivatives on NO at 20 μmol / L

[0225]

[0226] 4. RT-qPCR was used to determine the levels of pro-inflammatory factors TNF-α (tumor necrosis factor), IL-1β (interleukin-1β), and IL-6 (interleukin-6) in LPS-stimulated RAW264.7 cells.

[0227] An LPS-induced inflammation model was used in RAW264.7 cells, with sulindac (20 μmol / L) as a positive control, to evaluate the effect of a selenium-containing sulindac derivative (20 μmol / L) on the expression of pro-inflammatory cytokine mRNA. Logarithmically growing RAW264.7 cells were cultured at 5 × 10⁻⁶ cells per cell line. 5Cells were seeded at a density of 1 cell / mL in 6-well plates (2 mL / well). After 24 h of culture, the cells adhered to the plates. Then, a normal control group, a model group, a positive control group (sulindac), and a drug-treated group (containing a selenium-containing sulindac derivative) were established. The culture medium was discarded, and each group was pretreated with 2 mL of the corresponding drug or culture medium for 2 h. Except for the normal control group, all other groups were added to LPS solution at a final concentration of 100 ng / mL and cultured for another 18 h. Cells were collected, and total RNA was extracted using the SteadyPure kit. After purity testing with NanoDrop 2000 (A260 / A280 = 1.8–2.0), cDNA was obtained by reverse transcription using the 5X Evo M-MLV kit (stored at -20 °C). 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.

[0228] 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, the selenium-containing sulindac derivative at a concentration of 20 μmol / L significantly downregulated its level compared to the model group, and showed a better inhibitory effect than the positive control drug sulindac (20 μmol / L). For the inflammatory factor IL-1β, the selenium-containing sulindac derivative at 20 μmol / L also showed a better downregulation ability than sulindac. In addition, for the inflammatory factor TNF-α, although the selenium-containing sulindac derivative could downregulate at a concentration of 20 μmol / L, its downregulation ability was not significant compared to IL-6 and IL-1β.

[0229] Table 3 Effects of selenium-containing sulindac derivatives on LPS-induced IL-6, IL-1β, and TNF-α levels in RAW 264.7 cells (X±s, n=3)

[0230]

[0231] Table 4. Effects of selenium-containing sulindac derivatives on LPS-induced IL-6, IL-1β, and TNF-α levels in RAW 264.7 cells (X±s, n=3)

[0232]

[0233] 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. A selenium-containing sulindac derivative, characterized in that: The selenium-containing sulinic acid derivative, with sulinic acid as the parent structure, undergoes esterification and selenization reactions on the olefin of its five-membered ring. The general chemical structural formula of the selenium-containing sulinic acid derivative is as follows: ， Wherein, R is selected from any one of: phenyl, p-iodophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-tolyl, m-tolyl, ethyl, p-isopropylphenyl, 3,4-dimethylphenyl, o-bromophenyl, m-chlorophenyl, methyl, m-fluorophenyl, p-chlorophenyl, p-ethylphenyl, o-fluorophenyl, 2,4,6-trimethylphenyl, o-tolyl, p-cyanophenyl, o-methylthiophenyl, m-methylthiophenyl, p-methylthiophenyl.

2. A selenium-containing sulindac derivative, characterized in that: The selenium-containing sulinic acid derivative is selected from the following structures: 。 3. An electrochemical synthesis method for a selenium-containing sulinic acid derivative according to claim 1, characterized in that: Includes the following steps: In an electrolytic cell, the anode and cathode are set up, and sulinic acid, diselenide compounds, electrolyte and solvent are added in sequence. The reaction is carried out under constant current conditions. After the reaction is completed, the reaction solution is collected to obtain a selenium-containing sulinic acid derivative. The general chemical structural formula of the diselenide compounds is: RSeSeR; The electrolyte is tetrabutylammonium tetrafluoroborate, and the solvent is acetonitrile.

4. The electrochemical synthesis method according to claim 3, characterized in that: The diselenide compounds are selected from: diphenyldiselenide, 1,2-di-p-iodophenyldiselenide, 1,2-di-p-bromophenyldiselenide, 1,2-di-p-trifluoromethylphenyldiselenide, 1,2-di-p-tolyldiselenide, 1,2-di-m-tolyldiselenide, diethyldiselenide, 1,2-di-p-isopropylphenyldiselenide, 1,2-bis(3,4-xylyl)diselenide, 1,2-di-o-bromophenyldiselenide, 1,2-di-m-chlorophenyldiselenide, 1,2-dimethyldiselenide, 1,2-di-m-fluorophenyldiselenide, 1,2-di-p-chlorophenyldiselenide, 1,2-di-p-ethylphenyldiselenide, 1,2-di-o-fluorophenyldiselenide, 1,2-di(2,4, Any one of 6-trimethylyl)diselenoether, 1,2-di-o-methylyldiselenoether, 1,2-di-p-cyanophenyldiselenoether, 1,2-di-o-methylthiophenyldiselenoether, 1,2-di-m-methylthiophenyldiselenoether, and 1,2-di-p-methylthiophenyldiselenoether.

5. The electrochemical synthesis method according to claim 3, characterized in that: The molar ratio of sulindac, diselenyl ether compound, and electrolyte is 1:1:

1.

6. The electrochemical synthesis method according to claim 3, characterized in that: The anode is a carbon rod, the cathode is a platinum sheet, the constant current is 12-15 mA, and the reaction time is 6.5-12 h.

7. The electrochemical synthesis method according to claim 3, characterized in that: The electrochemical synthesis method further includes: the reaction solution is concentrated and purified by column chromatography to obtain a selenium-containing sulinic acid derivative, and the column chromatography conditions are: petroleum ether / ethyl acetate = 5 / 1, volume ratio.

8. The use of a selenium-containing sulindac derivative according to any one of claims 1-2 in the preparation of an anti-inflammatory drug.

9. A pharmaceutical preparation, characterized in that, It comprises the selenium-containing sulinic acid derivative as described in any one of claims 1-2, and one or more pharmaceutically acceptable carriers or excipients.

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