Preparation method and medical application of selenophosphate promoted by tri (pentafluorophenyl) borane

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to a preparation method and medical application of selenophosphate promoted by tris (pentafluorophenyl) borane. The preparation method of the selenophosphate ester comprises the following steps: under the action of tris (pentafluorophenyl) borane, taking seleno cyanate ester and phosphate ester as reaction raw materials, and carrying out stirring reaction under a certain temperature condition to obtain the selenophosphate ester compound. The synthesis method is mild in condition, does not need a metal catalyst and an oxidizing agent, and accords with the idea of green chemistry. The method also has the advantages of simplicity in operation, few byproducts, high purity and the like. In-vitro anti-inflammatory experiments prove that the selenophosphate compound disclosed by the invention has remarkable anti-inflammatory activity, can effectively inhibit the generation of inflammatory factors and cell inflammatory response, can be used as an active ingredient of anti-inflammatory drugs, and has a wide clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, specifically to a method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate and its pharmaceutical applications. Background Technology

[0002] Phosphate esters are widely found in biomolecules such as nucleic acids, phospholipids, and ATP. With their advantages of tunable structure and good biocompatibility, phosphate esters and their derivatives have long been used as key building blocks for drug delivery, prodrug design, and functional materials, providing a solid molecular platform for drug development and synthetic chemistry. Therefore, efficient synthetic strategies for constructing these frameworks have always been a research focus in organic chemistry and medicinal chemistry.

[0003] On the other hand, as an essential trace element, selenium plays an irreplaceable physiological role in organisms, widely participating in key biological processes such as redox regulation, immune responses, and cell signal transduction. From a chemical synthesis perspective, organoselenium compounds possess unique reactivity: they exhibit significant amphiphilicity (nucleophilic / electropophilic) and can participate in free radical reactions. This multi-reactivity characteristic makes them promising for applications in catalysis chemistry and molecular modification, and they are widely used in the structural optimization of drug molecules, functional materials, and agrochemicals. Based on these findings, selenization modification has become an important molecular design strategy for the development of anti-inflammatory and anti-tumor drugs. Currently, precise selenization modification of lead compounds through structural units such as selenophosphates, selenoglycosides, or selenium heterocycles has become one of the most promising frontier directions in anti-inflammatory drug development.

[0004] There is currently a considerable body of research on the preparation of selenophosphate compounds. For example, the synthesis of alkyl selenophosphate compounds is achieved through a one-pot aqueous process, with efficient coupling between selenium powder, alkyl halides (or alkyl sulfonates), and P(O)-H compounds under alkaline conditions (Shi Zheng, Aqueous-phase Synthesis of Thio(Seleno)phosphonates and Their Application in Allylation Reaction [D]. Shanghai University of Applied Technology, 2018); a method for preparing selenophosphates by coupling phosphites and diselen ethers under mild reaction conditions using tert-butyl hydroperoxide (TBHP) as an oxidant (Organic Chemistry, 2022). 42 (218-225); Chinese patent CN114805430A synthesizes selenophosphides using selenosulfonate and phosphite diester as starting materials under nitrogen atmosphere and room temperature conditions; Chinese patent CN114411180A uses an organic solution of alcohol, elemental selenium, diphenylphosphine, and electrolyte salt as electrolyte to obtain selenophosphate compounds via an electrochemical method. Developing simple, efficient, and environmentally friendly methods for preparing selenophosphates remains a common pursuit for chemists. Summary of the Invention

[0005] This invention provides a method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate and its pharmaceutical applications. One objective of this invention is to provide a class of selenophosphate derivatives with anti-inflammatory activity. Another objective is to provide a method for preparing and purifying the above-mentioned selenophosphate. A third objective is to apply the above-mentioned selenophosphate derivatives to the preparation of clinical anti-inflammatory drugs.

[0006] The above-mentioned objective of the present invention is achieved through the following technical solution: In an organic solvent, selenocyanate (I) and phosphate (II) react in an open-top stirred manner under the catalysis of tris(pentafluorophenyl)borane to give selenophosphate compound (III), as shown in the following equation:

[0007] Among them, R 1 For C1-C 10 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, and cyclohexyl), benzyl, naphthyl, phenyl, or phenyl substituted with one or more substituents, wherein the substituent on the phenyl group is alkyl, halogen, nitro, trifluoromethoxy, methoxy, or cyano; R 2 and R 3 Each is independently alkoxy, benzyloxy, naphthoxy, phenoxy, phenyl, and further, R 2 and R 3 same.

[0008] The molar ratio of the selenyl cyanate ester with the structure shown in formula (I) to the phosphate ester with the structure shown in formula (II) is 1:1 to 1:1.5, preferably 1:1.

[0009] The organic solvent is dichloromethane, acetonitrile, toluene, tetrahydrofuran, or N,N-dimethylformamide, preferably dichloromethane.

[0010] The preferred open-air stirred reaction is a reaction at room temperature for 5 h to 20 h.

[0011] After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was (1-10):1. The eluent was collected, and the solvent was evaporated by rotary evaporation to obtain the selenophosphate compound shown in formula (III).

[0012] The selenophosphate derivatives prepared by this invention have excellent anti-inflammatory properties and can be well applied to the preparation of drugs for anti-inflammatory diseases.

[0013] Furthermore, the selenophosphate derivatives obtained by this invention, or their pharmaceutically acceptable salts, solvates, and hydrates, can be used in combination with pharmaceutically acceptable carriers or diluents to form pharmaceutical formulations. Pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.

[0014] This invention first involves selenocyaniding an alkyl or aryl compound to introduce a selenium source, yielding selenocyanate compounds. Then, under tris(pentafluorophenyl)borane catalysis, a selenogroup is introduced into the phosphite to synthesize selenophosphate derivatives. This invention has at least one of the following beneficial effects: (1) The present invention has mild conditions and simple operation. It does not require harsh reaction conditions during the synthesis process, which reduces energy consumption and equipment requirements. At the same time, it has good compatibility with various functional groups.

[0015] (2) This invention does not require the use of metal catalysts, thus avoiding the pollution of products by metal residues and potential harm to the environment, which is in line with the environmental protection concept of green chemistry.

[0016] (3) Experiments have demonstrated that the selenophosphate derivatives provided in this invention selectively and significantly inhibit the inflammatory response of various inflammation-related cells (including LPS-induced RAW264.7 macrophages), significantly reducing the levels of inflammatory factors while having little impact on the physiological functions of normal cells. Therefore, the compounds of this invention have important application prospects in the development of anti-inflammatory drugs. Detailed Implementation

[0017] 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.

[0018] This invention provides the following technical solution: In an organic solvent, selenocyanate (I) and phosphate ester (II) are reacted under open-top stirring with tris(pentafluorophenyl)borane as a catalyst to obtain selenophosphate compound (III), and the reaction equation is shown below:

[0019] Among them, R 1 For C1-C 10Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, and cyclohexyl), benzyl, naphthyl, phenyl, or phenyl substituted with one or more substituents, wherein the substituent on the phenyl group is alkyl, halogen, nitro, trifluoromethoxy, methoxy, or cyano; R 2 and R 3 It can be alkoxy, benzyloxy, naphthoxy, phenoxy, or phenyl.

[0020] Compound (I) is prepared by the following route: If R 1 For C1-C 10 Alkyl and benzyl groups are used to synthesize selenyl cyanate (I) according to reaction equation (1); if R 1 Selenyl cyanate (I) is synthesized by reacting naphthyl, phenyl or substituted phenyl according to reaction equation (2).

[0021] Example 1

[0022] The reaction equation is shown below:

[0023] 4-Chlorobenzenediazotetrafluoroborate (1 equivalent) and potassium selenocyanate (1.5 equivalent) were added to a reaction tube equipped with a magnetic stirrer. Acetonitrile was added, and the reaction was carried out at room temperature for 30 minutes under open conditions. After the reaction was completed, the mixture was washed with water, and the organic phase was removed from the solvent by a rotary evaporator to obtain 1-chloro-4-selenocyanobenzene.

[0024] 0.1 mmol of 1-chloro-4-selenocyanobenzene, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added, and the reaction was carried out at room temperature under open conditions for 20 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound in 84% yield. 1 H NMR (400 MHz, CDCl3): δ7.50 (d, J = 8.5 Hz, 2H), 7.22 (d, J =8.5 Hz, 3H), 3.74 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 135.9 (d, J = 4.6 Hz), 134.5 (d, J = 3.1 Hz), 128.8 (d, J = 2.2 Hz), 120.3 (d, J = 8.8Hz), 53.1 (d, J = 5.9 Hz). 31 P NMR (162 MHz, CDCl3) δ: 21.2. Example 2

[0025] The reaction equation is shown below:

[0026] 1-Methoxy-4-selenocyanobenzene was synthesized from 4-methoxybenzene diazotetrafluoroborate using the method of Example 1.

[0027] 0.1 mmol of 1-methoxy-4-selenocyanobenzene, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added, and the reaction was carried out at room temperature under open conditions for 20 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound in 76% yield. 1 H NMR (400 MHz, CDCl3): δ7.46 (d, J = 8.8 Hz, 2H), 6.78 (d, J =8.8 Hz, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H). 13 C NMR (100 MHz, CDCl3)δ: 159.4 (d, J = 2.8 Hz), 136.3 (d, J = 4.2 Hz), 114.3 (d, J = 2.4 Hz), 112.0(d, J = 8.7 Hz), 54.3, 52.9 (d, J = 5.7 Hz). 31 P NMR (162 MHz, CDCl3) δ: 22.2. Example 3

[0028] The reaction equation is shown below:

[0029] 2-Selenocyanonaphthalene was synthesized from 2-naphthyldiazotetrafluoroborate using the method of Example 1.

[0030] 0.1 mmol of 2-selenocyanonaphthalene, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added. The reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound in 93% yield. 1 H NMR (400 MHz, CDCl3): δ8.38 (d, J = 8.4 Hz, 1H), 8.04 – 7.84 (m, 1H), 7.86 – 7.80 (m, 1H), 7.79 – 7.74 (m, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.4 Hz,1H), 7.45 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 3.66 (s, 3H), 3.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 135.5 (d, J = 4.9 Hz), 133.9 (d, J = 3.3 Hz), 133.2 (d, J = 2.2 Hz), 129.4 (d, J = 3.2 Hz), 127.7, 126.9,126.2, 125.5, 124.9 (d, J = 3.2 Hz), 121.6 (d, J = 9.4 Hz), 53.1 (d, J = 6.0Hz). 31 P NMR (162 MHz, CDCl3) δ: 21.1. Example 4

[0031] The reaction equation is shown below:

[0032] 1-Selenocyano-4-(trifluoromethoxy)benzene was synthesized from 4-trifluoromethoxybenzene diazonium tetrafluoroborate, following the method of Example 1.

[0033] 0.1 mmol of 1-selenocyano-4-(trifluoromethoxy)benzene, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added, and the reaction was carried out at room temperature under open conditions for 20 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain the target compound in 78% yield. 1 H NMR (400 MHz, CDCl3): δ7.60 (dd, J = 8.8Hz, 2H), 7.10 (d, J = 8.8Hz, 2H), 3.75 (s, 3H), 3.72 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ:151.32 –145.90 (m), 136.1 (d, J C-P = 4.6 Hz), 120.9 (d, J = 2.1 Hz), 120.4 (d, J = 8.6Hz), 119.3 (q, J = 256.0 Hz), 53.1 (d, J = 5.9 Hz). 19 F NMR (376 MHz, CDCl3) δ-57.9. 31 P NMR (162 MHz, CDCl3) δ: 21.0. Example 5

[0034] The reaction equation is shown below:

[0035] 1-Nitro-4-Selenocyanobenzene was synthesized from 4-nitrobenzene diazonium tetrafluoroborate using the method of Example 1.

[0036] 0.1 mmol of 1-nitro-4-selenocyanobenzene, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added, and the reaction was carried out at room temperature under open conditions for 20 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the target compound in 83% yield. 1 H NMR (500 MHz, CDCl3): δ 8.10 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.5Hz, 2H), 3.78 (d, J = 12.8 Hz, 6H). 13 C NMR (126 MHz, CDCl3): δ148.9, 136.03(d, J =5.1 Hz), 133.62 (d, J =5.1 Hz), 123.7, 53.8 (d, J =6.2 Hz). 31 P NMR (162MHz, CDCl3) δ: 19.7. Example 6

[0037] The reaction equation is shown below:

[0038] 4-Chloro-bromobenzyl (1 equivalent) and potassium selenocyanate (1.5 equivalent) were added to a reaction tube equipped with a magnetic stir bar. Acetonitrile was added, and the reaction was carried out at room temperature for 30 minutes under open conditions. After the reaction was completed, the mixture was washed with water, and the organic phase was removed from the solvent by a rotary evaporator to obtain 1-chloro-4-(selenocyanomethyl)benzene.

[0039] 0.1 mmol of 1-chloro-4-(selenocyanomethyl)benzene, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added, and the reaction was carried out at room temperature under open conditions for 20 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound in 75% yield. 1 H NMR (400MHz, CDCl3): δ7.29 (d, J= 0.8 Hz, 4H), 3.99 (d, J =14.7 Hz, 2H), 1.28 (t, J = 7.1 Hz, 6H); 13 C NMR (126 MHz, CDCl3): δ 137.0 (d, J = 4.2 Hz), 133.3, 130.3, 128.8, 53.6 (d, J = 5.5 Hz), 28.6 (d, J = 4.6 Hz). 31 P NMR (162 MHz, CDCl3) δ: 24.1. Example 7

[0040] The reaction equation is shown below:

[0041] 1-Selenocyanoheptane was synthesized from 1-bromoheptane using the method of Example 6.

[0042] 0.1 mmol of 1-selenocyanoheptane, 0.1 mmol of dimethyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added. The reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target compound in 58% yield. 1 H NMR (400 MHz, CDCl3) δ / ppm = 3.73 (s, 3H), 3.70 (s, 3H), 2.80 (dt, J = 14.1, 7.4 Hz, 2H), 1.75 – 1.58 (m, 2H), 1.40 – 1.12 (m, 8H), 0.81 (t, J =6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ / ppm = 52.5 (d, J = 5.6 Hz), 30.6, 30.2 (d, J = 4.5 Hz), 28.5, 27.6, 25.6 (d, J = 4.6 Hz), 21.5, 13.0.31 P NMR (162MHz, CDCl3) δ / ppm = 25.4. Example 8

[0043] The reaction equation is shown below:

[0044] To a 20 mL test tube equipped with a magnetic stirrer, phenyl selenocyanate (0.1 mmol), di(2-naphthyl)phosphite (0.1 mmol), and tris(pentafluorophenyl)borane (0.01 mmol) were added. After the addition was complete, dichloromethane (2 mL) was added, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound in 71% yield. 1 H NMR (400 MHz, CDCl3) δ / ppm=8.39 – 8.31 (m, 2H), 7.90 – 7.73 (m,6H), 7.53 – 7.43 (m, 7H), 7.20 – 7.01 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ / ppm=136.4 (d, J = 3.3 Hz), 134.8 (d, J = 2.7 Hz), 133.6 (d, J = 9.6 Hz), 132.4(d, J = 14.4 Hz), 131.5, 130.9 (d, J = 5.8 Hz), 129.3 (d, J = 1.7 Hz), 129.2,128.5, 128.4, 127.8, 127.7, 127.1, 126.1 (d, J = 12.0 Hz). 31 P NMR (162 MHz, CDCl3) δ / ppm= 40.0. Example 9

[0045] The reaction equation is shown below:

[0046] To a 20 mL test tube equipped with a magnetic stirrer, phenyl selenocyanate (0.1 mmol), diisopropyl phosphite (0.1 mmol), and tris(pentafluorophenyl)borane (0.01 mmol) were added. After the addition was complete, dichloromethane (2 mL) was added, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 7 / 1) to obtain the target compound in 79% yield. 1 H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.1 Hz, 2H), 7.33 – 7.17 (m,3H), 4.89 – 4.57 (m, 2H), 1.26 (d, J = 6.2 Hz, 6H), 1.18 (d, J = 6.2 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ : 134.1 (d, J = 5.0 Hz), 128.3 (d, J = 1.9 Hz), 127.5 (d, J = 2.5 Hz), 123.5 (d, J = 8.3 Hz), 72.1 (d, J = 6.6 Hz), 22.9 (d, J = 3.8 Hz), 22.5 (d, J = 5.9 Hz). 31 P NMR (162 MHz, CDCl3) δ: 14.7. Example 10

[0047] The reaction equation is shown below:

[0048] To a 20 mL test tube equipped with a magnetic stirrer, phenyl selenocyanate (0.1 mmol), diphenyl phosphite (0.1 mmol), and tris(pentafluorophenyl)borane (0.01 mmol) were added. After the addition was complete, dichloromethane (2 mL) was added, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound in 81% yield. 1H NMR (400 MHz, CDCl3): δ7.55 – 7.37 (m, 2H), 7.33 – 7.14 (m, 7H), 7.15 –7.07 (m, 6H). 13 C NMR (100 MHz, CDCl3) δ: 149.2 (d, J = 8.6 Hz), 135.2 (d, J =4.8 Hz), 128.7 (d, J = 1.3 Hz), 128.5 (d, J = 2.5 Hz), 128.3 (d, J = 2.9 Hz), 124.6 (d, J = 1.6 Hz), 121.6 (d, J = 9.1 Hz), 119.6 (d, J = 5.1 Hz). 31 P NMR (162 MHz, CDCl3) δ: 9.5. Example 11

[0049] The reaction equation is shown below:

[0050] 0.1 mmol of phenyl selenocyanate, 0.1 mmol of dibenzyl phosphite, and 0.01 mmol of tris(pentafluorophenyl)borane were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, 2 mL of dichloromethane was added. The reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound in 73% yield. 1 H NMR (400 MHz, CDCl3) δ: 7.48 (d, J = 8.1 Hz, 2H), 7.30 – 7.21 (m, 7H), 7.21 – 7.11 (m, 6H), 5.07 – 4.98 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ: 134.8 (d, J C-P = 4.7 Hz), 134.2 (d, J C-P = 7.8 Hz), 128.5 (d,J C-P = 2.2 Hz), 127.9 (d, J C-P = 2.7 Hz), 127.52, 127.50, 127.0, 122.2 (d, J C-P = 8.6 Hz), 68.1 (d, J C-P =6.1 Hz). 31 P NMR (162 MHz, CDCl3) δ: 18.5. Example 12

[0051] The reaction equation is shown below:

[0052] To a 20 mL test tube equipped with a magnetic stirrer, phenyl selenocyanate (0.1 mmol), diphenylphosphine (0.1 mmol), and tris(pentafluorophenyl)borane (0.01 mmol) were added. After the addition was complete, dichloromethane (2 mL) was added. The reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target compound in 84% yield. 1 H NMR (400 MHz, CDCl3) δ: 7.87 – 7.64 (m, 4H), 7.51 – 7.26 (m, 8H), 7.16(t, J = 8.0 Hz, 1H), 7.07 (t, J = 7.5 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ:136.3(d, J C-P = 3.3 Hz), 133.9, 133.0, 132.3 (d, J C-P = 3.3 Hz), 131.4 (d, J C-P = 10.6 Hz), 129.3 (d, J C-P = 1.7 Hz), 128.5 (d, J C-P = 13.2 Hz), 123.7 (d, J C-P= 15.7 Hz). 31 P NMR (162 MHz, CDCl3) δ:40.0. Example 13 Anti-inflammatory activity study

[0053] The selenophosphate compounds prepared in Examples 1-12 are designated as IIIa-1, respectively. The effect of each test compound on the viability of mouse monocyte / macrophage RAW264.7 cells was determined by the MTT assay: RAW264.7 cells in logarithmic growth phase were cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution, and the cell concentration was adjusted to 5 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of 100 μL / mL into 96-well plates. The blank control group received only culture medium. The remaining wells were divided into a cell control group (cells + culture medium) and an LPS model control group (cells + culture medium + 1 µg / mL LPS). Each well contained 100 μL of cell suspension, with three replicates per group. The 96-well plates were incubated at 37°C. C. After culturing in a 5% CO2 incubator for 24 h, different concentrations of the test sample were added to achieve a final concentration of 0.1-10 μM, and culturing continued for another 72 h. The absorbance (A) at 450 nm was measured using an ELISA reader according to the MTT assay. Cell viability (%) = [(A experiment)] (A blank) / (A control) [A blank)]×100%.

[0054] The effect of each tested compound on LPS-induced NO release in RAW264.7 cells was determined using the Griess method: the cell concentration was adjusted to 2 × 10⁻⁶. 5 Cells were seeded at a density of 100 μL / mL in 96-well plates, with three replicates per group. The plates included a blank control group (culture medium only), a normal control group (cells + culture medium), an LPS model control group (cells + culture medium + 1 μg / mL LPS), and a drug treatment group (cells + culture medium + 1 μg / mL LPS + 0.1–10 μM test compound), with three replicates per group. After culturing at 37°C and 5% CO2 for 24 h, the cells adhered to the plates. The drug treatment groups were pretreated with the drug for 1 h, followed by the addition of LPS (final concentration 1 μg / mL) to each well, except for the normal control group. The cells were cultured for another 12 h, and the supernatant was collected. The NO level in the supernatant was measured according to the kit instructions. Data were analyzed using SPSS Statistics 25 software.

[0055] Based on the results of the MTT and Griess methods, the effect of the selenophosphate compound of the present invention on LPS-induced NO release in RAW264.7 cells was calculated, and the results are shown in Table 1.

[0056] Table 1. Results of test samples inhibiting LPS-induced NO release in RAW264.7 cells

[0057] The results showed that the selenophosphate compounds of the present invention did not exhibit significant cytotoxic activity against RAW264.7 cells, but could significantly reduce the release level of the inflammatory factor NO induced by LPS in RAW264.7 cells, demonstrating significant anti-inflammatory activity and thus serving as active ingredients for anti-inflammatory drugs.

[0058] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate, characterized in that: In an organic solvent, selenocyanate (I) and phosphate (II) react in an open-top stirred manner under the catalysis of tris(pentafluorophenyl)borane to give selenophosphate compound (III), as shown in the following equation: Among them, R 1 For C1-C 10 Alkyl, benzyl, naphthyl, phenyl, or substituted phenyl; R 2 and R 3 Each is independently selected from alkoxy, benzyloxy, naphthoxy, phenoxy, and phenyl.

2. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: The substituted phenyl group is a phenyl group substituted with one or more substituents, each of which is independently selected from alkyl, halogen, nitro, trifluoromethoxy, methoxy, and cyano groups.

3. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: R 2 and R 3 Same, selected from one of alkoxy, benzyloxy, naphthoxy, phenoxy, and phenyl.

4. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: The molar ratio of the selenyl cyanate ester with the structure shown in formula (I) to the phosphate ester with the structure shown in formula (II) is 1:1~1.

5.

5. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: The molar ratio of selenyl cyanate to tris(pentafluorophenyl)borane is 1:0.

1.

6. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: The organic solvent is one or more of dichloromethane, acetonitrile, toluene, tetrahydrofuran, and N,N-dimethylformamide.

7. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: The open-air stirred reaction was carried out at room temperature for 5-20 hours.

8. The method for preparing tris(pentafluorophenyl)borane-promoted selenophosphate according to claim 1, characterized in that: After stirring and reaction, the mixture was concentrated under reduced pressure and separated by column chromatography. A mixture of petroleum ether and ethyl acetate was used as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was 1 to 10:

1.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a selenophosphate compound (III) prepared by the method according to any one of claims 1-8, a medically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

10. Use of the pharmaceutical composition of claim 9 in the preparation of an anti-inflammatory drug.

Images