Tetrahydrothiophene sulfone derivative, preparation method thereof and application of tetrahydrothiophene sulfone derivative in preparation of acaricidal drugs

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a tetrahydrothiophene sulfone derivative, a preparation method thereof and application of the tetrahydrothiophene sulfone derivative in preparation of acaricidal drugs. The chemical structural formula of the tetrahydrothiophene sulfone derivative is as shown in formula I, and R is fluorine, chlorine, bromine or trifluoromethyl. The preparation method comprises the following steps: mixing and stirring elemental sulfur and an alkaline raw material, sequentially adding substituted benzaldehyde and acetophenone, reacting to obtain an intermediate, and finally oxidizing, distilling, cleaning and recrystallizing to obtain the sulfur-containing compound. Experiments prove that the acaricidal activity of the tetrahydrothiophene sulfone derivative is obviously superior to that of ivermectin, and the median lethal concentration and time are lower. The compound is simple in preparation process, mild in condition and high in yield, has important application value in the aspect of preparing acaricides, provides a new choice for preventing and treating animal acariasis, and is beneficial to reducing the loss of the breeding industry.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a tetrahydrothiophene sulfone derivative, its preparation method, and its application in the preparation of acaricides. Background Technology

[0002] Animal mite infestations are skin diseases caused by mites that parasitize the skin of animals. Ear mites, a type of animal mite, primarily parasitize the ear canals of animals. Their host range is extremely wide, infecting not only rabbits, horses, sheep, pigs, and rats, but also humans. In farms, if even one animal is infected with ear mites and control measures are not implemented promptly, the entire herd can become infected within a few days. Humans who come into contact with infected animals may also experience symptoms such as itchy skin and rashes.

[0003] Animal mite infestations pose a significant threat to human and animal health. Once an animal is infected with ear mites, the mites burrow tunnels in the epidermis and feed on bodily fluids, triggering an immune response that often results in intense itching, inflammation, hair loss, serous effusion, loss of appetite, and many other symptoms. Due to the unbearable itching, infected animals will constantly bite and rub the affected areas, leading to skin damage and secondary bacterial and fungal infections, further worsening the condition. In severe cases, animals may die due to prolonged inability to eat, organ failure, and other complications. Furthermore, ear mite infestations are highly contagious and can spread rapidly through direct and indirect contact, making them a widespread global disease. According to statistics, outbreaks of ear mites in large-scale farms can reduce animal survival rates by 20%–30% and reduce productivity by more than 30%, causing significant economic losses to the animal husbandry industry and becoming a major disease factor hindering its development.

[0004] Currently, the treatment and control of animal mites mainly rely on drugs and chemicals, such as organochlorines, organophosphates, ivermectin, abamectin, and pyrethroids. More specifically:

[0005] (i) Although organochlorine drugs have played a role in killing mites, their use has been restricted or banned in many countries due to their long residual period in the environment and high toxicity.

[0006] (ii) Organophosphate pesticides have a good acaricidal effect, but they are also highly toxic to animals. The dosage must be strictly controlled when using them, otherwise they can easily lead to animal poisoning.

[0007] (iii) Ivermectin is the main commercially available drug for this type of disease, and it can have a certain acaricidal effect in the initial use. However, due to its single mechanism of action, long-term use will cause the itch mites to gradually develop drug resistance, resulting in a significant reduction in the drug's acaricidal effect. This not only leads to treatment failure but also causes the disease to recur, increasing the difficulty and cost of treatment. Moreover, the high production cost of ivermectin results in a high market price. For large-scale farmers, long-term use will significantly increase breeding costs, greatly limiting its widespread application in actual production and daily life.

[0008] (iv) Avermectin and ivermectin both belong to the macrolide class of drugs and have similar mechanisms of action. Long-term use can easily lead to cross-resistance in itch mites, and their toxicity is relatively high. If the dosage is not properly controlled during use, it may produce toxic side effects on animals and affect their health. These chemical drugs have varying degrees of deficiencies in terms of the persistence of their acaricidal effect, safety to animals, and cost-effectiveness, making it difficult to meet the comprehensive needs of efficient, safe, economical, and convenient drugs in actual pest control work.

[0009] (v) Although pyrethroids are fast-acting, their effective period is short, requiring frequent application to maintain their acaricidal effect, which increases the workload and cost of application. At the same time, they are not very stable to light and heat, and are prone to decomposition and inactivation during storage and use, affecting the control effect.

[0010] Clearly, with the continued and widespread use of these drugs, numerous problems have arisen. For example, drug resistance is becoming increasingly apparent. Due to the development of resistance and inherent limitations of the drugs themselves, the acaricidal effect of ivermectin-based drugs is gradually weakening, frequently leading to treatment failure or disease recurrence. In some areas, mites' resistance to ivermectin has increased several times or even dozens of times. On the other hand, the widespread use of ivermectin also results in drug residues. These residues enter the soil and water bodies through animal excrement, disrupting the living environment of normal microorganisms and arthropods, affecting the balance of the ecosystem, and adversely impacting the ecological environment. Therefore, developing new and highly effective drugs for the treatment and control of animal mite diseases is of great significance for protecting human and animal health, reducing economic losses in the livestock industry, promoting the sustainable development of the livestock industry, and maintaining ecological balance.

[0011] Existing data indicates that sulfur-containing compounds have wide applications in pesticides, pharmaceuticals, and synthesis, playing an irreplaceable role in academic research and industrial production. In the pesticide field, many sulfur-containing compounds, with their highly effective bactericidal and insecticidal properties, have become important agents for controlling crop diseases and pests. For example, some thiophosphate compounds can effectively inhibit the cholinesterase activity of pests, thereby achieving an insecticidal effect. In the pharmaceutical field, sulfur-containing compounds are core structural units of many drugs; for instance, the sulfur atoms in penicillin antibiotics play a crucial role in their antibacterial activity. In the synthetic field, sulfur-containing compounds often serve as important intermediates in the construction of various complex organic compounds, providing crucial support for the research and development of new materials.

[0012] However, to date, there are no research reports on the acaricidal activity of tetrahydrothiophene sulfone compounds against rabbit ear mites. Rabbit ear mites are a significant parasite affecting the livestock industry, causing substantial losses to farmers due to the diseases they cause, while existing control drugs have many limitations. Whether tetrahydrothiophene sulfone compounds, as an important branch of sulfur-containing compounds, possess potential acaricidal activity is a topic worthy of further investigation.

[0013] Therefore, based on this, the technical solution of the present invention is proposed. Summary of the Invention

[0014] To address the problems existing in the prior art, the present invention provides a tetrahydrothiophene sulfone derivative, the chemical structural formula of which is shown in Formula I:

[0015]

[0016] Wherein, R is fluorine, chlorine, bromine or trifluoromethyl.

[0017] Based on the same technical concept, another aspect of the present invention is to provide a method for preparing a tetrahydrothiophene sulfone derivative, the method comprising the following steps:

[0018] (1) Mix elemental sulfur and alkaline raw materials, then add the first solvent and stir to obtain the first mixture;

[0019] (2) Add substituted benzaldehyde and acetophenone to the first mixture and stir to react. After the reaction is completed, collect the solid by vacuum filtration to obtain the intermediate.

[0020] (3) The intermediate is added to a second solvent for dissolution, and then a solution of m-chloroperoxybenzoic acid dichloromethane is added for stirring reaction. After completion, the mixture is distilled under reduced pressure, washed, and recrystallized to obtain the tetrahydrothiophene sulfone derivative.

[0021] Its synthesis route is shown in Equation II.

[0022]

[0023] Preferably, in step (1), the alkaline raw material is sodium hydroxide;

[0024] And / or, the first solvent is methanol.

[0025] Sodium hydroxide is moderately alkaline, inexpensive, and readily available; methanol is highly soluble, has a low boiling point, and is easy to remove, enabling the reaction to proceed efficiently, reducing costs, simplifying operations, and facilitating industrial production.

[0026] Preferably, in step (1), the stirring time is 10 to 20 minutes.

[0027] Specifically, limiting the stirring time to 10–20 minutes ensures that elemental sulfur and alkaline raw materials are fully mixed and reacted to generate stable reaction intermediates, thereby improving reaction efficiency and avoiding energy waste and equipment wear caused by excessive stirring.

[0028] Preferably, in step (2), the temperature of the stirring reaction is 20-25°C and the stirring reaction time is 48-72h.

[0029] Specifically, controlling the stirring reaction temperature at 20–25°C and setting the time at 48–72 h are suitable reaction conditions. Within this temperature range, the reaction rate is moderate, ensuring the reaction proceeds fully while minimizing side reactions; a sufficiently long reaction time allows the substituted benzaldehyde and acetophenone to react completely, improving the intermediate yield and purity.

[0030] Preferably, in step (3), the second solvent is dichloromethane;

[0031] And / or, the stirring reaction time is 6 to 8 hours.

[0032] Among them, dichloromethane has good solubility for the intermediate, which allows the intermediate and m-chloroperoxybenzoic acid to fully react; appropriate stirring time ensures complete oxidation reaction, improving product purity and yield.

[0033] Preferably, in step (3), the method of vacuum distillation, washing, and recrystallization is as follows: excess solvent is evaporated under vacuum conditions, the solid obtained is washed with ethanol, and the residue is recrystallized with methanol.

[0034] Among these methods: removing excess solvent under vacuum conditions can lower the distillation temperature and prevent product decomposition; washing with ethanol can remove impurities; and recrystallization with methanol can further purify the product, improve the purity of the tetrahydrothiophene sulfone derivative, and meet the quality requirements of acaricides.

[0035] Based on the same technical concept, another aspect of the present invention is to provide the application of a tetrahydrothiophene sulfone derivative in the preparation of acaricides.

[0036] Based on the same technical concept, another aspect of the present invention is to provide an acaricide comprising the aforementioned tetrahydrothiophene sulfone derivative.

[0037] The beneficial effects of this invention are as follows:

[0038] 1. Highly effective acaricidal activity: In vitro acaricidal activity tests showed that the tetrahydrothiophene sulfone derivatives (samples 1-4) of this invention achieved a 100% mortality rate against rabbit ear mites at a concentration of 0.5 mg / mL, significantly superior to the positive control drug ivermectin (76.7%). Furthermore, the median lethal concentration (LC50) was also high. 50 ) and median lethal time (LT) 50 The test results show that the compound of the present invention has a lower LC50. 50 and LT 50 The value indicates that it has higher acaricidal activity and faster action.

[0039] 2. Structural Diversity and Controllability: This invention synthesizes a variety of tetrahydrothiophene sulfone derivatives by introducing different substituents (fluorine, chlorine, bromine, or trifluoromethyl), and this structural diversity provides more possibilities for optimizing drug activity and selectivity. Experimental data show that different substituents have a certain influence on acaricidal activity, especially the trifluoromethyl-substituted derivative (sample 4) which shows the best effect (LC). 50 38.2 μg / mL, LT 50 (3.4h), providing an important reference for subsequent drug development.

[0040] 3. Simple and efficient preparation method: The preparation method of this invention is simple in steps, with mild reaction conditions (stirring at room temperature), and has a high yield (intermediate yield 80%–92%, final product yield 83%–95%). Solvents and raw materials are readily available, making it suitable for large-scale production and possessing high potential for industrial application.

[0041] 4. Overcoming the limitations of existing drugs: Compared with existing acaricides (such as ivermectin, organophosphates, etc.), the tetrahydrothiophene sulfone derivative of this invention is less prone to drug resistance and has lower toxicity to the environment and animals. Its unique mechanism of action provides a new approach for the development of acaricides and is expected to solve the problems of high drug resistance, high toxicity, and short duration of action of existing drugs.

[0042] 5. Broad Application Prospects: The compounds of this invention can not only be used to treat rabbit ear mite infestation, but can also be extended to the prevention and treatment of mite infestations in other animals (such as rabbits, horses, sheep, and pigs), and may even have potential therapeutic effects on human mite infections. Their high efficiency, safety, and economical characteristics make them promising for applications in animal husbandry and public health.

[0043] In summary, the tetrahydrothiophene sulfone derivative and its preparation method of the present invention have significant advantages in acaricidal activity, structural design, preparation process and application scope, providing a novel drug option that is efficient, safe and economical for the prevention and control of animal mite diseases. Attached Figure Description

[0044] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 It is sample 1. 1 H-NMR spectrum.

[0046] Figure 2 It is sample 1. 13 C-NMR spectrum.

[0047] Figure 3 This is the HRMS (ESI) spectrum of sample 1.

[0048] Figure 4 It is sample 2. 1 H-NMR spectrum.

[0049] Figure 5 It is sample 2. 13 C-NMR spectrum.

[0050] Figure 6 This is the HRMS (ESI) spectrum of sample 2.

[0051] Figure 7 It is sample 3. 1 H-NMR spectrum.

[0052] Figure 8 It is sample 3. 13 C-NMR spectrum.

[0053] Figure 9 This is the HRMS (ESI) spectrum of sample 3.

[0054] Figure 10 It is sample 4. 1 H-NMR spectrum.

[0055] Figure 11 It is sample 4. 13 C-NMR spectrum.

[0056] Figure 12 This is the HRMS (ESI) spectrum of sample 4.

[0057] Figure 13 This is a graph showing the change in mortality rates of rabbit itch mites in samples 1-4 and ivermectin as a function of concentration.

[0058] Figure 14 This is a graph showing the change in the mortality rate of rabbit itch mites in samples 1-4 and ivermectin over time. Detailed Implementation

[0059] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0060] Example 1

[0061] This embodiment provides a method for preparing a tetrahydrothiophene sulfone derivative, the method comprising the following steps:

[0062] (1) Prepare experimental equipment and materials: Prepare round-bottom flasks, stirring devices, thermometers, vacuum filtration devices, rotary evaporators, ultrasonic instruments and other equipment; accurately weigh 30.0 mmol of elemental sulfur, 30.0 mmol of sodium hydroxide, 10.0 mmol of fluorinated substituted benzaldehyde and 10.0 mmol of acetophenone, measure 60 mL of methanol, 100 mL of dichloromethane and 12.0 mmol of m-chloroperoxybenzoic acid to prepare 20 mL of dichloromethane solution, and ethanol and methanol are used for subsequent cleaning and recrystallization.

[0063] (2) Preparation of the first mixture: At room temperature (about 20°C), weighed sulfur and sodium hydroxide were placed in a round-bottom flask, and 60 mL of methanol was slowly added. The stirring device was turned on and stirred for 10 min. Methanol, as a solvent, can fully contact and disperse sulfur and sodium hydroxide. Stirring can accelerate dissolution and mixing to form a uniform first mixture, which is ready for subsequent reactions.

[0064] (3) Intermediate synthesis reaction: 10.0 mmol of fluorinated benzaldehyde and 10.0 mmol of acetophenone were added sequentially to the first mixture, and the mixture was stirred at room temperature for 48 h. During this period, the reaction progress was monitored every 6 h using silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v). This reaction was carried out at room temperature, which reduces additional heating or cooling operations, lowers energy consumption and experimental complexity; regular monitoring of the reaction progress allows for timely determination of whether the reaction is complete, avoids waste of raw materials and side reactions, and ensures the formation of the target intermediate.

[0065] (4) Collection of crude intermediate: After the reaction is completed, the reaction solution is filtered using a vacuum filtration device to collect the solid. Vacuum filtration can quickly separate solids and liquids, improving experimental efficiency. The solid obtained is a crude product containing intermediates.

[0066] (5) Preliminary purification of intermediates: The collected solid was placed in a beaker containing 100 mL of dichloromethane and sonicated for 10 min to fully dissolve the solid. Ultrasound can utilize the energy of ultrasound to accelerate the dissolution of the solid in dichloromethane and improve the dissolution effect; then, it was filtered again under reduced pressure to remove insoluble impurities and the filtrate was collected.

[0067] (6) Further purification of the intermediate: The filtrate was transferred to a rotary evaporator for vacuum distillation to remove the dichloromethane solvent under vacuum conditions, yielding a concentrated residue. Vacuum distillation removes the solvent at a lower temperature, preventing the intermediate from decomposing at high temperatures. The residue was then recrystallized from ethyl acetate to further remove impurities, yielding a high-purity white solid intermediate with a yield of 80–92%.

[0068] (7) Synthesis of the target product: At room temperature (approximately 20°C), 3 mmol of the intermediate was dissolved in 20 mL of dichloromethane and placed in a reaction vessel. Then, 20 mL of a pre-prepared 12.0 mmol solution of m-chloroperoxybenzoic acid in dichloromethane was added dropwise to the above solution, and the mixture was stirred vigorously for 6 hours. During this period, the reaction progress was monitored every hour using silica gel thin-layer chromatography (ethyl acetate:petroleum ether = 1:2, v:v). The dropwise addition of the oxidant controlled the reaction rate and prevented the reaction from becoming too vigorous; stirring and timed monitoring ensured the reaction proceeded fully, generating the target tetrahydrothiophene sulfone derivative.

[0069] (8) Separation and purification of target product: After the reaction, excess solvent is evaporated under vacuum using a rotary evaporator to reduce subsequent impurities; the solid obtained is washed with a small amount of ethanol to remove residual impurities on the surface of the solid; finally, the residue is recrystallized with methanol to further improve the purity of the product and obtain the final product tetrahydrothiophene sulfone compounds with a yield of 83-95%.

[0070] Example 2

[0071] This embodiment provides a method for preparing a tetrahydrothiophene sulfone derivative. The operation of this embodiment is basically the same as that of Example 1, except that some raw materials (such as substituted benzaldehyde) and some operating parameters are different from those of Example 1. The preparation method includes the following steps (briefly described):

[0072] (1) At room temperature (about 25°C), sulfur (30.0 mmol) and sodium hydroxide (30.0 mmol) were placed in a round-bottom flask, and 60 mL of methanol was added and stirred for 20 min to obtain the first mixture.

[0073] (2) Add substituted benzaldehyde (10.0 mmol, substituent is chlorine) and acetophenone (10.0 mmol) to the first mixture above, stir at room temperature for 72 h, and monitor the reaction progress every 6 h using silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v) until the reaction is complete, then filter under reduced pressure and collect the solid.

[0074] The collected solid was placed in a beaker containing 100 mL of dichloromethane and sonicated for 10 min. The mixture was then filtered under reduced pressure, and the liquid was collected. The residue was distilled under reduced pressure, and recrystallized from the residue with ethyl acetate to give a white solid (intermediate) in 80–92% yield.

[0075] (3) The intermediate (3 mmol) obtained from the above reaction was dissolved in 20 mL of dichloromethane at room temperature (approximately 25 °C). A pre-prepared solution of m-chloroperoxybenzoic acid (12.0 mmol) in dichloromethane (20 mL) was added dropwise to the above solution. Vigorous stirring was continued for 6 h, during which the reaction progress was monitored every 1 h using silica gel thin-layer chromatography (ethyl acetate:petroleum ether = 1:2, v:v) until the reaction was complete. Excess solvent was evaporated under vacuum, and the solid was washed with a small amount of ethanol. The residue was recrystallized from methanol to obtain the final product, a tetrahydrothiophene sulfone compound, in yield of 83–95%.

[0076] Example 3

[0077] This embodiment provides a method for preparing a tetrahydrothiophene sulfone derivative. The operation of this embodiment is basically the same as that of Example 1, except that some raw materials (such as substituted benzaldehyde) and some operating parameters are different from those of Example 1. The preparation method includes the following steps (briefly described):

[0078] (1) At room temperature (about 25°C), sulfur (30.0 mmol) and sodium hydroxide (30.0 mmol) were placed in a round-bottom flask, and 60 mL of methanol was added and stirred for 15 min to obtain the first mixture.

[0079] (2) Add substituted benzaldehyde (10.0 mmol, with bromine as the substituent) and acetophenone (10.0 mmol) to the first mixture above, stir at room temperature for 60 h, and monitor the reaction progress every 6 h using silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v) until the reaction is complete, then filter under reduced pressure and collect the solid.

[0080] The collected solid was placed in a beaker containing 100 mL of dichloromethane and sonicated for 10 min. The mixture was then filtered under reduced pressure, and the liquid was collected. The residue was distilled under reduced pressure, and recrystallized from the residue with ethyl acetate to give a white solid (intermediate) in 80–92% yield.

[0081] (3) The intermediate (3 mmol) obtained from the above reaction was dissolved in 20 mL of dichloromethane at room temperature (approximately 25 °C). A pre-prepared solution of m-chloroperoxybenzoic acid (12.0 mmol) in dichloromethane (20 mL) was added dropwise to the above solution. Vigorous stirring was continued for 6 h, during which the reaction progress was monitored every 1 h using silica gel thin-layer chromatography (ethyl acetate:petroleum ether = 1:2, v:v) until the reaction was complete. Excess solvent was evaporated under vacuum, and the solid was washed with a small amount of ethanol. The residue was recrystallized from methanol to obtain the final product, a tetrahydrothiophene sulfone compound, in yield of 83–95%.

[0082] Example 4

[0083] This embodiment provides a method for preparing a tetrahydrothiophene sulfone derivative. The operation of this embodiment is basically the same as that of Example 1, except that some raw materials (such as substituted benzaldehyde) and some operating parameters are different from those of Example 1. The preparation method includes the following steps (briefly described):

[0084] (1) At room temperature (about 20°C), sulfur (30.0 mmol) and sodium hydroxide (30.0 mmol) were placed in a round-bottom flask, and 60 mL of methanol was added and stirred for 12 min to obtain the first mixture.

[0085] (2) Add substituted benzaldehyde (10.0 mmol, substituent is trifluoromethyl) and acetophenone (10.0 mmol) to the first mixture above, stir at room temperature for 60 h, and monitor the reaction progress every 6 h using silica gel thin layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v) until the reaction is complete. Then filter under reduced pressure and collect the solid.

[0086] The collected solid was placed in a beaker containing 100 mL of dichloromethane and sonicated for 10 min. The mixture was then filtered under reduced pressure, and the liquid was collected. The residue was distilled under reduced pressure, and recrystallized from the residue with ethyl acetate to give a white solid (intermediate) in 80–92% yield.

[0087] (3) The intermediate (3 mmol) obtained from the above reaction was dissolved in 20 mL of dichloromethane at room temperature (approximately 20 °C). A pre-prepared solution of m-chloroperoxybenzoic acid (12.0 mmol) in dichloromethane (20 mL) was added dropwise to the above solution. Vigorous stirring was continued for 6 h, during which the reaction progress was monitored every 1 h using silica gel thin-layer chromatography (ethyl acetate:petroleum ether = 1:2, v:v) until the reaction was complete. Excess solvent was evaporated under vacuum, and the solid was washed with a small amount of ethanol. The residue was recrystallized from methanol to obtain the final product, a tetrahydrothiophene sulfone compound, in yield of 83–95%.

[0088] Verification Example

[0089] (I) Structural verification of tetrahydrothiophene sulfone derivatives

[0090] This invention employs nuclear magnetic resonance (NMR) 1 H-NMR, 13 The structure of the synthesized tetrahydrothiophene sulfone derivative compound was identified by C-NMR and high-resolution mass spectrometry (HRMS). The specific structural formula and structural identification of the tetrahydrothiophene sulfone derivative compound are as follows:

[0091] Sample 1 (obtained in Example 1): (3,5-bis(4-fluorophenyl)-1,1-tetrahydrothiophene-2,4-diyl)bis(phenyl ketone), as shown in Formula III.

[0092]

[0093] 1 H NMR (400MHz, DMSO-d6) δ8.10 (d, J=7.4Hz, 2H), 7.82-7.55 (m, 9H), 7.50 (t, J=7.4Hz, 1H), 7.32 (t, J=7.8Hz, 2H), 7.23 (t, J=8.8 Hz, 2H), 7.01 (t, J=8.8Hz, 2H), 6.06 (d, J=11.7Hz, 1H), 5.31 (t, J=11.8Hz, 1H), 4.93 (d, J=12.0Hz, 1H), 4.38 (t, J=11.6Hz, 1H);

[0094] 13 C NMR (100MHz, DMSO-d6) δ197.81, 188.65, 163.19 (d, J=246.9Hz), 161.98 (d, J=244.5H z), 136.26 (d, J=32.1Hz), 135.46, 134.69, 133.09 (d, J=8.6Hz), 133.09 (d, J=8.6Hz), 132.55 (d, J=3.1Hz), 130.97 (d, J=8.2Hz), 129.71, 129.50, 129.12, 128.71, 125.59 (d , J=3.0Hz), 116.14 (d, J=21.5Hz), 115.90 (d, J=21.7Hz), 72.77, 71.87, 50.97, 46.29;

[0095] HR-ESI-MS[M+H] + calcd for C 30 H 23 F2O4S + , 517.1280, found 517.1290.

[0096] Among them, sample 1 1 H-NMR spectrum, 13 The C-NMR spectrum and HRMS (ESI) spectrum are shown below. Figures 1-3 As shown.

[0097] Sample 2 (obtained in Example 2): (3,5-bis(4-chlorophenyl)-1,1-tetrahydrothiophene-2,4-diyl)bis(phenyl ketone), as shown in Formula IV.

[0098]

[0099] 1 H NMR (400MHz, DMSO-d6) δ 8.11-8.08 (m, 2H), 7.78-7.70 (m, 5H), 7.65-7.59 (m, 4H), 7.53-7.45 (m, 3H), 7.33 (t, J=7.8Hz, 2 H), 7.25 (d, J=8.5Hz, 2H), 6.07 (d, J=1.7Hz, 1H), 5.33 (t, J=11.8Hz, 1H), 4.94 (d, J=12.0Hz, 1H), 4.38 (t, J=11.6Hz, 1H);

[0100] 13 C NMR (100MHz, DMSO-d6) δ197.61, 188.54, 136.34, 136.04, 135.50, 135.34, 134.90, 134.78, 133.0 6, 132.71, 130.83, 129.71, 129.53, 129.18, 129.06, 128.75, 128.41, 72.78, 71.83, 50.64, 46.33;

[0101] HR-ESI-MS[M+H] + calcd for C 30 H 23 Cl2O4S + , 549.0689, found 549.0693.

[0102] Among them, sample 2 1 H-NMR spectrum, 13 The C-NMR spectrum and HRMS (ESI) spectrum are as follows: Figures 4-6 As shown.

[0103] Sample 3 (obtained in Example 3): (3,5-bis(4-bromophenyl)-1,1-tetrahydrothiophene-2,4-diyl)bis(phenyl ketone), as shown in Formula V.

[0104]

[0105]

[0106] 1 H NMR (400MHz, DMSO-d6) δ8.10-8.08(m, 2H), 7.78-7.58(m, 9H), 7.57-7.49(m, 3H), 7.55-7.50(m, 4H ), 6.07 (d, J=11.8Hz, 1H), 5.33 (t, J=11.8Hz, 1H), 4.92 (d, J=12.0Hz, 1H), 4.37 (t, J=11.6Hz, 1H);

[0107] 13 C NMR (100MHz, DMSO-d6) δ197.59, 188.53, 136.32, 136.03, 135.75, 135.50, 134.80, 132.97, 132.12, 13 1.98, 131.15, 129.71, 129.53, 129.19, 128.80, 128.76, 123.66, 121.67, 72.87, 71.78, 50.49, 46.39;

[0108] HR-ESI-MS[M+H] + calcd for C 30 H 23 Br2O4S + , 638.9658, found 638.9657.

[0109] Among them, sample 3 1 H-NMR spectrum, 13 The C-NMR spectrum and HRMS (ESI) spectrum are as follows: Figures 7-9 As shown.

[0110] Sample 4 (obtained in Example 4): (1,1-dioxide-3,5-bis(4-(trifluoromethyl)phenyl)tetrahydrothiophene-2,4-diyl)bis(phenyl ketone), as shown in Formula VI.

[0111]

[0112] 1H NMR (400MHz, DMSO-d6) δ8.11 (d, J=7.4Hz, 2H), 7.98 (d, J=8.2Hz, 2H), 7.80 (dd, J=19.9, 8.4Hz, 5H), 7.71-7.60 (m, 4H), 7.56 (d, J=8.2Hz, 2H), 7.47 (t, J=7.4Hz, 1H), 7.28 (t, J=7.8Hz, 2H), 6.23 (d, J=11.7Hz, 1H), 5.44 (t, J=11.8Hz, 1H), 5.12 (d, J=11.9Hz, 1H), 4.50 (t, J=11.6Hz, 1H);

[0113] 13 C NMR (100MHz, DMSO-d6) δ197.28, 188.43, 141.04, 136.29, 135.94, 135.56, 134.69, 134.20, 131.84, 130.28 (q, J=32.1Hz), 130.12, 129.69, 129 .61, 128.96 (q, J=31.9Hz), 129.06, 128.72, 125.94 (q, J=3.4Hz), 124.36 (d, J=272.4Hz), 124.33 (d, J=272.2Hz), 72.54, 71.84, 50.73, 46.63;

[0114] HR-ESI-MS[M+H] + calcd for C 32 H 23 F6O4S + , 617.1216, found 617.1207.

[0115] Among them, sample 4 1 H-NMR spectrum, 13 The C-NMR spectrum and HRMS (ESI) spectrum are shown below. Figures 10-12 As shown.

[0116] (II) Pharmacological Effects Experiments

[0117] Experimental materials:

[0118] This invention employs an in vitro acaricidal activity test method to conduct in vitro pharmacological studies on the above-mentioned compounds (samples 1-4). In the acaricidal activity test, the lethality rate of the test drug against mites was used as an indicator, and ivermectin, a commonly used commercially available acaricidal drug, was used as a positive control. The acaricidal activity of the above-mentioned compounds was analyzed, demonstrating that the tetrahydrothiazide compounds involved in this invention are an effective class of drugs that can be used to treat animal mite infestations.

[0119] Taking the acaricidal activity sample against rabbit ear mites as an example, the specific operation is as follows:

[0120] (1) Determination of drug concentration

[0121] Accurately weigh 5.0 mg of the test compound, dissolve it in 1.0 mL of DMSO, add 1.0 mL of Tween-80, and dilute with deionized water to 10.0 mL. The sample concentration is then 0.5 mg / mL. Dilute the stock solution with 10% DMSO aqueous solution to different concentrations: 0.4, 0.3, 0.25, 0.2, 0.15, 0.12, 0.1, 0.08, 0.06, 0.05, 0.04, and 0.03 mg / mL. Prepare a test solution of the same concentration using the same method as a positive control, and use a blank solution without the test compound as a blank control.

[0122] (2) Reagents

[0123] Ivermectin (Sigma, Ivermectin, ≥91%, 22,23-dihydroavermectin B1, composed of 95% avermectin B1a and 5% avermectin B1b).

[0124] (3) Test methods

[0125] The rabbit ear mites used in the test were isolated from scabs within the ear canals of naturally infected rabbits. The prepared test solution was placed in 24-well plates, 0.6 mL per well, with six parallel controls for each test drug. Under a microscope, healthy adult rabbit ear mites were picked up using an insect separation needle and immersed in the test solution in a 24-well plate, 10 mites per well. Simultaneously, a blank control group (6 wells with 0.6 mL of 10% DMSO solution) and a positive control group for ivermectin were set up.

[0126] The 24-well plate was placed in an incubator with 80% humidity and 28°C for 24 hours. The mites were stimulated with an inoculation needle; mites that did not respond were considered dead. The number of mite deaths in each parallel run was counted, and the mortality rate was calculated.

[0127] Experimental results: The mortality rate of the tested compound against rabbit ear mites at a concentration of 0.5 mg / mL is shown in Table 1.

[0128] Table 1. Killing effect of the sample on *Tetranychus rubrum* at a concentration of 0.5 mg / mL.

[0129] Sample number Total number of cases Death count mortality rate Sample 1 60 60 100.0％ Sample 2 60 60 100.0％ Sample 3 60 60 100.0％ Sample 4 60 60 100.0％ Ivermectin 60 46 76.7％ Blank group 60 0 0.00％

[0130] Figure 13 and Figure 14 The images show the kill efficacy curves of samples 1-4 and ivermectin at different experimental concentrations and durations against rabbit ear mites.

[0131] Tables 2 and 3 present the acaricidal virulence equations and median lethal concentrations (LC50) of samples 1–4. 50 ) and median lethal time (LT) 50 ).

[0132] Table 2. Concentration-Effect Median Lethal Concentration (LC50) of Test Compounds and Ivermectin 50 (24h) and toxicity equation

[0133]

[0134] Note: y is the probability value of the average mortality rate; x is the logarithmic value of the mass concentration lg[C(μg / mL)].

[0135] Table 3. Time-effect LD50 (LT) of the tested compounds and ivermectin. 50 (4.5 μmol / mL) and toxicity equation

[0136]

[0137] Note: y is the probability value of the average mortality rate; x is the logarithmic value of the treatment time lg[T(h)].

[0138] The results showed that, compared with ivermectin (positive control), a commonly used acaricide in clinical practice, the tested compounds (samples 1–4) exhibited lower LC values. 50 and LT 50 The acaricidal activity of the tetrahydrothiophene sulfone derivative involved in this invention is significantly superior to that of ivermectin, indicating that the tetrahydrothiophene sulfone derivative has the potential use as an acaricidal agent.

[0139] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A tetrahydrothiophene sulfone derivative, characterized in that, The chemical structural formula of the tetrahydrothiophene sulfone derivative is shown in Formula I: Wherein, R is fluorine, chlorine, bromine or trifluoromethyl.

2. The method for preparing the tetrahydrothiophene sulfone derivative according to claim 1, characterized in that, The preparation method includes the following steps: (1) Mix elemental sulfur and alkaline raw materials, then add the first solvent and stir to obtain the first mixture; (2) Add substituted benzaldehyde and acetophenone to the first mixture and stir to react. After the reaction is completed, collect the solid by vacuum filtration to obtain the intermediate. (3) The intermediate is added to a second solvent for dissolution, and then a solution of m-chloroperoxybenzoic acid dichloromethane is added for stirring reaction. After completion, the mixture is distilled under reduced pressure, washed, and recrystallized to obtain the tetrahydrothiophene sulfone derivative.

3. The method for preparing the tetrahydrothiophene sulfone derivative according to claim 2, characterized in that, In step (1), the alkaline raw material is sodium hydroxide; And / or, the first solvent is methanol.

4. The method for preparing the tetrahydrothiophene sulfone derivative according to claim 2, characterized in that, In step (1), the stirring time is 10 to 20 minutes.

5. The method for preparing the tetrahydrothiophene sulfone derivative according to claim 2, characterized in that, In step (2), the temperature of the stirring reaction is 20-25°C and the stirring reaction time is 48-72h.

6. The method for preparing the tetrahydrothiophene sulfone derivative according to claim 2, characterized in that, In step (3), the second solvent is dichloromethane; And / or, the stirring reaction time is 6 to 8 hours.

7. The method for preparing the tetrahydrothiophene sulfone derivative according to claim 2, characterized in that, In step (3), the vacuum distillation, washing, and recrystallization are carried out as follows: excess solvent is evaporated under vacuum conditions, the solid obtained is washed with ethanol, and the residue is recrystallized with methanol.

8. The use of the tetrahydrothiophene sulfone derivative of claim 1 in the preparation of acaricides.

9. An acaricide, characterized in that, It includes the tetrahydrothiophene sulfone derivative as described in claim 1.

Images