Tetrahydrothiapyran compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a tetrahydrothiapyran compound as well as a preparation method and application thereof. The chemical structural formula of the tetrahydrothiapyran compound is shown as a formula I. According to the invention, not only is a series of tetrahydrothiapyran compounds designed, but also a synthesis method is established, and structural identification is completed. In-vitro activity tests prove that the tetrahydrothiapyran compound has extremely high killing activity on pruritus inarus and is a mite killing drug with potential application value, and theoretical and technical data are provided for application and development of the compound. The acaricidal activity of the tetrahydrothiapyran compound disclosed by the invention is obviously higher than that of currently common clinically applied acaricidal drugs, and the tetrahydrothiapyran compound has the advantages of short synthesis route, mild conditions, low raw material price, simple post-treatment and the like, and is suitable for industrial large-scale production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a tetrahydropyran compound, a preparation method thereof, and an application thereof. Background Art

[0002] Animal acariasis is a kind of skin disease caused by mites on the epidermis of animals. Otodectes cynotis is one of the animal mites, mainly parasitizing in the ear canals of animals. It has a wide range of hosts and can infect animals such as rabbits, horses, sheep, pigs, mice, etc., and even humans. Animal acariasis poses a major threat to the health of humans and animals. Animals infected with this mite will show symptoms such as intense itching, inflammation, hair loss, serous exudation, loss of appetite, etc., and in severe cases, it can lead to the death of animals. In addition, sarcoptic mange is highly contagious. At present, sarcoptic mange has become a global disease, causing serious economic losses to the animal husbandry industry and becoming one of the important disease factors restricting the development of the breeding industry.

[0003] At present, animal acariasis needs to be treated and controlled with drugs and chemicals, such as: drugs like organochlorines, organophosphates, pyrethrins, ivermectin, and avermectin. Among them, avermectin is a new type of macrolide drug developed in the 1980s. Ivermectin, as a second-generation product of avermectin, has a strong killing effect on parasites in or outside the animal body and is one of the representative acaricidal drugs. However, with the continuous and extensive use of the above drugs, problems such as the generation of drug resistance and environmental pollution have occurred. Due to the generation of drug resistance and the defects of the drugs themselves, ivermectin drugs often lead to treatment failure or recurrence of the disease. The widespread use of ivermectin will cause drug residues, damage the living environment of normal microorganisms and arthropods, and have an adverse impact on the ecological environment. Therefore, it is of great significance to develop new and highly efficient drugs for the treatment and control of animal acariasis.

[0004] Therefore, based on this, the technical solution of the present invention is proposed. Summary of the Invention

[0005] In order to solve the problems existing in the prior art, the present invention provides a tetrahydropyran compound, and its chemical structural formula is shown as Formula I:

[0006]

[0007] Wherein, R is fluorine, chlorine or bromine.

[0008] Based on the same technical concept, another solution of the present invention is to provide a preparation method of a tetrahydropyran compound, and the preparation method includes the following steps:

[0009] (1) Dissolve substituted benzaldehyde and acetophenone in methanol, and then add Na 2 S·9H2 Stir and react until the reaction solution is obtained after completion.

[0010] (2) Add dichloromethane to the reaction solution and stir, then wash with deionized water and collect to obtain the organic phase.

[0011] (3) Wash the organic phase with saturated brine, then dry, filter by suction in sequence, remove the solvent under reduced pressure, chromatograph, and elute to obtain the intermediate.

[0012] (4) Dissolve the intermediate in dichloromethane and stir. After sufficient stirring, add a dichloromethane solution of 3-chloroperoxybenzoic acid dropwise to obtain a mixed solution.

[0013] (5) Stir the mixed solution until the reaction is complete, then remove the organic layer, purify, and elute in sequence to obtain the tetrahydropyran compound.

[0014] For easy understanding of the present invention, the synthesis route of the tetrahydropyran compound is shown in Formula II:

[0015]

[0016] Preferably, in step (1), the substituted benzaldehyde is fluorine-substituted benzaldehyde, chlorine-substituted benzaldehyde, or bromine-substituted benzaldehyde.

[0017] And / or, in step (1), the temperature of the stirring reaction is room temperature, and the time of the stirring reaction is 12 - 24 h.

[0018] Preferably, in step (2), the time of the stirring is 5 - 10 min.

[0019] And / or, in step (2), the number of washings is 3 - 4 times.

[0020] Preferably, in step (3), the drying is carried out using anhydrous sodium sulfate for drying.

[0021] And / or, in step (3), the elution is carried out using ethyl acetate - petroleum ether for elution.

[0022] Preferably, in step (4), the temperature of the stirring is 0 °C, and the time of the stirring is 5 - 10 min.

[0023] And / or, in step (4), the time of the dropwise addition is 8 - 10 min.

[0024] Preferably, in step (5), the temperature of the reaction is 0 °C, and the time of the reaction is 2 - 5 h.

[0025] And / or, in step (5), the elution is carried out using ethyl acetate - petroleum ether for elution.

[0026] Based on the same inventive concept, another solution of the present invention is to provide an application of tetrahydropyran compounds in the preparation of acaricidal drugs.

[0027] Based on the same inventive concept, another solution of the present invention is to provide an acaricidal drug comprising the tetrahydropyran compounds described above.

[0028] The beneficial effects of the present invention are as follows:

[0029] The present invention not only designs a series of tetrahydropyran compounds, but also establishes a synthesis method and completes the structure identification. Through in vitro activity tests, it is proved that the tetrahydropyran compounds have extremely strong killing activity against Psoroptes cuniculi, and are a class of acaricidal drugs with potential application value, providing theoretical and technical materials for the application development of such compounds.

[0030] The acaricidal activity of the tetrahydropyran compounds of the present invention is significantly stronger than that of the commonly used clinically applied acaricidal drugs at present, and has the advantages of short synthesis route, mild conditions, low raw material price, simple post-treatment, etc., and is suitable for large-scale industrial production. Description of the Drawings

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0032] Figure 1 is the 1 1H-NMR spectrum of Sample 1.

[0033] Figure 2 is the 13 13C-NMR spectrum of Sample 1.

[0034] Figure 3 is the HRMS(ESI) spectrum of Sample 1.

[0035] Figure 4 is the 1 1H-NMR spectrum of Sample 2.

[0036] Figure 5 is the 13 13C-NMR spectrum of Sample 2.

[0037] Figure 6 is the HRMS(ESI) spectrum of Sample 2.

[0038] Figure 7 is the 1H-NMR spectrum.

[0039] Figure 8 It is of Sample 3 13 C-NMR spectrum.

[0040] Figure 9 It is the HRMS(ESI) spectrum of Sample 3.

[0041] Figure 10 It is the curve graph showing the change of the mortality rate of rabbit ear mites of Samples 1 - 3 and ivermectin with concentration.

[0042] Figure 11 It is the curve graph showing the change of the mortality rate of rabbit ear mites of Samples 1 - 3 and ivermectin with time. Detailed implementation mode

[0043] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be described in detail below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other implementation manners obtained by those of ordinary skill in the art based on the embodiments in the present invention without creative efforts fall within the scope protected by the present invention.

[0044] Example 1

[0045] This example provides a preparation method of a tetrahydropyran compound, and the preparation method includes the following steps:

[0046] (1) At room temperature, dissolve fluorine-substituted benzaldehyde (5.5 mmol) and acetophenone (5 mmol) in 30 mL of methanol, stir well for 5 min, and then add Na 2 S·9H 2 O (5.0 mmol) and stir at room temperature for 12 h. During this period, detect the reaction by silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:5, v:v) every 2 h until the reaction is complete to obtain a reaction solution.

[0047] (2) Add 20 mL of dichloromethane to the reaction solution and stir for 5 min, then wash it 3 times with 20 mL of deionized water, and collect the organic phase;

[0048] (3) Wash the organic phase with 20 mL of saturated brine, then add anhydrous sodium sulfate for drying, filter by suction, remove the solvent under reduced pressure, and subject the residue to silica gel column chromatography (diameter 60 mm), and elute with ethyl acetate - petroleum ether (1:5, v:v) to obtain a white solid intermediate (the statistical yield is 72 - 87%);

[0049] (4) Dissolve the intermediate (2 mmol) in 10 mL of dichloromethane, stir well at 0 °C for 5 min, and then dropwise add (dropwise addition time: 8 min) the prepared mixed solution of 3-chloroperoxybenzoic acid (5.0 mmol) and dichloromethane solution (10 mL) to obtain a mixed solution.

[0050] (5) Stir the mixed solution vigorously at 0 °C for another 2 h. During this period, detect the reaction by silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v) every 0.5 h until the reaction is complete. Then evaporate the organic layer under vacuum conditions, and purify the residue by silica gel column chromatography, eluting with ethyl acetate - petroleum ether (1:2, v:v) to obtain the tetrahydropyran compound (the statistical yield is 65 - 81%).

[0051] Example 2

[0052] This example provides a method for preparing a tetrahydropyran compound, and the preparation method includes the following steps:

[0053] (1) At room temperature, dissolve chlorosubstituted benzaldehyde (5.5 mmol) and acetophenone (5 mmol) in 30 mL of methanol, stir well for 5 min, and then add Na 2 S·9H 2 O (5.0 mmol) and stir at room temperature for 24 h. During this period, detect the reaction by silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:5, v:v) every 2 h until the reaction is complete to obtain a reaction solution.

[0054] (2) Add 20 mL of dichloromethane to the reaction solution and stir for 10 min, then wash it 4 times with 20 mL of deionized water, and collect the organic phase.

[0055] (3) Wash the organic phase with 20 mL of saturated brine, add anhydrous sodium sulfate for drying, filter by suction, remove the solvent under reduced pressure, and perform silica gel column chromatography (diameter 60 mm) on the residue, eluting with ethyl acetate - petroleum ether (1:5, v:v) to obtain a white solid intermediate (the statistical yield is 72 - 87%).

[0056] (4) Dissolve the intermediate (2 mmol) in 10 mL of dichloromethane, stir well at 0 °C for 10 min, and then dropwise add (dropwise addition time: 10 min) the prepared mixed solution of 3-chloroperoxybenzoic acid (5.0 mmol) and dichloromethane solution (10 mL) to obtain a mixed solution.

[0057] (5) Stir the mixture vigorously at 0 °C for an additional 5 h, and monitor the reaction by silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v) every 0.5 h until the reaction is complete. Then, evaporate the organic layer under vacuum, and purify the residue by silica gel column chromatography, eluting with ethyl acetate - petroleum ether (1:2, v:v) to obtain the tetrahydropyran compound (the statistical yield is 65 - 81%).

[0058] Example 3

[0059] This example provides a method for preparing a tetrahydropyran compound, and the preparation method includes the following steps:

[0060] (1) At room temperature, dissolve bromo-substituted benzaldehyde (5.5 mmol) and acetophenone (5 mmol) in 30 mL of methanol, stir well for 5 min, and then add Na 2 S·9H 2 O (5.0 mmol) and stir at room temperature for 18 h. Monitor the reaction by silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:5, v:v) every 2 h until the reaction is complete to obtain the reaction solution.

[0061] (2) Add 20 mL of dichloromethane to the reaction solution and stir for 8 min, then wash 4 times with 20 mL of deionized water, and collect the organic phase;

[0062] (3) Wash the organic phase with 20 mL of saturated brine, add anhydrous sodium sulfate for drying, filter by suction, remove the solvent under reduced pressure, and subject the residue to silica gel column chromatography (diameter 60 mm), eluting with ethyl acetate - petroleum ether (1:5, v:v) to obtain a white solid intermediate (the statistical yield is 72 - 87%);

[0063] (4) Dissolve the intermediate (2 mmol) in 10 mL of dichloromethane, stir well at 0 °C for 8 min, and then dropwise add (the dropping time is 9 min) a mixed solution of 3-chloroperoxybenzoic acid (5.0 mmol) and dichloromethane solution (10 mL) prepared in advance to obtain a mixture;

[0064] (5) Stir the mixture vigorously at 0 °C for an additional 3 h, and monitor the reaction by silica gel thin-layer chromatography (ethyl acetate: petroleum ether = 1:2, v:v) every 0.5 h until the reaction is complete. Then, evaporate the organic layer under vacuum, and purify the residue by silica gel column chromatography, eluting with ethyl acetate - petroleum ether (1:2, v:v) to obtain the tetrahydropyran compound (the statistical yield is 65 - 81%).

[0065] Detection Example

[0066] (I) Compound Structure Identification

[0067] The present invention uses nuclear magnetic resonance ( 1 1H-NMR, 13 13C-NMR) and high-resolution mass spectrometry (HRMS) to identify the structure of the synthesized tetrahydropyran compounds. The following are the specific structural formulas and structure identifications of the tetrahydropyran compounds obtained in Examples 1 to 3:

[0068] (i) The compound obtained in Example 1 is named "Sample 1", and its name is: (2,6-bis(4-fluorophenyl)-4-hydroxy-1,1-dioxido-4-phenyltetrahydro-2H-thiopyran-3-yl)(phenyl)methanone, and its structural formula is as shown in Formula III:

[0069]

[0070] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.65–7.53 (m, 6H), 7.44 (d, J = 7.7 Hz, 2H), 7.31–7.26 (m, 3H), 7.13–7.03 (m, 6H), 6.92 (t, J = 7.1 Hz, 1H), 5.95 (s, 1H), 5.35 (d, J = 11.7 Hz, 1H), 5.13 (d, J = 11.8 Hz, 2H), 3.57 (t, J = 13.6 Hz, 1H), 2.26–2.14 (m, 1H);

[0071] 13 13C NMR (100 MHz, DMSO-d 6 ) δ 197.26, 163.01 (d, J = 245.5 Hz), 162.73 (d, J = 245.8 Hz), 144.51, 137.74, 132.96, 132.87, 128.42, 128.25, 128.21, 127.59, 126.85 (d, J = 2.9 Hz), 125.87, 125.66 (d, J = 2.7 Hz), 115.89 (d, J = 21.4 Hz), 115.56 (d, J = 21.6 Hz), 74.02, 64.27, 60.87, 55.56, 43.81;

[0072] HR-ESI-MS [M+H] + calcd for C 30 H 25 F 2 O 4 S + , 519.1436, found 519.1410.

[0073] Among them, the nuclear magnetic resonance ( 1 ¹H-NMR, 13 ¹³C-NMR) and high-resolution mass spectrometry (HRMS) spectra of Sample 1 are shown in Figures 1 to 3 Figure

[0074] (ii) The compound obtained in Example 2 is named "Sample 2", and its name is: (2,6-bis(4-chlorophenyl)-4-hydroxy-1,1-dioxido-4-phenyltetrahydro-2H-thiopyran-3-yl)(phenyl)methanone, and its structural formula is shown in Formula IV:

[0075]

[0076] 1 ¹H NMR (400 MHz, DMSO-d 6 ) δ 7.63–7.52 (m, 8H), 7.45 (d, J = 7.6 Hz, 2H), 7.32–7.28 (m, 3H), 7.13–7.03 (m, 4H), 6.93 (t, J = 7.3 Hz, 1H), 5.99 (s, 1H), 5.38 (d, J = 11.7 Hz, 1H), 5.22–5.06 (m, 2H), 3.59 (t, J = 13.7 Hz, 1H), 2.22 (dd, J = 14.5, 2.9 Hz, 1H);

[0077] 13 ¹³C NMR (100 MHz, DMSO-d 6 ) δ 197.10, 144.42, 137.72, 134.42, 134.22, 132.97, 132.63, 129.55, 129.01, 128.68, 128.44, 128.23, 127.62, 125.89, 73.99, 64.47, 61.05, 55.52, 43.58;

[0078] HR-ESI-MS [M+H] + calcd for C 30 H 25 Cl 2 O 4 S + , 551.0845, found 551.0847.

[0079] Among them, the nuclear magnetic resonance ( 1 ¹H-NMR, 13 ¹³C-NMR) and high-resolution mass spectrometry (HRMS) spectra of Sample 2 are shown in Figures 4 to 6 Figure

[0080] (iii) The compound obtained in Example 3 is named "Sample 3", and its name is: (2,6-bis(4-bromophenyl)-4-hydroxy-1,1-dioxido-4-phenyltetrahydro-2H-thiopyran-3-yl)(phenyl)methanone, and its structural formula is as shown in Formula V:

[0081]

[0082] 1 H NMR (400 MHz, Chloroform-d) δ 7.53–7.50 (m, 2H), 7.45–7.38 (m, 7H), 7.36–7.28 (m, 6H), 7.15–7.13 (m, 3H), 5.32 (d, J = 2.7 Hz, 1H), 5.14 (d, J = 11.8 Hz, 1H), 5.08–5.02 (m, 2H), 3.28–3.21 (m, 1H), 2.39 (dd, J = 14.6, 3.0 Hz, 1H);

[0083] 13 C NMR (100 MHz, CDCl 3 ) δ 201.4, 142.6, 135.2, 131.8, 131.7, 130.7, 130.1, 129.8, 129.7, 129.6, 129.4, 129.2, 128.8, 128.7, 127.1, 126.4, 122.1, 74.6, 65.2, 62.2, 54.3, 44.0;

[0084] HR-ESI-MS [M+H] + calcd for C 30 H 25 Br 2 O 4 S + , 640.9814, found 640.9822.

[0085] Among them, the nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR) and high-resolution mass spectrometry (HRMS) spectra of Sample 3 are shown in Figures 7 to 9 respectively.

[0086] (II) Pharmacological effect experiments

[0087] Using the in vitro acaricidal activity test method, in vitro pharmacological studies were conducted on the above compounds (Samples 1 - 3). In the acaricidal activity test, the lethality rate of the drug against mites was used as an index, and compared with ivermectin, a highly effective acaricidal drug commonly used in clinical practice. The acaricidal activity of each test compound was analyzed, demonstrating that the tetrahydrothiophene compounds described in the present invention are effective drugs for treating animal acariasis.

[0088] Taking the acaricidal activity test sample of rabbit ear mites as an example, the specific operation is as follows:

[0089] (1) Determination of drug solution concentration

[0090] Weigh 5 mg of the sample to be tested with a ten-thousandth balance, dissolve it with 1.0 mL of DMSO, and then dilute it to 10.0 mL with deionized water to prepare a stock solution, so the sample concentration is 0.5 mg / mL. Then, according to the required concentration for the test, dilute the stock solution to 0.4, 0.3, 0.25, 0.2, 0.15, 0.12, 0.1, 0.08, 0.06, 0.05, 0.04, 0.03 mg / mL, etc. with 10% DMSO aqueous solution. The ivermectin solution treated in the same way is used as a positive control, and the blank solution without the test drug solution is used as a blank control.

[0091] (2) Reagents

[0092] Ivermectin (Sigma, Ivermectin, ≥91%, 22,23-dihydroavermectin B 1 , composed of 95% avermectin B 1a and 5% avermectin B 1b ).

[0093] (3) Test method

[0094] Rabbit ear mites were isolated from the scabs in the ear canals of naturally infected rabbits. Under a microscope, healthy adult rabbit ear mites were picked with an insect isolation needle. Add 0.6 mL of the test solution to each well of a 24-well plate, and set 6 parallel controls for each test drug. Immerse the picked rabbit ear mites into the test drug solution in the 24-well plate, with 10 mites placed in each well. At the same time, set a blank control group (add 0.6 mL of 10% DMSO solution to 6 wells) and a positive drug control group of ivermectin.

[0095] Place the above 24-well plate in an incubator with a humidity of 80% and a temperature of 28 °C for 24 hours. Stimulate the mites with an inoculation needle, and the mites without response are regarded as dead. Count the number of dead mites in each parallel group and calculate the mortality rate.

[0096] Test results: The mortality rate of the test compounds against rabbit ear mites at a concentration of 0.5 mg / mL is shown in Table 1.

[0097] Table 1 Mortality results of the samples against *Psoroptes cuniculi* at a concentration of 0.5 mg / mL

[0098]

[0099]

[0100] Figure 10 and Figure 11 are the killing activity curves of the samples and ivermectin at different experimental concentrations and different test times against *Psoroptes cuniculi* respectively.

[0101] Tables 2 and 3 are about the acaricidal toxicity equations of the samples and ivermectin and their median lethal concentration (LC 50 ) and median lethal time (LT 50 ).

[0102] Table 2 Median lethal concentration (LC 50 , 24 h) and toxicity equation of the test compounds and ivermectin for concentration-effect

[0103]

[0104] Note: y is the probit value of the average mortality rate; x is the logarithm of the mass concentration lg[C (μg / mL)].

[0105] Table 3 Median lethal time (LT 50 , 4.5 μmol / mL) and toxicity equation of the test compounds and ivermectin for time-effect

[0106]

[0107]

[0108] Note: y is the probit value of the average mortality rate; x is the logarithm of the treatment time lg[T (h)].

[0109] The results show that compared with ivermectin (positive control), a commonly used clinical acaricidal drug, the test compounds (Sample 1 - Sample 3) showed lower LC 50 and LT 50 values, and their acaricidal activity was significantly better than that of ivermectin, indicating that the tetrahydropyran compounds involved in the present invention have potential uses as acaricidal drugs.

[0110] The above is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should be covered by the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claimed rights.

Claims

1. A tetrahydrothiopyran compound, characterized in that The chemical structure is shown in Formula I: Wherein, R is fluorine, chlorine or bromine.

2. The method for preparing tetrahydrothiopyran compounds according to claim 1, characterized in that: The preparation method comprises the following steps: (1) dissolving substituted benzaldehyde and acetophenone in methanol, adding Na2S·9H2O and stirring to react, and obtaining a reaction solution after completion; (2) adding dichloromethane to the reaction solution and stirring, then washing with deionized water and collecting to obtain an organic phase; (3) washing the organic phase with saturated brine, then drying, filtering, removing the solvent under reduced pressure, chromatography, and eluting to obtain an intermediate; (4) dissolving the intermediate in dichloromethane and stirring, and after sufficient stirring, adding dropwise a dichloromethane solution of 3-chloroperbenzoic acid to obtain a mixed solution; (5) Stirring the mixed solution until the reaction is complete, and then removing the organic layer, purifying, and eluting in sequence to obtain the tetrahydrothiopyran compound.

3. The method for preparing tetrahydrothiopyran compounds according to claim 2, characterized in that: In step (1), the substituted benzaldehyde is fluorine-substituted benzaldehyde, chlorine-substituted benzaldehyde or bromine-substituted benzaldehyde; And / or, in step (1), the stirring reaction temperature is room temperature, and the stirring reaction time is 12 to 24 hours.

4. The method for preparing tetrahydrothiopyran compounds according to claim 2, characterized in that: In step (2), the stirring time is 5 to 10 minutes; And / or, in step (2), the washing is performed 3 to 4 times.

5. The method for preparing tetrahydrothiopyran compounds according to claim 2, characterized in that: In step (3), the drying is performed using anhydrous sodium sulfate; And / or, in step (3), the elution is carried out using ethyl acetate-petroleum ether.

6. The method for preparing tetrahydrothiopyran compounds according to claim 2, characterized in that: In step (4), the stirring temperature is 0°C and the stirring time is 5 to 10 minutes; And / or, in step (4), the dropping time is 8 to 10 minutes.

7. The method for preparing tetrahydrothiopyran compounds according to claim 2, characterized in that: In step (5), the reaction temperature is 0°C and the reaction time is 2 to 5 hours; And / or, in step (5), the elution is carried out using ethyl acetate-petroleum ether.

8. Use of the tetrahydrothiopyran compound according to claim 1 in the preparation of acaricides.

9. A mite-killing drug, characterized in that: Contains the tetrahydrothiopyran compound according to claim 1.

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