8, 8-difluoro-2-oxaspiro [4, 5] decane-1, 3-diketone compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of spiro compounds, in particular to an 8, 8-difluoro-2-oxaspiro [4, 5] decane-1, 3-diketone compound as well as a preparation method and application thereof. The invention provides the 8, 8-difluoro-2-oxaspiro [4, 5] decane-1, 3-diketone compound, the compound shows excellent biological activity, and through test comparison, when the mass concentration is 0.1 mu g / mL, the insecticidal effect of the compound is increased by nearly 10% compared with that of a common insecticide chlorantraniliprole. It means that the compound shows a more efficient insecticidal effect on lepidoptera pests such as plutella xylostella and the like under a lower dosage, and cost reduction and synergism are realized. Due to the characteristic, the compound or the agronomically acceptable salt thereof shows important potential application value in the field of insecticides, and a new thought is provided for upgrading and updating of insecticides in the future.

Description

Technical Field

[0001] The present invention belongs to the technical field of spiro compounds and more specifically relates to an 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound and a preparation method and application thereof. Background Art

[0002] Agricultural pest control, a critical line of defense for ensuring food security and sustainable agricultural development, is facing unprecedented challenges. In recent years, pest damage has significantly intensified due to multiple factors, including global climate change, adjustments in crop planting structures, and the increasing sophistication of pest biology. According to authoritative agricultural statistics, the proportion of crop yield losses caused by pests has climbed annually, resulting in significant economic losses and a serious threat to global food security and farmers' livelihoods.

[0003] Among numerous agricultural pests, Lepidoptera pests such as the leaf roller, cotton bollworm, and diamondback moth pose a major threat to agricultural production due to their widespread distribution, rapid reproduction, and severe damage. These pests not only directly deplete crops, leading to reduced yields and quality, but can also spread viruses and trigger secondary disasters, dealing a double blow to agricultural production.

[0004] While chemical control remains the primary means of agricultural pest control, some pests have gradually developed resistance to existing insecticides (such as chlorantraniliprole), resulting in reduced efficacy and making it difficult to meet the needs of modern agriculture. Faced with this dilemma, the agricultural science and technology community is actively seeking breakthroughs and developing new, highly effective insecticides to alleviate the challenges posed by resistance to existing insecticides. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of existing insecticides, such as poor insecticidal effects, and to provide an 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or an agronomically acceptable salt thereof.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or an agriculturally acceptable salt thereof.

[0007] Another object of the present invention is to provide the use of the above-mentioned 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or an agriculturally acceptable salt thereof in the preparation of pesticides.

[0008] The above-mentioned purpose of the present invention is achieved through the following technical solutions: The present invention protects an 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or an agriculturally acceptable salt thereof. The structural formula of the 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound is shown in formula (I): .

[0009] The present invention provides an 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound that exhibits excellent biological activity. Comparative testing has shown that, at a mass concentration of 0.1 μg / mL, its insecticidal effect increased by nearly 10% compared to the commonly used insecticide chlorantraniliprole. This means that at lower dosages, the compound exhibits a more efficient insecticidal effect against Lepidoptera pests such as the diamondback moth. This not only reduces the cost of use but also the potential impact on the environment. This characteristic gives the compound or its agronomically acceptable salts significant potential application value in the field of insecticide research and development, providing new ideas and directions for future insecticide upgrades.

[0010] The present invention provides a method for preparing the above-mentioned 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or an agriculturally acceptable salt thereof. The method for preparing the 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound comprises the following steps: mixing compound 3 with acetic anhydride, allowing the mixture to react sufficiently, and post-treating the mixture to obtain compound (I); .

[0011] Furthermore, the preparation of compound 3 includes the following steps: S1. Under alkaline conditions, compound 1 and nitromethane are mixed in an organic solvent, reacted fully, and post-treated to obtain compound 2; S2. Compound 2 obtained in step S1, a non-oxidizing acid and acetic acid are mixed, reacted sufficiently, and post-treated to obtain compound 3; .

[0012] Furthermore, in step S1, the compound 1 can be prepared in-house or purchased commercially.

[0013] Furthermore, as a preferred method, the preparation method of compound 1 comprises the following steps: At 0-5°C, triethyl phosphonoacetate was dissolved in an organic solvent, and sodium hydride was added dropwise. After mixing, 4,4-difluorocyclohexanone was added and the mixture was fully reacted. After post-treatment, compound 1 was obtained.

[0014] Furthermore, the organic solvent includes one or more of tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0015] Preferably, the organic solvent is THF.

[0016] Preferably, the mass volume ratio of the triethyl phosphonoacetate to the organic solvent is 1:(1-3) g / mL.

[0017] Preferably, the molar ratio of triethyl phosphonoacetate to sodium hydride is 1:(1-2).

[0018] More preferably, the molar ratio of triethyl phosphonoacetate to sodium hydride is 1:1.

[0019] Furthermore, the molar ratio of triethyl phosphonoacetate to 4,4-difluorocyclohexanone is (1-3):1.

[0020] Preferably, the molar ratio of triethyl phosphonoacetate to 4,4-difluorocyclohexanone is (1-1.5):1.

[0021] More preferably, the molar ratio of triethyl phosphonoacetate to 4,4-difluorocyclohexanone is 1.1:1.

[0022] Preferably, the temperature for the sufficient reaction is 20-30°C.

[0023] Furthermore, the sufficient reaction time is 6 to 12 hours.

[0024] Furthermore, the post-treatment includes quenching, extraction and purification.

[0025] Furthermore, the quenching is to add water to the reaction solution to quench the reaction.

[0026] Preferably, the amount of water added is 30-80 mL.

[0027] Furthermore, the extraction is to extract the quenched solution with ethyl acetate 3 to 4 times, and collect the organic phase.

[0028] Furthermore, the purification is performed by column chromatography.

[0029] Specifically, the post-treatment includes adding water to the reaction solution to quench the reaction, extracting the quenched solution with ethyl acetate 3 to 4 times, collecting the organic phase, and then purifying by column chromatography.

[0030] Furthermore, in step S1, the molar ratio of compound 1 to nitromethane is 1:(1-5).

[0031] Preferably, in step S1, the molar ratio of compound 1 to nitromethane is 1:(1-2).

[0032] More preferably, in step S1, the molar ratio of compound 1 to nitromethane is 1:1.1.

[0033] Furthermore, in step S1, the alkaline condition is provided by an organic base.

[0034] Furthermore, in step S1, the organic base is one or more of tetrabutylammonium fluoride, tetrabutylammonium chloride, and tetrabutylammonium bromide.

[0035] Preferably, in step S1, the alkaline condition is provided by tetrabutylammonium fluoride.

[0036] Furthermore, the molar ratio of the compound 1 to the organic base is 1:(0.05-0.2).

[0037] Furthermore, in step S1, the organic solvent is one or more of THF, DMF, and DMSO.

[0038] Preferably, in step S1, the organic solvent is THF.

[0039] Furthermore, in step S1, the mass volume ratio of the compound 1 to the organic solvent is 1: (0.1~1) g / mL.

[0040] Preferably, in step S1, the mass volume ratio of the compound 1 to the organic solvent is 1: (0.3-0.8) g / mL.

[0041] Furthermore, in step S1, the temperature for the sufficient reaction is 50-75°C.

[0042] Preferably, in step S1, the sufficient reaction time is 18 to 24 hours.

[0043] Furthermore, in step S1, the post-treatment includes terminating the reaction (acidification), extraction, drying and purification.

[0044] Furthermore, the termination reaction is carried out by adding hydrochloric acid for acidification.

[0045] Preferably, the amount of hydrochloric acid added is 80-120 mmol.

[0046] Furthermore, the extraction solvent is ethyl acetate.

[0047] Furthermore, the extraction is to use ethyl acetate to extract the reaction solution treated with the acidic reagent 3 to 4 times, and collect the organic phase.

[0048] Furthermore, the purification is column chromatography purification.

[0049] Specifically, the post-treatment includes adding hydrochloric acid for acidification, extracting the reaction solution treated with the acidic reagent with ethyl acetate 3 to 4 times, collecting the organic phase, drying and concentrating the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain compound 2.

[0050] Furthermore, in step S2, the mass volume ratio of the compound 2 to acetic acid is 1:(1-3) g / mL.

[0051] Preferably, in step S2, the mass volume ratio of the compound 2 to acetic acid is 1:(1.2-2) g / mL.

[0052] Furthermore, in step S2, the non-oxidizing acid includes one or more of hydrochloric acid, hydrobromic acid, and hydrofluoric acid. A non-oxidizing acid refers to an acid that can only exhibit weak oxidizing properties of hydrogen ions in the reaction.

[0053] Preferably, in step S2, the non-oxidizing acid is hydrochloric acid.

[0054] Preferably, in step S2, the volume ratio of the acetic acid to the non-oxidizing acid is 1:(1-3).

[0055] More preferably, in step S2, the volume ratio of the acetic acid to the non-oxidizing acid is 1:1.

[0056] Furthermore, in step S2, the reaction temperature is 85-95°C.

[0057] Furthermore, in step S2, the sufficient reaction time is 6 to 12 hours.

[0058] Furthermore, in step S2, the post-treatment includes cooling and recrystallization.

[0059] Furthermore, the mass volume ratio of the compound 3 and acetic anhydride is 1: (1-5) g / mL.

[0060] Furthermore, the temperature for the full reaction is 100-120°C.

[0061] Furthermore, the sufficient reaction time is 4 to 8 hours.

[0062] Furthermore, the post-processing includes cooling, removing the solvent, and purification.

[0063] Furthermore, the purification is performed using high performance liquid chromatography (HPLC).

[0064] Specifically, the post-treatment includes cooling the reaction solution to room temperature, removing the solvent, and purifying the concentrated crude product using HPLC to obtain compound (I).

[0065] The present invention protects the use of the above-mentioned 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or a pharmaceutically acceptable salt thereof in the preparation of insecticides.

[0066] Furthermore, the insecticide kills pests of the order Lepidoptera.

[0067] Furthermore, the lepidopteran pests include one or more of diamondback moth, cabbage looper, beet armyworm, leaf roller, and cotton bollworm.

[0068] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides an 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound that exhibits excellent biological activity. Comparative testing has shown that at a mass concentration of 0.1 μg / mL, its insecticidal effect increased by nearly 10% compared to the commonly used insecticide chlorantraniliprole. This means that at lower dosages, the compound exhibits a more efficient insecticidal effect against Lepidoptera pests such as the diamondback moth, achieving cost reduction and increased efficiency. This characteristic gives the compound or its agronomically acceptable salts significant potential application value in the field of insecticides, providing new ideas for future insecticide upgrades. DETAILED DESCRIPTION

[0069] The present invention is further described below with reference to specific examples, which, however, are not intended to limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the art.

[0070] Unless otherwise specified, all reagents and materials used in the following examples were commercially available.

[0071] In the example of activity determination, due to the small size of the diamondback moth, it is difficult to ensure that the number of test organisms in each treatment and each repetition is consistent, but the number of test individuals is kept within a small range. Therefore, the mortality rate calculated in Table 1 may not be an integer.

[0072] Example 1 Preparation of intermediate compounds 1 to 3 The synthetic route is as follows:

[0073] (1) Preparation of compound 1 At 0°C, triethyl phosphonoacetate (47.113 g, 220 mmol) was dissolved in 100 mL of THF. Sodium hydride (220 mmol) was added dropwise, and after stirring, 4,4-difluorocyclohexanone (200 mmol) was slowly added. The reaction solution was then transferred to 25°C and allowed to react for 6 h. Thin-layer chromatography (TLC) indicated the reaction was complete. The reaction was quenched by the addition of 50 mL of water and extracted three times with ethyl acetate. The organic phase was collected, dried, and concentrated to obtain the crude product. This crude product was then separated by column chromatography to afford compound 1, ethyl 2-(4,4-difluorocyclohexyl)enoate (148 mmol, 74% yield).

[0074] (2) Preparation of compound 2 Compound 1 (29.93 g, 148 mmol) was dissolved in 60 mL of THF, followed by the addition of nitromethane (163 mmol) and 15 mL of a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran. The mixture was refluxed at 66°C for 20 h. TLC indicated the reaction was complete. After acidification with 90 mL of 1 mol / L hydrochloric acid, the mixture was extracted three times with ethyl acetate. The organic phases were collected, dried, and concentrated to obtain the crude product, which was then separated by column chromatography to afford compound 2, ethyl 2-(1-nitromethyl-4,4-difluorocyclohexyl)acetate (80 mmol, 54% yield).

[0075] (3) Preparation of compound 3 Compound 2 (22.02 g, 80 mmol) was dissolved in 64 mL of acetic acid and concentrated hydrochloric acid (volume ratio of 1:1), reacted at 90°C for 6 h, and then cooled to room temperature. Compound 3, i.e., 1-carboxymethyl-4,4-difluorocyclohexanecarboxylic acid (64 mmol, yield 80%), was obtained by recrystallization.

[0076] 1 HNMR (300 MHz, DMSO): 12.35 (s, 2H), 2.53 (s, 2H), 2.10-1.77 (m,6H), 1.72-1.53 (m, 2H). LC-MS: M / Z = 223.1 [M+H]+, t R =1.71 min. HPLC: 97%(214nm), 99%(254nm), t R = 4.83 min. Example 2 Preparation of 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione The synthetic route is as follows:

[0077] Compound 3 (14.22 g, 64 mmol) prepared in Example 1 was dissolved in 43 mL of acetic anhydride, refluxed at 120°C for 4 h, and then cooled to room temperature. After removing the solvent, the crude product was purified by HPLC to obtain compound (I), i.e., 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione (51 mmol, yield 80%).

[0078] 1 HNMR (300 MHz, DMSO): 3.04 (s, 2H), 2.16-1.94 (m, 5H), 1.93-1.81 (m, 3H). LC-MS: M / Z = 205.1 [M+H]+, t R =1.68 min. HPLC: 97%(214nm), 99%(254nm), t R = 4.63 min. Example 3 Biological Activity Test of 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione Compound 1. Experimental Methods The immersion method proposed by the International Resistance Action Committee (IRAC) follows: First, compound (I) (8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione) in Example 2 is prepared to the mass concentration required for the test. Next, use straight ophthalmic forceps to grasp the cabbage leaves and immerse them in the prepared solution for 3-5 seconds, then shake off the excess solution on the leaves. Treat one leaf at a time, and set up three replicates for each sample. Place the numbered samples on the treatment paper in order. After the solution is naturally air-dried, place the samples in a marked straight tube. Then, inoculate the tube with diamondback moth larvae and cover the tube with gauze. Finally, place the experimental treatment group in a standard treatment room. After 72 hours, check and record the test results, and calculate the test mortality rate (using chlorfenapyr as the control agent). The mortality rate calculation formula is as follows: Mortality rate (%) = (number of dead pests after the experiment / total number of pests before the experiment) × 100 The final mortality test result was the average of the results of three repeated tests, and the test results are shown in Table 1.

[0079] 2. Experimental Results Table 1 Biological activity test of 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compounds

[0080] As shown in Table 1, at a concentration of 1 μg / mL, 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione achieved 100% lethality against Plutella xylostella, demonstrating comparable insecticidal activity to the control agent, chlorantraniliprole. This indicates that the compound possesses excellent insecticidal activity. To further compare the activity of 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione and chlorantraniliprole, the concentrations of both were reduced to 0.1 μg / mL. The results showed that at this concentration, 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione still caused 100% mortality against Plutella xylostella, while chlorantraniliprole reduced its mortality to 90.7%. This result indicates that the insecticidal activity of 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione is significantly superior to that of chlorantraniliprole. Therefore, at lower dosages, this compound exhibits more effective insecticide activity against Lepidoptera pests such as Plutella xylostella, which not only reduces its cost but also its potential environmental impact. This property gives this compound or its agronomically acceptable salt significant potential application value in the field of insecticides, providing new ideas for future insecticide upgrades.

[0081] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or a pharmaceutically acceptable salt thereof, characterized in that: The structural formula of the 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound is shown in formula (I): 。 2. The method for preparing the 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The preparation method of the 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound comprises the following steps: mixing compound 3 with acetic anhydride, allowing the mixture to react sufficiently, and post-treating the mixture to obtain the target compound (I); 。 3. The preparation method according to claim 2, characterized in that: The preparation of compound 3 comprises the following steps: S1. Under alkaline conditions, compound 1 and nitromethane are mixed in an organic solvent, reacted fully, and post-treated to obtain compound 2; S2. Compound 2 obtained in step S1, a non-oxidizing acid and acetic acid are mixed, reacted sufficiently, and post-treated to obtain compound 3; 。 4. The preparation method according to claim 3, characterized in that In step S1, the alkaline condition is provided by an organic base.

5. The preparation method according to claim 4, characterized in that: The organic base is one or more of tetrabutylammonium fluoride, tetrabutylammonium chloride and tetrabutylammonium bromide.

6. The preparation method according to claim 3, characterized in that: In step S2, the non-oxidizing acid includes one or more of hydrochloric acid, hydrobromic acid, and hydrofluoric acid.

7. The preparation method according to claim 2, characterized in that: The temperature for the full reaction is 100-120°C.

8. Use of the 8,8-difluoro-2-oxaspiro[4,5]decane-1,3-dione compound or an agriculturally acceptable salt thereof according to claim 1 in the preparation of an insecticide.

9. The application according to claim 8, characterized in that: The pests killed by the insecticide are lepidoptera pests.

10. The use according to claim 9, characterized in that: The lepidopteran pests include one or more of the diamondback moth, cabbage looper, beet armyworm, leaf roller, and cotton bollworm.

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