Preparation method, product and application of norbornene acid oxadiazole thioester compounds

Abstract

The present invention discloses a preparation method, product and application of norbornane acid oxadiazole thioester compounds. Norbornanol is oxidized to synthesize norbornane acid, and then norbornane acid is subjected to acyl chlorination to obtain norbornanoyl chloride, which further reacts with different substituted oxadiazole thiols in one step to synthesize norbornane acid oxadiazole thioester compounds. The compounds have the general formula I: wherein R is a benzene ring, thiophene or furan with different substituents respectively; under in vitro conditions, the compounds have good control effects against Sclerotinia sclerotiorum and can be used for controlling fungal diseases of agricultural plants. The preparation method of the compounds is simple, and the properties of the products are stable.

Description

Technical Field

[0001] The present invention belongs to the field of pesticide synthesis, and particularly relates to a preparation method and product of norbornane acid oxadiazole thioester compounds and their applications. Background Art

[0002] The diseases and pests of crops are one of the important restrictive factors affecting the sustainable and healthy development of agricultural products and forest resources. As a special commodity for controlling biological hazards such as diseases and pests of forest and agricultural crops, pesticides play an extremely important role in protecting the normal growth of forest and agricultural crops, improving agricultural production, and promoting food security.

[0003] However, the long-term use of a single pesticide variety will also cause plant pathogens, pests, and weeds to develop drug resistance. Therefore, the development of new targeted pesticide varieties is crucial for the effective control of plant diseases.

[0004] So far, there has been no report on the use of norbornane acid oxadiazole thioester compounds as agricultural fungicides. Summary of the Invention

[0005] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. In this part, as well as in the abstract and title of the present application, some simplifications or omissions may be made to avoid obscuring the purpose of this part, the abstract, and the title. However, such simplifications or omissions shall not be used to limit the scope of the present invention.

[0006] In view of the above and / or problems existing in the prior art, the present invention is proposed.

[0007] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a preparation method of norbornane acid oxadiazole thioester compounds.

[0008] To solve the above technical problems, the present invention provides the following technical solutions: A preparation method of norbornane acid oxadiazole thioester compounds, comprising:

[0009] Oxidizing norbornanol to synthesize norbornane acid;

[0010] Reacting norbornane acid to synthesize norbornanoyl chloride;

[0011] Reacting each substituted formylhydrazine to synthesize each substituted oxadiazole thiol;

[0012] Reacting norbornanoyl chloride with each substituted oxadiazole thiol to synthesize norbornane acid oxadiazole thioester compounds;

[0013] Among them, the norbornane acid oxadiazole thioester compounds have the following structural formula:

[0014]

[0015] Among them,

[0016]

[0017] As a preferred embodiment of the preparation method of the present invention, wherein: for the synthesis of nopinic acid, the synthesis method includes,

[0018] Take nopinol in a single-necked flask, add acetone, and slowly drip Jones reagent into it with a dropping funnel under ice bath conditions, react for 1 h, detect by TLC, after the reaction is completed, rotary evaporate to remove most of the acetone;

[0019] Add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, rotary evaporate to obtain the crude product of nopinic acid, and separate and purify it by silica gel column chromatography with 200 - 300 mesh, purify with petroleum ether / ethyl acetate volume ratio of 40:1 to 10:1 to obtain oily nopinic acid;

[0020] Among them, the molar ratio of the nopinol, acetone, and Jones reagent is 1:20.6:2.2.

[0021] As a preferred embodiment of the preparation method of the present invention, wherein: for the synthesis of each substituent oxadiazole mercaptan, the synthesis method includes,

[0022] Dissolve various substituent formylhydrazines in absolute ethanol, then add KOH, dropwise add CS2, after adding, reflux at 85 °C for reaction, detect by TLC until the raw materials react completely, add 5% hydrochloric acid for acidification, dilute the reaction solution with distilled water, filter, wash the solid with water and dry, and finally recrystallize with absolute ethanol to obtain the target compound oxadiazole mercaptan.

[0023] As a preferred embodiment of the preparation method of the present invention, wherein: the synthesis of nopinoyl chloride includes,

[0024] Add nopinic acid and dichloromethane to a round-bottom flask, stir in an ice bath, and dropwise add oxalyl chloride;

[0025] Stir the reaction mixture at room temperature for 2 - 3 h, after completion, vacuum concentrate to remove the excess oxalyl chloride and solvent to obtain nopinoyl chloride, which is directly used for the next step without further purification.

[0026] As a preferred embodiment of the preparation method of the present invention, wherein: the synthesis of nopinic acid oxadiazole thioester compounds includes,

[0027] Dissolve various substituent oxadiazole mercaptans in acetone, add K2CO3, dropwise add nopinoyl chloride, react at room temperature for 3 - 4 h, rotary evaporate to remove most of the acetone, add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, rotary evaporate to obtain the crude product;

[0028] Purify by silica gel column chromatography with 200 - 300 mesh, and purify with petroleum ether / ethyl acetate at a volume ratio of 40:1 - 10:1 to obtain nootkatonic acid oxadiazole thioester.

[0029] As a preferred embodiment of the preparation method of the present invention, wherein: the substituent hydrazide includes benzoyl hydrazide, 4-methylbenzoyl hydrazide, 4-methoxybenzoyl hydrazide, 4-fluorobenzoyl hydrazide, 2-chlorobenzoyl hydrazide, 3-chlorobenzoyl hydrazide, 4-chlorobenzoyl hydrazide, 4-bromobenzoyl hydrazide, 2-thiophenecarbonyl hydrazide and 2-furoyl hydrazide.

[0030] Another object of the present invention is to overcome the deficiencies in the prior art and provide nootkatonic acid oxadiazole thioester compounds.

[0031] Another object of the present invention is to overcome the deficiencies in the prior art and provide the application of nootkatonic acid oxadiazole thioester compounds in controlling plant fungi in agriculture or forestry, and the plant fungi include Rhizoctonia solani, Botrytis cinerea and Sclerotinia sclerotiorum.

[0032] Advantages of the present invention:

[0033] (1) The compounds of the present invention are derivatives containing nootkatonic acid oxadiazole thioester, with novel molecular structures, all being new compounds, having distinct chemical structure characteristics. The chemical structure contains nootkatonic acid and oxadiazole groups, and nootkatonic acid is connected to oxadiazole through a sulfur bond; the preparation method of the compounds of the present invention is simple, the raw materials are easily available, and the reaction conditions are mild and easy to control.

[0034] (2) The compounds of the present invention are agents for controlling plant fungi in the field of agriculture or forestry, and such agents show good effects in controlling Rhizoctonia solani, Botrytis cinerea and Sclerotinia sclerotiorum. Description of the Drawings

[0035] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings. Among them:

[0036] Figure 1 It is a schematic diagram of the preparation method of nootkatonic acid oxadiazole thioester compounds in the embodiments of the present invention. Detailed Embodiments

[0037] To make the above objects, features and advantages of the present invention more obvious and understandable, the following will give a detailed description of the specific embodiments of the present invention in combination with the embodiments of the specification.

[0038] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention may be practiced in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0039] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation manner of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it an embodiment that is separate or selectively mutually exclusive with other embodiments.

[0040] A schematic diagram of the preparation method of the nopinic acid amide compound of the present invention is shown in Figure 1 , and includes the following steps:

[0041] (1) Oxidize nopinol to synthesize nopinic acid;

[0042] (2) React with nopinic acid to synthesize nopinoyl chloride.

[0043] (3) React with each substituted formylhydrazine to synthesize each substituted oxadiazolethiol.

[0044] (4) React nopinoyl chloride with each substituted oxadiazolethiol to synthesize nopinic acid oxadiazolethiol ester.

[0045] The specific steps are as follows:

[0046] (1) Preparation of nopinic acid

[0047] Take nopinol (6.6 g, 39.6 mmol) in a 250 ml single-necked flask, add 60 ml of acetone to dissolve it, slowly drop 33 ml of Jones reagent into it with a dropping funnel under ice bath conditions, react for 1 h under ice bath conditions, detect by TLC. After the reaction is completed, rotate and concentrate to remove most of the acetone, add ethyl acetate for extraction (50 ml × 3), combine the organic layers, wash with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, rotate and concentrate to obtain the crude product of nopinic acid, and purify it by silica gel column chromatography with 200 - 300 mesh, purify with petroleum ether / ethyl acetate volume ratio of 40:1 to 10:1 to obtain 2.1 g of oily nopinic acid;

[0048] (2) Preparation of nopinoyl chloride

[0049] Add nobilic acid (220.6 mg, 1.11 mmol) and CH2Cl2 (4 mL) to a round-bottom flask, stir in an ice bath, and add oxalyl chloride (281.8 mg, 2.22 mmol) dropwise. Stir the reaction mixture at room temperature for 2 h. After completion, concentrate under vacuum to remove excess oxalyl chloride and solvent to obtain nobloyl chloride, which is directly used for the next step without further purification.

[0050] (3) Preparation of different substituted oxadiazole thiols

[0051] Respectively take benzoyl hydrazide, 4-methylbenzoyl hydrazide, 4-methoxybenzoyl hydrazide, 4-fluorobenzoyl hydrazide, 2-chlorobenzoyl hydrazide, 3-chlorobenzoyl hydrazide, 4-chlorobenzoyl hydrazide, 4-bromobenzoyl hydrazide, 2-thiophenecarbonyl hydrazide, 2-furoyl hydrazide (2.38 mmol) and add them to a round-bottom flask. After dissolving with 10 mL of anhydrous ethanol, add KOH (2.62 mmol), and add CS2 (4.76 mmol) dropwise. Reflux the reaction at 85 °C overnight. After the reaction is completed, concentrate under vacuum to remove the solvent. Dissolve the solid with water, acidify the solution to pH 2-3 with 5% hydrochloric acid, filter the solid, dry it, and recrystallize it with ethanol to obtain the target compound oxadiazole thiol.

[0052] (4) Preparation of different substituted nobilic acid oxadiazole thioesters

[0053] Add different substituted oxadiazole thiols (1.11 mmol) to a round-bottom flask. After dissolving with 6 mL of acetone, add K2CO3 (2.22 mmol). Dissolve nobloyl chloride (1.11 mmol) with 4 mL of acetone and add it dropwise. React at room temperature for 1 h. After the reaction is completed, concentrate under vacuum to remove acetone. Add 10 mL of water, extract with ethyl acetate (3×10 mL), combine the organic phases, wash successively with water, saturated sodium bicarbonate aqueous solution and saturated sodium chloride, and dry over anhydrous sodium sulfate. Concentrate the organic phase under vacuum to remove ethyl acetate, and finally purify the crude product on a silica gel column (200-300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the nobilic acid oxadiazole thioester compound.

[0054] Example 1

[0055] Prepared nobilic acid oxadiazole thioester derivative (I-1):

[0056]

[0057] 5-Phenyl-1,3,4-oxadiazole-2-thiol (197.8 mg, 1.11 mmol) was dissolved in 10 mL of acetone. K2CO3 (306.8 mg, 2.22 mmol) was added, and then nobornyl chloride (220.6 mg, 1.11 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h. TLC was used to monitor the complete reaction of the raw materials. Most of the acetone was removed by rotary evaporation. Ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude nobornyl oxadiazole thioester. Finally, the crude product was purified on a silica gel chromatographic column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nobornyl oxadiazole thioester derivative (I-1): white solid; yield, 80%.

[0058] 1 H NMR (600 MHz, chloroform) δ8.03–7.97 (m, 2H), 7.63–7.57 (m, 1H), 7.55–7.50 (m, 2H), 6.81–6.77 (m, 1H), 3.46 (ddt, J = 20.9, 9.2, 1.7 Hz, 1H), 2.90 (dddt, J = 20.2, 8.5, 5.6, 2.5 Hz, 1H), 2.75 (t, J = 5.3 Hz, 1H), 2.48 (dt, J = 10.6, 5.8 Hz, 1H), 2.17–2.11 (m, 1H), 2.09–2.01 (m, 1H), 2.00–1.91 (m, 1H), 1.45 (d, J = 10.2 Hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) δ180.2, 174.2, 160.8, 157.8, 133.1, 129.3, 127.2, 122.0, 110.9, 55.1, 41.5, 40.5, 27.5, 26.2, 24.4, 23.9, 22.4.

[0059] Example 2

[0060] The nobornyl oxadiazole thioester derivative (I-2) was prepared:

[0061]

[0062] Dissolve 5-(4-methyl)phenyl-1,3,4-oxadiazole-2-thiol (213.3 mg, 1.11 mmol) in 10 mL of acetone, add K2CO3 (306.8 mg, 2.22 mmol), and then dropwise add nobeloyl chloride (220.6 mg, 1.11 mmol). React at room temperature for 1 h. Monitor the reaction of the raw materials by TLC until it is complete. Rotate and concentrate to remove most of the acetone, add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and rotate and concentrate to obtain the crude nobeloyl oxadiazole thioester. Finally, purify the crude product on a silica gel chromatographic column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nobeloyl oxadiazole thioester derivative (I-2): light yellow solid; yield, 80%.

[0063] 1 H NMR (600 MHz, chloroform) δ 7.89 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.81–6.77 (m, 1H), 3.45 (ddt, J = 20.9, 9.2, 1.6 Hz, 1H), 2.89 (dddt, J = 20.2, 8.5, 5.6, 2.6 Hz, 1H), 2.74 (t, J = 5.3 Hz, 1H), 2.48 (dt, J = 10.6, 5.7 Hz, 1H), 2.44 (s, 3H), 2.17–2.11 (m, 1H), 2.09–2.00 (m, 1H), 1.99–1.91 (m, 1H), 1.44 (d, J = 10.2 Hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.04, 174.28, 160.80, 157.94, 143.91, 130.04, 127.12, 119.17, 110.95, 55.08, 41.48, 40.47, 27.52, 26.18, 24.36, 23.85, 22.39, 21.92.

[0064] Example 3

[0065] Prepared nobeloyl oxadiazole thioester derivative (I-3):

[0066]

[0067] 5-(4-Methoxy)phenyl-1,3,4-oxadiazole-2-thiol (231.1 mg, 1.11 mmol) was dissolved in 10 mL of acetone. K2CO3 (306.8 mg, 2.22 mmol) was added, and then noberyl chloride (220.6 mg, 1.11 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h. TLC was used to monitor the complete reaction of the starting materials. Most of the acetone was removed by rotary evaporation. Ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude noboxic acid oxadiazole thioester. Finally, the crude product was purified on a silica gel column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target noboxic acid oxadiazole thioester derivative (I-3): a pale yellow solid; yield, 79%.

[0068] 1 H NMR (600 MHz, chloroform) δ 7.96–7.92 (m, 2H), 7.03–6.98 (m, 2H), 6.81–6.78 (m, 1H), 3.89 (s, 3H), 3.45 (ddt, J = 20.9, 9.2, 1.6 Hz, 1H), 2.93–2.85 (m, 1H), 2.74 (t, J = 5.3 Hz, 1H), 2.48 (dt, J = 10.7, 5.8 Hz, 1H), 2.18–2.11 (m, 1H), 2.08–2.01 (m, 1H), 1.99–1.91 (m, 1H), 1.44 (d, J = 10.1 Hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 179.88, 174.30, 163.41, 160.85, 157.81, 129.07, 114.80, 114.22, 111.02, 55.71, 55.08, 41.48, 40.48, 27.52, 26.19, 24.35, 23.86, 22.39.

[0069] Example 4

[0070] The noboxic acid oxadiazole thioester derivative (I-4) was prepared:

[0071]

[0072] 5-(4-Fluoro)phenyl-1,3,4-oxadiazole-2-thiol (217.6 mg, 1.11 mmol) was dissolved in 10 mL of acetone. K2CO3 (306.8 mg, 2.22 mmol) was added, and then noberyl chloride (220.6 mg, 1.11 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h. TLC was used to monitor the complete reaction of the starting materials. Most of the acetone was removed by rotary evaporation. Ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude nobeloyl oxadiazole thioester. Finally, the crude product was purified on a silica gel column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nobeloyl oxadiazole thioester derivative (I-4): a pale yellow solid; yield, 83%.

[0073] 1 H NMR (600 MHz, chloroform) δ8.01 (m, 2H), 7.23–7.16 (m, 2H), 6.78–6.74 (m, 1H), 3.49–3.35 (m, 1H), 2.88 (dddd, J = 20.2, 10.5, 5.7, 2.6 Hz, 1H), 2.73 (t, J = 5.3 Hz, 1H), 2.47 (dt, J = 10.9, 5.8 Hz, 1H), 2.18–2.10 (m, 1H), 2.08–2.00 (m, 1H), 1.99–1.90 (m, 1H), 1.43 (d, J = 10.2 Hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) δ180.23, 174.01, 165.55 (d, J = 253.5 Hz), 160.57, 156.89, 129.56 (d, J = 9.1 Hz), 118.32 (d, J = 3.3 Hz), 116.79 (d, J = 22.4 Hz), 110.83, 55.11, 41.47, 40.46, 27.49, 26.16, 24.36, 23.81, 22.35.

[0074] Example 5

[0075] The nobeloyl oxadiazole thioester derivative (I-5) was prepared:

[0076]

[0077] Dissolve 5-(2-chloro)phenyl-1,3,4-oxadiazole-2-thiol (217.6 mg, 1.11 mmol) in 10 mL of acetone, add K2CO3 (306.8 mg, 2.22 mmol), and then dropwise add nopyl chloride (220.6 mg, 1.11 mmol). React at room temperature for 1 h. Monitor the reaction by TLC until the raw materials are completely reacted. Rotate and concentrate to remove most of the acetone, add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and rotate and concentrate to obtain the crude product of nopyl oxadiazole thioester. Finally, purify the crude product on a silica gel chromatographic column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nopyl oxadiazole thioester derivative (I-5): white solid; yield, 69%.

[0078] 1 H NMR (600 MHz, chloroform) δ 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 (dd, J = 8.1, 1.0 Hz, 1H), 7.52 (td, J = 7.8, 1.6 Hz, 1H), 7.43 (td, J = 7.8, 1.2 Hz, 1H), 6.78–6.72 (m, 1H), 3.46 (ddt, J = 21.0, 9.2, 1.7 Hz, 1H), 2.89 (dddt, J = 20.5, 8.5, 5.8, 2.6 Hz, 1H), 2.72 (t, J = 5.3 Hz, 1H), 2.47 (dt, J = 10.7, 5.8 Hz, 1H), 2.13 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.43 (d, J = 10.1 Hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.44, 173.62, 160.66, 155.68, 133.69, 133.43, 131.73, 130.98, 127.32, 121.12, 110.74, 55.15, 41.46, 40.45, 27.53, 26.16, 24.38, 23.83, 22.37.

[0079] Example 6

[0080] Prepared nopyl oxadiazole thioester derivative (I-6):

[0081]

[0082] Dissolve 5-(3-chloro)phenyl-1,3,4-oxadiazole-2-thiol (217.6 mg, 1.11 mmol) in 10 mL of acetone, add K2CO3 (306.8 mg, 2.22 mmol), and then dropwise add nopoloyl chloride (220.6 mg, 1.11 mmol). React at room temperature for 1 h. Monitor the reaction by TLC until the raw materials are completely reacted. Rotate and concentrate to remove most of the acetone, add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and rotate and concentrate to obtain the crude nopalic acid oxadiazole thioester. Finally, purify the crude product on a silica gel chromatographic column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nopalic acid oxadiazole thioester derivative (I-6): white solid; yield, 69%.

[0083] 1 H NMR (600 MHz, chloroform) δ 8.00 (t, J = 1.7 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.56 (ddd, J = 8.0, 1.8, 0.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.79–6.72 (m, 1H), 3.44 (ddt, J = 20.9, 9.2, 1.8 Hz, 1H), 2.89 (dddd, J = 20.3, 10.7, 5.7, 2.7 Hz, 1H), 2.75 (t, J = 5.3 Hz, 1H), 2.48 (dt, J = 10.8, 5.8 Hz, 1H), 2.14 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.44 (d, J = 10.2 Hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.69, 173.85, 160.52, 156.46, 135.61, 133.07, 130.70, 127.06, 125.19, 123.67, 110.68, 55.12, 41.51, 40.44, 27.50, 26.16, 24.42, 23.82, 22.38.

[0084] Example 7

[0085] Prepared nopalic acid amide derivative (I-7):

[0086]

[0087] 5-(4-Chloro)phenyl-1,3,4-oxadiazole-2-thiol (217.6 mg, 1.11 mmol) was dissolved in 10 mL of acetone. K2CO3 (306.8 mg, 2.22 mmol) was added, and then nobeloyl chloride (220.6 mg, 1.11 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h. The raw materials were completely reacted as monitored by TLC. Most of the acetone was removed by rotary evaporation. Ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude nobelate oxadiazole thioester. Finally, the crude product was purified on a silica gel column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nobelate oxadiazole thioester derivative (I-7): white solid; yield, 73%.

[0088] 1 H NMR (600 MHz, chloroform) δ 7.99–7.89 (m, 2H), 7.56–7.47 (m, 2H), 6.83–6.73 (m, 1H), 3.44 (ddt, J = 20.9, 9.3, 1.8 Hz, 1H), 2.89 (dddd, J = 20.2, 10.7, 5.6, 2.6 Hz, 1H), 2.74 (t, J = 5.3 Hz, 1H), 2.53–2.46 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.45 (d, J = 10.2 Hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.46, 174.00, 160.57, 156.94, 139.53, 129.80, 128.41, 120.53, 110.82, 55.17, 41.53, 40.51, 27.53, 26.20, 24.43, 23.86, 22.40.

[0089] Example 8

[0090] The nobelate oxadiazole thioester derivative (I-8) was prepared:

[0091]

[0092] Dissolve 5-(4-bromo)phenyl-1,3,4-oxadiazole-2-thiol (285.4 mg, 1.11 mmol) in 10 mL of acetone, add K2CO3 (306.8 mg, 2.22 mmol), and then dropwise add nobeloyl chloride (220.6 mg, 1.11 mmol). React at room temperature for 1 h. Monitor the reaction by TLC until the raw materials are completely reacted. Rotate and concentrate to remove most of the acetone. Add ethyl acetate for extraction. Combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and rotate and concentrate to obtain the crude nobelate oxadiazole thioester. Finally, purify the crude product on a silica gel column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nobelate oxadiazole thioester derivative (I-8): white solid; yield, 78%.

[0093] 1 H NMR (600 MHz, chloroform) δ 7.87 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 3.44 (ddt, J = 20.9, 9.2, 1.8 Hz, 1H), 2.89 (dddd, J = 20.3, 10.7, 5.7, 2.7 Hz, 1H), 2.74 (t, J = 5.3 Hz, 1H), 2.48 (dt, J = 11.0, 6.0 Hz, 1H), 2.14 (m, 1H), 2.09–1.91 (m, 2H), 1.44 (d, J = 10.2 Hz, 1H), 1.33 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.60, 173.96, 160.56, 157.01, 132.75, 128.47, 128.02, 120.92, 110.75, 55.12, 41.51, 40.45, 27.50, 26.18, 24.43, 23.83, 22.39.

[0094] Example 9

[0095] Prepared nobelate oxadiazole thioester derivative (I-9):

[0096]

[0097] Dissolve 2-thiophene-1,3,4-oxadiazole-2-thiol (204.5 mg, 1.11 mmol) in 10 mL of acetone, add K2CO3 (306.8 mg, 2.22 mmol), and then dropwise add nopoloyl chloride (220.6 mg, 1.11 mmol). React at room temperature for 1 h. Monitor the reaction by TLC until the raw materials are completely reacted. Rotate and concentrate to remove most of the acetone. Add ethyl acetate for extraction. Combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and rotate and concentrate to obtain the crude nopol oxadiazole thioester. Finally, purify the crude product on a silica gel column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target nopol oxadiazole thioester derivative (I-9): pale yellow solid; yield, 65%.

[0098] 1 H NMR (600 MHz, chloroform) δ 7.81–7.78 (m, 1H), 7.65–7.61 (m, 1H), 7.21–7.16 (m, 1H), 6.74 (s, 1H), 3.44 (ddt, J = 20.9, 9.2, 1.8 Hz, 1H), 2.88 (dddd, J = 20.2, 10.7, 5.7, 2.7 Hz, 1H), 2.74 (t, J = 5.3 Hz, 1H), 2.48 (dt, J = 11.1, 5.9 Hz, 1H), 2.16–2.12 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.43 (d, J = 10.1 Hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.23, 173.58, 160.56, 154.21, 131.87, 128.51, 123.21, 110.84, 55.09, 41.47, 40.49, 27.53, 26.18, 24.37, 23.85, 22.37.

[0099] Example 10

[0100] Prepared nopol oxadiazole thioester derivative (I-10):

[0101]

[0102] Dissolve 2-furan-1,3,4-oxadiazole-2-thiol (0.39 g, 2 mmol) in 10 mL of acetone, add K2CO3 (306.8 mg, 2.22 mmol), and then dropwise add norpinoyl chloride (220.6 mg, 1.11 mmol). React at room temperature for 1 h. Monitor the reaction by TLC until the raw materials are completely reacted. Rotate and concentrate to remove most of the acetone. Add ethyl acetate for extraction. Combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and rotate and concentrate to obtain the crude norpinic acid oxadiazole thioester. Finally, purify the crude product on a silica gel column (200 - 300 mesh, petroleum ether / ethyl acetate = 40:1 - 10:1 v / v) to obtain the target norpinic acid oxadiazole thioester derivative (I-10): a pale yellow solid; yield, 70%.

[0103] 1 H NMR (600 MHz, chloroform) δ 7.67 (dd, J = 1.7, 0.7 Hz, 1H), 7.21 (dd, J = 3.6, 0.7 Hz, 1H), 6.72–6.70 (m, 1H), 6.62 (dd, J = 3.6, 1.8 Hz, 1H), 3.43 (ddt, J = 20.9, 9.2, 1.7 Hz, 1H), 2.91–2.83 (m, 1H), 2.73 (t, J = 5.3 Hz, 1H), 2.49–2.42 (m, 1H), 2.16–2.10 (m, 1H), 2.03 (m, 1H), 1.93 (m, 1H), 1.42 (d, J = 10.2 Hz, 1H), 1.30 (s, 3H), 0.78 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.55, 173.05, 160.56, 150.44, 147.05, 137.47, 116.84, 112.59, 110.59, 55.01, 41.45, 40.41, 27.45, 26.13, 24.36, 23.81, 22.35.

[0104] Example 11

[0105] For the last step of the synthetic route, that is, the synthetic reaction conditions for generating the target compound were explored, and the effects of different types of catalysts and solvents on the reaction yield were studied. Taking the synthesis of compound I-1 as an example, add 5-phenyl-1,3,4-oxadiazole-2-thiol (197.8 mg, 1.11 mmol) to a single-necked flask, dissolve it in the corresponding solvent, add the catalyst under stirring, and then dropwise add norpinoyl chloride (220.6 mg, 1.11 mmol). After addition, react at room temperature (25 °C) and monitor by TLC.

[0106] Table 1 Exploration of condensation reaction conditions

[0107]

[0108] Four reaction conditions were explored. Using K2CO3 / acetone as the experimental condition gave the best reaction situation and a relatively high yield; the other reaction situations were average, and new impurities were generated.

[0109] Example 12

[0110] Antibacterial activity (in vitro) experiment:

[0111] All test strains in this experiment were purchased from the China Center for Agricultural Culture Collection (ACCC) and the China Forestry Culture Collection Center (CFCC), including Gibberella zeae (ACCC 31060), Rhizoctonia solani (ACCC 38870), Phytophthora capsici (ACCC 36279), Botrytis cinerea (ACCC 36027), Sclerotinia sclerotiorum (ACCC 30096), Colletotrichum capsici (ACCC 37623) and Phytophthora infestans ( MYA-1113 TM )

[0112] The medium used was potato dextrose agar medium (abbreviated as PDA). PDA medium formula: 200 g of potato (peeled), 20 g of glucose, 15 g of agar, 1000 mL of distilled water. Preparation method: Wash and peel the potato, weigh 200 g and cut it into small pieces, add water and boil until soft (boil for 20 - 30 minutes until it can be pierced with a glass rod), filter through eight layers of gauze into a beaker, add 15 - 20 g of agar according to experimental needs, add 20 g of glucose, stir evenly, cool slightly after full dissolution, make up the volume to 1000 mL, dispense and sterilize at 121 °C for 15 minutes, and reserve after cooling.

[0113] Experimental method: The growth rate method was adopted.

[0114] (1) First, cultivate the 7 plant fungi on PDA plates at 25 °C for about 3 - 6 d for later use;

[0115] (2) Heat and melt the PDA medium, cool it to 45 - 50 °C, add the test compound at a concentration of 50 mg / L to make a medium containing 50 mg / L of the medicinal solution, and pour it into petri dishes and cool. Bixafen was used as the positive control;

[0116] (3) With aseptic operation procedures, use a punch to punch out circular mycelial discs (diameter 0.50 cm) at the edge of the mycelium of each strain cultured for 6 d (with as consistent growth status as possible), then use an inoculation needle to pick them to the center of the medicated plate, and then place the petri dishes upside down in an incubator (28 °C) for cultivation;

[0117] (4) Observe and measure the growth of hyphae at different times after treatment, measure the diameter using the cross-cross method, process the data, and calculate the inhibition rate; Inhibition rate (%) = (control hypha diameter - treated hypha diameter) / (control hypha diameter - 0.5) × 100; Each treatment is repeated 3 times.

[0118] Table 2 Test results of the inhibitory activities of norbornene oxadiazole thioester compounds against six agricultural pathogenic fungi

[0119]

[0120] Note: Each treatment in the experiment was set with three replicates, and the data in the table are the averages of the three replicates.

[0121] Table 3 EC of some compounds against Sclerotinia sclerotiorum 50 Value

[0122]

[0123] The bactericidal activity determination results of experimental groups I-1 to I-10 and the control agent boscalid are shown in Table 2. As can be seen from Table 2, at a concentration of 50 mg / L, compounds I-1 to I-10 showed different degrees of antibacterial activity against 6 plant fungi. Among them, compounds I-5 and I-6 showed relatively good antibacterial activity against Sclerotinia sclerotiorum, with inhibition rates of 90.5% and 90.0%, approaching the positive control boscalid. In addition, compounds I-4 and I-7 showed moderate inhibitory activity against Sclerotinia sclerotiorum. Compounds I-2 and I-9 showed moderate inhibitory activity against Rhizoctonia solani, and the inhibition rate was stronger than that of the positive control agent boscalid.

[0124] In view of the good inhibitory effects of compounds I-5 and I-6 against Sclerotinia sclerotiorum, the EC 50 values of these two compounds against Sclerotinia sclerotiorum were tested. As can be seen from Table 3, both of these two compounds showed strong inhibitory activity, and the EC 50 values were 1.38 and 1.51 mg / L respectively, which were comparable to that of the positive control boscalid (1.19 mg / L). This indicates that these two compounds have the potential to develop antifungal agents.

[0125] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the present invention.

Claims

1. Preparation method of nootkatonic oxadiazole thioester compounds, characterized in that: including, synthesizing nopolonic acid by oxidizing nopol; reacting nopolonic acid to synthesize nopoloyl chloride; reacting with each substituted formylhydrazine to synthesize each substituted oxadiazolethiol; reacting nopoloyl chloride with each substituted oxadiazolethiol to synthesize nopolonic acid oxadiazolethiol esters; Among them, the nopolonic acid oxadiazolethiol esters have the structural formula: Among them, R is selected from the following groups: 。 2. The preparation method according to claim 1, characterized in that: For the synthesis of nopolonic acid, its synthesis method includes, Take nopol in a single-necked flask, add acetone, and slowly drip Jones reagent into it with a dropping funnel under ice bath conditions. React for 1 h, detect by TLC. After the reaction is completed, rotate and concentrate to remove most of the acetone; Add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, rotate and concentrate to obtain the crude nopolonic acid, and separate and purify it by silica gel column chromatography with 200 - 300 mesh, purify with petroleum ether / ethyl acetate volume ratio of 40:1 - 10:1 to obtain oily nopolonic acid; Among them, the molar ratio of nopol, acetone, and Jones reagent is 1:20.6:2.

2.

3. The preparation method according to claim 2, characterized in that: For the synthesis of each substituted oxadiazolethiol, its synthesis method includes, Dissolve various substituted formylhydrazines in absolute ethanol, then add KOH, dropwise add CS2. After adding, reflux and react at 85 °C. Detect by TLC until the raw materials react completely. Add 5% hydrochloric acid for acidification, dilute the reaction solution with distilled water, filter, wash the solid with water and dry, and finally recrystallize with absolute ethanol to obtain the target compound oxadiazolethiol.

4. The preparation method according to claim 1, characterized in that: For the synthesis of nopoloyl chloride, it includes, Add nopolonic acid and dichloromethane to a round-bottom flask, stir in an ice bath, and dropwise add oxalyl chloride; Stir the reaction mixture at room temperature for 2 - 3 h. After completion, vacuum concentrate to remove the excess oxalyl chloride and solvent to obtain nopoloyl chloride, which is directly used for the next step without further purification.

5. The preparation method according to claim 1, characterized in that: For the synthesis of nopolonic acid oxadiazolethiol esters, it includes, Dissolve various substituted oxadiazolethiols in acetone, add K2CO3, dropwise add nopoloyl chloride, react at room temperature for 3 - 4 h, rotate and concentrate to remove most of the acetone, add ethyl acetate for extraction, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, rotate and concentrate to obtain the crude product; Separate and purify by silica gel column chromatography with 200 - 300 mesh, purify with petroleum ether / ethyl acetate volume ratio of 40:1 - 10:1 to obtain nopolonic acid oxadiazolethiol esters.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The substituted formylhydrazine is selected from benzoylhydrazine, 4-methylbenzoylhydrazine, 4-methoxybenzoylhydrazine, 4-fluorobenzoylhydrazine, 2-chlorobenzoylhydrazine, 3-chlorobenzoylhydrazine, 4-chlorobenzoylhydrazine, 4-bromobenzoylhydrazine, 2-thiophenecarbonylhydrazine, and 2-furoylhydrazine.

7. The nopolonic acid oxadiazolethiol esters prepared by the preparation method according to any one of claims 1 - 6.

8. Use of the norbornane acid oxadiazole thioester compound according to claim 7 in controlling plant fungi in agriculture or forestry, characterized in that: The plant fungi are selected from Rhizoctonia solani.

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