Preparation method, product and application of norbornene carboxylic acid formyl hydrazide compounds

Abstract

The present invention discloses a preparation method, product and application of norbornene carboxylic acid hydrazide compounds. The norbornene carboxylic acid hydrazide compounds are synthesized by one-step reaction of 5-norbornene-2-carboxylic acid with substituted phenylhydrazine. The compound has the general formula I: wherein R is independently selected from H, halogen, and alkyl. The application of the norbornene carboxylic acid hydrazide in preventing and controlling fungal diseases of agricultural or forestry plants shows good control effects against Sclerotinia sclerotiorum, Gibberella zeae, and Botryosphaeria dothidea. The preparation method of the compound is simple, with a high yield and stable product properties.

Description

Technical Field

[0001] The present invention belongs to the field of pesticide synthesis, and specifically relates to a preparation method, product and application of norbornene carboxylic acid hydrazide compounds. Background Art

[0002] Trees are the backbone of forestry, defining the landscape of China's forestry and serving as the cornerstone for constructing ecological gardens, sponge cities, and livable cities. As people's requirements for the forestry environment in life and residence increase, the variety of tree species in forestry is also growing. The diversity of plant species brings about the diversity of pests and diseases, which can cause fatal damage to the greening and ornamental functions of trees.

[0003] Currently, using chemical pesticides and biological pesticides is the most direct, rapid, economical and effective means to control diseases on forest trees. As a special commodity for controlling biological hazards such as pests and diseases of agricultural and forestry crops, pesticides play an extremely important role in protecting the normal growth of agricultural and forestry crops, improving agricultural production, and promoting food security. However, the long-term use of a single pesticide variety will also cause plant pathogens, pests and weeds to develop drug resistance. Therefore, developing new pesticide varieties with targeted effects is crucial for the effective control of plant diseases.

[0004] Norbornene is an important bicyclic chemical entity formed by the addition of cyclopentadiene and olefins. Its unique olefin double bond structure gives norbornene special reactivity. A series of research results have been obtained on norbornene and its derivatives in the fields of flame retardant materials, exchange membranes, nanomaterials, biomedicine, etc. In the field of biomedicine, norbornene and its derivatives have great development prospects, mainly concentrated on drug delivery materials, and there are few reports on their applications in medicine or pesticides.

[0005] Currently, the preparation method of norbornene carboxylic acid hydrazide compounds and their application in agricultural fungicides have not been reported. Summary of the Invention

[0006] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Simplifications or omissions may be made in this part, as well as in the abstract and title of the present application, to avoid obscuring the purpose of this part, the abstract, and the title, but such simplifications or omissions shall not be used to limit the scope of the present invention.

[0007] In view of the above and / or problems existing in the prior art, the present invention is proposed.

[0008] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a preparation method of norbornene carboxylic acid hydrazide compounds.

[0009] To solve the above technical problems, the present invention provides the following technical solutions: A preparation method of norbornene carboxylic acid hydrazide compounds, comprising:

[0010] Reacting 5-norbornene-2-carboxylic acid with substituted phenylhydrazine to synthesize norbornene carboxylic acid hydrazide compounds;

[0011] Among them, the structural formula of the norbornene carboxylic acid hydrazide compound is:

[0012]

[0013] Among them, R is selected from the groups of H, 4-F, 3-F, 4-Cl, 3-Cl, 4-Br, 3-Br, 4-I, 4-CN, 4-CH3, 4-OCF3, 2,4-diF, 2,4-diCl, 2-Cl-4-F, 2,4,6-tr Cl.

[0014] As a preferred embodiment of the preparation method of the present invention, it includes: dissolving the oily substance 5-norbornene-2-carboxylic acid in DCM, successively adding substituted phenylhydrazine hydrochloride, EDCI, 4-dimethylaminopyridine and triethylamine, after adding, reacting at room temperature, and detecting by TLC that the raw materials have completely reacted;

[0015] Washing successively with water, saturated sodium bicarbonate, and saturated sodium chloride, rotating and concentrating the organic phase to remove most of the DCM to obtain an oily substance, and finally purifying the crude product by silica gel column chromatography with 200-300 mesh, with the volume ratio of petroleum ether / ethyl acetate being 20∶1 to 5∶1, to obtain the target compound norbornene carboxylic acid hydrazide compounds.

[0016] As a preferred embodiment of the preparation method of the present invention, the molar ratio of the 5-norbornene-2-carboxylic acid, substituted phenylhydrazine hydrochloride, triethylamine, EDCI and 4-dimethylaminopyridine is 1.2∶1∶2∶1.2∶0.1.

[0017] As a preferred embodiment of the preparation method of the present invention, the reaction temperature of the 5-norbornene-2-carboxylic acid and the substituted phenylhydrazine is 25 °C, and the reaction time is 1-5 h.

[0018] As a preferred embodiment of the preparation method of the present invention, the substituted phenylhydrazine includes phenylhydrazine, 4-fluorophenylhydrazine, 3-F phenylhydrazine, 4-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-bromophenylhydrazine, 3-bromophenylhydrazine, 4-iodophenylhydrazine, 4-cyanophenylhydrazine, 4-methylphenylhydrazine, 4-trifluoromethoxyphenylhydrazine, 2,4-difluorophenylhydrazine, 2,4-dichlorophenylhydrazine, 2-chloro-4-fluorophenylhydrazine and 2,4,6-trichlorophenylhydrazine.

[0019] Another object of the present invention is to overcome the deficiencies in the prior art and provide norbornene carboxylic acid hydrazide compounds prepared by a method for preparing norbornene carboxylic acid hydrazide compounds.

[0020] Another object of the present invention is to overcome the deficiencies in the prior art and provide the application of norbornene carboxylic acid hydrazide compounds in controlling plant fungi in agriculture or forestry, wherein the plant fungi include Sclerotinia sclerotiorum, Gibberella zeae, and Botryosphaeria dothidea.

[0021] Advantages of the present invention:

[0022] (1) The norbornene carboxylic acid hydrazide compounds provided by the present invention have novel molecular structures and are all new compounds; their chemical structure features are distinct, and the structural formula contains 5-norbornene-2-carboxylic acid and phenylhydrazine groups, wherein the substituted phenylhydrazine group is connected to 5-norbornene-2-carboxylic acid through a hydrazide bond; the preparation method of the compounds is simple, the raw materials are easily available, the reaction conditions are easy to control, and the product can be obtained through column chromatography.

[0023] (2) The compounds of the present invention are agents for controlling plant fungi in the field of agriculture or forestry, and such agents have good control effects on Sclerotinia sclerotiorum, Gibberella zeae, and Botryosphaeria dothidea. Description of the Drawings

[0024] 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, and those of ordinary skill in the art can also obtain other drawings based on these drawings without creative efforts. Among them:

[0025] Figure 1 It is a schematic diagram of the method for preparing norbornene carboxylic acid hydrazide compounds in the embodiments of the present invention.

[0026] Figure 2 It is a schematic diagram of the in vitro experiment (plate) of the compounds on Sclerotinia sclerotiorum, Gibberella zeae, and Botryosphaeria dothidea in the embodiments of the present invention (the concentrations from left to right are 0mg / L, 12.5mg / L, 6.25mg / L, 3.13mg / L, 1.56mg / L, and 0.78mg / L).

[0027] Figure 3 It is a schematic diagram of the in vivo experiment (apple) of compound I-2 on Botryosphaeria dothidea in the embodiments of the present invention. Detailed Embodiments

[0028] In order to make the above objects, features, and advantages of the present invention more obvious and understandable, the following will provide a detailed description of the specific embodiments of the present invention in conjunction with the embodiments of the specification.

[0029] In the following description, many 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 than those specifically described herein, and those skilled in the art can make similar generalizations without departing from the spirit of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0030] Secondly, as used herein, "an embodiment" or "embodiment" means a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The appearances of "in one embodiment" in different places in this specification do not all refer to the same embodiment, nor are they separate or alternative embodiments that exclude each other with other embodiments.

[0031] A schematic diagram of the preparation method of the norbornene carboxylic acid hydrazide compounds of the present invention is shown in Figure 1 .

[0032] The specific steps are as follows:

[0033] Dissolve 5-norbornene-2-carboxylic acid (1.2 mmol) in anhydrous dichloromethane, and successively add EDCI (1.2 mmol), triethylamine (2 mmol), and 4-dimethylaminopyridine (0.1 mmol). Finally, add substituted phenylhydrazine hydrochloride. After adding, react at room temperature for 1 - 5 h.

[0034] Monitor the reaction of the raw materials by TLC until it is complete. Wash the organic layer with water 3 times (8 ml * 3), wash with saturated sodium bicarbonate (5 ml), and wash with saturated brine 3 times (8 mL * 3). Dry, filter by suction, concentrate to remove dichloromethane, and purify by silica gel column chromatography with 200 - 300 mesh silica gel. Purify with petroleum ether / ethyl acetate in a volume ratio of 20:1 to 5:1 to obtain the target compounds I-1 to I-15.

[0035] A schematic diagram of the preparation method of the norbornene carboxylic acid hydrazide compounds I-1 to I-15 is shown in Figure 1 .

[0036] 5-Norbornene-2-carboxylic acid, 4-dimethylaminopyridine, triethylamine, EDCI, and substituted phenylhydrazine hydrochloride are all purchased from Shanghai Bide Technology Co., Ltd.; dichloromethane is purchased from Nanjing Wanqing Co., Ltd.; silica gel plates and silica gel powder are purchased from Yantai Ocean Fine Chemical Co., Ltd.

[0037] Example 1

[0038] Phenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane, and the reaction was carried out at 25 °C for 1-5 h. The reaction of the raw materials was monitored by TLC until completion. The organic layer was washed with water three times (8 ml * 3) and saturated brine three times (8 mL * 3). The organic phase was concentrated by rotary evaporation to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with 200-300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1-5:1 to obtain the target compound I-1.

[0039]

[0040] I-1, white solid; yield 68.8%; m.p. 121.3 - 122.8 °C; 1 H NMR (600 MHz, chloroform) δ 7.31 - 7.26 (m, 1H), 7.24 - 7.20 (m, 2H), 6.89 (t, J = 7.3 Hz, 1H), 6.80 (d, J = 7.8 Hz, 2H), 6.27 (dd, J = 5.1, 3.0 Hz, 1H), 6.03 (dd, J = 5.1, 2.4 Hz, 1H), 3.29 - 3.19 (m, 1H), 3.01 - 2.87 (m, 2H), 2.02 - 1.97 (m, 1H), 1.50 (d, J = 8.2 Hz, 1H), 1.45 - 1.39 (m, 1H), 1.34 (d, J = 8.3 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.38, 148.17, 138.15, 132.11, 129.13, 121.25, 113.69, 50.08, 46.30, 43.21, 42.69, 29.71.

[0041] Example 2

[0042] 4-Fluorophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane, and the reaction was carried out at 25 °C for 1-5 h. The reaction of the raw materials was monitored by TLC until completion. The organic layer was washed with water three times (8 ml * 3) and saturated brine three times (8 mL * 3). The organic phase was concentrated by rotary evaporation to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with 200-300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1-5:1 to obtain the target compound I-2.

[0043]

[0044] I-2, a white solid; yield 63.6%; m.p. 130.3 - 131.8 °C; 1 H NMR (600 MHz, chloroform) δ 7.56 (s, 1H), 6.92 - 6.87 (m, 2H), 6.73 - 6.70 (m, 2H), 6.23 (dd, J = 5.8, 3.1 Hz, 1H), 5.96 (dd, J = 5.7, 2.9 Hz, 1H), 3.18 (s, 1H), 2.94 (s, 1H), 2.91 - 2.88 (m, 1H), 1.97–1.93 (m, 1H), 1.50–1.46 (m, 1H), 1.40–1.37 (m, 1H), 1.30 (d, J = 8.3 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.80, 158.01 (d, J = 237 HZ), 144.36, 138.26, 132.07, 115.725 (d, J = 22.5 HZ), 115.18 (d, J = 7.5 HZ), 50.16, 46.38, 43.20, 42.77, 29.67.

[0045] Example 3

[0046] 3-Fluorophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane and reacted at 25 °C for 1 - 5 h. TLC monitored the complete reaction of the raw materials. The organic layer was washed with water 3 times (8 ml * 3) and saturated brine 3 times (8 mL * 3). The organic phase was rotary evaporated to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with 200 - 300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I-3.

[0047]

[0048] I-3, a white solid; yield 56.6%; m.p. 128.2 - 129.8 °C; 11H NMR (600 MHz, chloroform) δ 7.42 (s, 1H), 7.15 - 7.11 (m, 1H), 6.57–6.53 (m, 2H), 6.47 (dt, J = 10.8, 2.3 Hz, 1H), 6.26 (dd, J = 5.7, 3.1 Hz, 1H), 6.00 (dd, J = 5.8, 2.9 Hz, 1H), 3.20 (s, 1H), 2.96 (s, 1H), 2.93 (dt, J = 9.4, 4.0 Hz, 1H), 2.00 - 1.95 (m, 1H), 1.51–1.48 (m, 1H), 1.42–1.38 (m, 1H), 1.32 (d, J = 8.4 Hz, 1H). 13 13C NMR (150 MHz, chloroform) δ 174.35, 163.54 (d, J = 243.2 HZ), 147.53 (d, J = 760.5 HZ), 137.98, 131.76, 130.12 (d, J = 9.2 Hz), 108.96 (d, J = 3.1 Hz), 107.38 (d, J = 21.3 Hz), 100.51 (d, J = 25.5 Hz), 49.86, 46.07, 42.92, 42.45, 29.43.

[0049] Example 4

[0050] 4-Chlorophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane, and the reaction was carried out at 25 °C for 1 - 5 h. TLC was used to monitor the complete reaction of the raw materials. The organic layer was washed with water 3 times (8 ml * 3) and saturated brine 3 times (8 mL * 3). The organic phase was rotary evaporated to remove most of the dichloromethane to obtain the crude product, which was separated and purified by silica gel column chromatography with 200 - 300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I-4.

[0051]

[0052] I-4, white solid; yield 73.1%; m.p. 160.2 - 161.5 °C; 11H NMR (600 MHz, chloroform) δ 7.45 (s, 1H), 7.15 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 6.25 (dd, J = 5.5, 3.1 Hz, 1H), 5.97 (dd, J = 5.5, 2.7 Hz, 1H), 3.19 (s, 1H), 2.95 (s, 1H), 2.91 (dt, J = 8.6, 4.0 Hz, 1H), 1.99–1.94 (m, 1H), 1.51–1.47 (m, 1H), 1.39 (dt, J = 11.8, 3.4 Hz, 1H), 1.31 (d, J = 8.3 Hz, 1H). 13 13C NMR (150 MHz, chloroform) δ 174.43, 146.57, 137.90, 131.69, 128.74, 125.60, 114.62, 49.81, 46.03, 42.83, 42.42, 29.32.

[0053] Example 5

[0054] 3-Chlorophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane and reacted at 25 °C for 1 - 5 h. The reaction of the raw materials was monitored by TLC until completion. The organic layer was washed with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). The organic phase was concentrated by rotary evaporation to remove most of the dichloromethane to obtain the crude product, which was separated and purified by silica gel column chromatography with 200 - 300 mesh silica gel, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I-5.

[0055]

[0056] I-5, white solid; yield 51.2%; m.p. 129.1 - 130.8 °C; 1 1H NMR (600 MHz, chloroform) δ 7.60 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.85–6.81 (m, 1H), 6.74 (t, J = 1.8 Hz, 1H), 6.65–6.61 (m, 1H), 6.24 (dd, J = 5.5, 3.1 Hz, 1H), 5.98 (dd, J = 5.5, 2.7 Hz, 1H), 3.19 (s, 1H), 2.98–2.86 (m, 2H), 1.96–1.92 (m, 1H), 1.50–1.45 (m, 1H), 1.42–1.37 (m, 1H), 1.30 (d, J = 8.3 Hz, 1H). 1313C NMR (150 MHz, chloroform) δ 174.51, 149.26, 137.97, 134.67, 131.68, 129.90, 120.67, 113.16, 111.52, 49.84, 46.10, 42.80, 42.42, 29.27.

[0057] Example 6

[0058] Dissolve 4-bromophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) in anhydrous dichloromethane in sequence, and react at 25 °C for 1 - 5 h. Monitor the reaction of raw materials by TLC until complete. Wash the organic layer with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). Concentrate the organic phase by rotary evaporation to remove most of the dichloromethane to obtain the crude product, and separate and purify it by silica gel column chromatography with 200 - 300 mesh silica gel, with the volume ratio of petroleum ether / ethyl acetate being 20:1 - 5:1 to obtain the target compound I-6.

[0059]

[0060] I-6, white solid; yield 55.3%; m.p. 173.2 - 174.1 °C; 1 1H NMR (600 MHz, chloroform) δ 7.30 (d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.27 (dd, J = 5.8, 3.1 Hz, 1H), 6.00 (dd, J = 5.7, 2.8 Hz, 1H), 3.21 (s, 1H), 2.97 (s, 1H), 2.94 (dt, J = 8.6, 4.0 Hz, 1H), 2.01–1.97 (m, 1H), 1.51 (dd, J = 8.2, 2.3 Hz, 1H), 1.42 - 1.38 (m, 1H), 1.33 (d, J = 8.3 Hz, 1H). 13 13C NMR (150 MHz, chloroform) δ 174.31, 147.10, 138.04, 131.74, 131.72, 115.11, 113.02, 49.87, 46.07, 42.95, 42.45, 29.47.

[0061] Example 7

[0062] 3-Bromophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane and reacted at 25 °C for 1 - 5 h. The reaction of the raw materials was monitored by TLC until completion. The organic layer was washed with water three times (8 ml * 3) and saturated brine three times (8 mL * 3). The organic phase was rotary evaporated to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with 200 - 300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I-7.

[0063]

[0064] I-7, pale yellow solid; yield 56.1%; m.p. 162.5 - 163.8 °C; 1 HNMR (600 MHz, chloroform) δ 7.52 (s, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.25 (dd, J = 5.8, 3.1 Hz, 1H), 5.99 (dd, J = 5.8, 2.8 Hz, 1H), 3.19 (s, 1H), 2.95 (s, 1H), 2.91 (dt, J = 8.8, 4.1 Hz, 1H), 1.97–1.93 (m, 1H), 1.49 (d, J = 7.4 Hz, 1H), 1.40 (dt, J = 11.7, 3.1 Hz, 1H), 1.31 (d, J = 8.3 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.44, 149.40, 137.98, 131.72, 130.19, 123.63, 122.82, 116.10, 112.03, 49.86, 46.12, 42.86, 42.44, 29.31.

[0065] Example 8

[0066] Dissolve 4-iodophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) successively in anhydrous dichloromethane, and react at 25 °C for 1 - 5 h. Monitor the reaction of the raw materials by TLC until completion. Wash the organic layer with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). Rotate and concentrate the organic phase to remove most of the dichloromethane to obtain the crude product, and separate and purify it by silica gel column chromatography with 200 - 300 mesh, with the volume ratio of petroleum ether / ethyl acetate being 20:1 - 5:1 to obtain the target compound I-8.

[0067]

[0068] I-8, white solid; yield 55.1%; m.p. 156.1 - 156.9 °C; 1 H NMR (600 MHz, chloroform) δ 7.30 (s, 1H), 7.18–7.14 (m, 2H), 6.75–6.71 (m, 2H), 6.27 (dd, J = 5.7, 3.1 Hz, 1H), 6.00 (dd, J = 5.7, 2.8 Hz, 1H), 3.21 (s, 1H), 3.00–2.91 (m, 2H), 2.01 - 1.97 (m, 1H), 1.50 (dq, J = 8.4, 2.1 Hz, 1H), 1.42–1.38 (m, 1H), 1.33 (d, J = 8.5 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.39, 146.53, 137.94, 131.71, 128.77, 125.71, 114.70, 49.82, 46.04, 42.87, 42.43, 29.37.

[0069] Example 9

[0070] Dissolve 4-cyanophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) successively in anhydrous dichloromethane, and react at 25 °C for 1 - 5 h. Monitor the reaction of the raw materials by TLC until completion. Wash the organic layer with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). Rotate and concentrate the organic phase to remove most of the dichloromethane to obtain the crude product, and separate and purify it by silica gel column chromatography with 200 - 300 mesh, with the volume ratio of petroleum ether / ethyl acetate being 20:1 - 5:1 to obtain the target compound I-9.

[0071]

[0072] I-9, light yellow solid; yield 59.9%; m.p. 148.2 - 149.6 °C; 1 HNMR (600 MHz, chloroform) δ 7.46 (d, J = 8.6 Hz, 2H), 7.31 (s, 1H), 6.76 (d, J = 8.6 Hz, 2H), 6.28 (dd, J = 5.8, 3.1 Hz, 1H), 6.00 (dd, J = 5.8, 2.8 Hz, 1H), 3.23 (s, 1H), 2.98 (d, J = 4.9 Hz, 1H), 2.97–2.94 (m, 1H), 2.03–1.99 (m, 1H), 1.55–1.50 (m, 1H), 1.44–1.39 (m, 1H), 1.35 (d, J = 8.4 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.63, 151.92, 138.45, 133.56, 131.84, 119.51, 113.05, 103.24, 50.14, 46.32, 43.20, 42.69, 29.75.

[0073] Example 10

[0074] Dissolve 4-methylphenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) in anhydrous dichloromethane in sequence, and react at 25 °C for 1 - 5 h. Monitor the reaction of raw materials by TLC until completion. Wash the organic layer with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). Rotate and concentrate the organic phase to remove most of the dichloromethane to obtain the crude product, and separate and purify it by silica gel column chromatography with 200 - 300 mesh, with the volume ratio of petroleum ether / ethyl acetate being 20:1 - 5:1 to obtain the target compound I-10.

[0075]

[0076]

[0077] I-10, white solid; yield 52.1%; m.p. 152.1 - 153.1 °C; 11H NMR (600 MHz, chloroform) δ 7.32 (s, 1H), 7.02 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.25 (dd, J = 5.6, 3.1 Hz, 1H), 6.01 (dd, J = 5.7, 2.9 Hz, 1H), 3.21 (s, 1H), 2.95 (s, 1H), 2.94–2.91 (m, 1H), 2.25 (s, 3H), 2.00 - 1.95 (m, 1H), 1.50 - 1.47 (m, 1H), 1.42–1.38 (m, 1H), 1.32 (d, J = 8.3 Hz, 1H). 13 13C NMR (150 MHz, chloroform) δ 174.10, 145.55, 137.71, 131.86, 130.29, 129.34, 113.72, 49.75, 46.00, 42.84, 42.41, 29.30, 20.28.

[0078] Example 11

[0079] 4-Trifluoromethoxyphenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane, and the reaction was carried out at 25 °C for 1 - 5 h. TLC was used to monitor the complete reaction of the raw materials. The organic layer was washed with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). The organic phase was rotary evaporated to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with 200 - 300 mesh silica gel, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I-11.

[0080]

[0081] I-11, white solid; yield 54.1%; m.p. 127.5 - 128.1 °C; 1 1H NMR (600 MHz, chloroform) δ 7.31 (s, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.80–6.77 (m, 2H), 6.27 (dd, J = 5.7, 3.1 Hz, 1H), 6.01 (dd, J = 5.8, 2.8 Hz, 1H), 3.22 (s, 1H), 2.99–2.93 (m, 2H), 2.02–1.98 (m, 1H), 1.52 - 1.49 (m, 1H), 1.42–1.39 (m, 1H), 1.34 (d, J = 8.4 Hz, 1H). 13CNMR (150 MHz, chloroform) δ 174.54, 146.44, 143.07 (d, J = 1.5 HZ), 138.02, 131.69, 121.88, 121.53 (d, J = 105 HZ), 114.24, 49.84, 46.06, 42.91, 42.44, 29.41.

[0082] Example 12

[0083] Dissolve 2,4-difluorophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) successively in anhydrous dichloromethane, and react at 25 °C for 1 - 5 h. Monitor the reaction of raw materials by TLC until complete. Wash the organic layer with water 3 times (8 ml * 3) and with saturated brine 3 times (8 mL * 3). Rotate and concentrate the organic phase to remove most of the dichloromethane to obtain the crude product, and separate and purify it by silica gel column chromatography with 200 - 300 mesh, with the volume ratio of petroleum ether / ethyl acetate being 20:1 - 5:1 to obtain the target compound I-12.

[0084]

[0085] I-12, white solid; yield 64.5%; m.p. 116.2 - 117.1 °C; 1 H NMR (600 MHz, chloroform) δ 7.37 (s, 1H), 6.82–6.76 (m, 2H), 6.75–6.71 (m, 1H), 6.25 (dd, J = 5.7, 3.1 Hz, 1H), 5.97 (dd, J = 5.7, 2.9 Hz, 1H), 3.19 (s, 1H), 2.96 (s, 1H), 2.92 (dt, J = 8.3, 4.0 Hz, 1H), 2.00 - 1.95 (m, 1H), 1.51–1.47 (m, 1H), 1.41 - 1.37 (m, 1H), 1.32 (d, J = 8.3 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.32, 156.77 (q, J = 229.5 HZ), 151.08 (q, J = 231.0 HZ), 137.97, 132.48 (q, J = 7.5 HZ), 131.66, 115.32 (q, J = 4.5 HZ), 110.52 (q, J = 18 HZ), 103.71 (q, J = 3 HZ) 49.82, 46.04, 42.86, 42.44, 29.37.

[0086] Example 13

[0087] 2,4 - Dichlorophenylhydrazine hydrochloride (1.0 mmol), 5 - norbornene - 2 - carboxylic acid (1.2 mmol), 4 - dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane, and the reaction was carried out at 25 °C for 1 - 5 h. The reaction of the raw materials was monitored by TLC until completion. The organic layer was washed with water 3 times (8 ml * 3) and saturated brine 3 times (8 mL * 3). The organic phase was concentrated by rotary evaporation to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with a 200 - 300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I - 13.

[0088]

[0089] I - 13, white solid; yield 67.1%; m.p. 140.2 - 141.1 °C; 1 H NMR (600 MHz, chloroform) δ 7.27 (d, J = 2.3 Hz, 1H), 7.23 (s, 1H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.27 (dd, J = 5.7, 3.1 Hz, 1H), 6.01 (dd, J = 5.8, 2.8 Hz, 1H), 3.22 (s, 1H), 2.99–2.93 (m, 2H), 2.03–1.98 (m, 1H), 1.51 (dd, J = 8.4, 2.2 Hz, 1H), 1.43 - 1.39 (m, 1H), 1.34 (d, J = 8.3 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.14, 142.76, 138.08, 131.67, 128.86, 127.38, 125.31, 119.87, 114.16, 49.87, 46.08, 42.88, 42.45, 29.46.

[0090] Example 14

[0091] 2 - Chloro - 4 - fluorophenylhydrazine hydrochloride (1.0 mmol), 5 - norbornene - 2 - carboxylic acid (1.2 mmol), 4 - dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) were successively dissolved in anhydrous dichloromethane, and the reaction was carried out at 25 °C for 1 - 5 h. The reaction of the raw materials was monitored by TLC until completion. The organic layer was washed with water 3 times (8 ml * 3) and saturated brine 3 times (8 mL * 3). The organic phase was concentrated by rotary evaporation to remove most of the dichloromethane to obtain a crude product, which was separated and purified by silica gel column chromatography with a 200 - 300 mesh, and the volume ratio of petroleum ether / ethyl acetate was 20:1 - 5:1 to obtain the target compound I - 14.

[0092]

[0093] I-14, white solid; yield 65.7%; m.p. 130.1 - 131.1 °C; 1 H NMR (600 MHz, chloroform) δ 7.39 (s, 1H), 7.06–7.00 (m, 1H), 6.86 (dd, J = 11.3, 5.4 Hz, 1H), 6.77 (dd, J = 8.6, 5.3 Hz, 1H), 6.27–6.24 (m, 1H), 6.00–5.97 (m, 1H), 3.20 (s, 1H), 2.96 (s, 1H), 2.95–2.91 (m, 1H), 2.00 - 1.96 (m, 1H), 1.49 (d, J = 8.2 Hz, 1H), 1.43–1.38 (m, 1H), 1.32 (d, J = 8.3 Hz, 1H). 13 C NMR (150 MHz, chloroform) δ 174.41, 156.85 (d, J = 240 HZ), 140.73 (d, J = 3 HZ), 138.26, 131.93, 120.10 (d, J = 10.5 HZ), 116.69 (d, J = 25.5 HZ), 114.53 (d, J = 9 HZ) 114.32 (d, J = 21 HZ), 50.09, 46.30, 43.14, 42.69, 29.69.

[0094] Example 15

[0095] Dissolve 2,4,6-trichlorophenylhydrazine hydrochloride (1.0 mmol), 5-norbornene-2-carboxylic acid (1.2 mmol), 4-dimethylaminopyridine (0.1 mmol), EDCI (1.2 mmol) and triethylamine (2 mmol) in anhydrous dichloromethane in sequence, and react at 25 °C for 1 - 5 h. Monitor the reaction of raw materials by TLC until complete. Wash the organic layer with water three times (8 ml * 3) and with saturated brine three times (8 mL * 3). Rotate and concentrate the organic phase to remove most of the dichloromethane to obtain the crude product, and purify it by silica gel column chromatography with 200 - 300 mesh, with the volume ratio of petroleum ether / ethyl acetate being 20:1 - 5:1 to obtain the target compound I-15.

[0096]

[0097] I-15, white solid; yield 63.3%; m.p. 151.1 - 152.2 °C; 11H NMR (600 MHz, chloroform) δ 7.57 (s, 1H), 7.25 (s, 2H), 6.67–6.63 (m, 1H), 6.21 (dd, J = 5.7, 3.1 Hz, 1H), 5.90 (dd, J = 5.7, 2.8 Hz, 1H), 3.15 (s, 1H), 2.92 (s, 1H), 2.86 (dt, J = 9.3, 4.0 Hz, 1H), 1.94–1.89 (m, 1H), 1.48–1.45 (m, 1H), 1.40–1.36 (m, 1H), 1.29 (d, J = 8.3 Hz, 1H). 13 13C NMR (150 MHz, chloroform) δ 173.18, 140.03, 137.90, 131.61, 128.41, 127.96, 126.00, 49.78, 45.97, 42.59, 42.40, 29.19.

[0098] Example 16

[0099] Antibacterial Activity (in vitro) Experiment

[0100] In this experiment, all test strains were purchased from the official websites of the China Center for Agricultural Culture Collection (ACCC) and the China Forestry Culture Collection Center (CFCC), and were Sclerotinia sclerotiorum, Fusarium graminearum, Botryosphaeria dothidea, Phytophthora capsici, Phytophthora infestans, Phytophthora nicotianae, and Botrytis cinerea. The medium used was potato dextrose agar medium (abbreviated as PDA).

[0101] 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 20 g of agar and 20 g of glucose according to experimental needs, stir evenly, cool slightly after full dissolution, make up the volume to 1000 mL with water, dispense into containers and sterilize at 121 °C for 15 minutes, and use after cooling.

[0102] Experimental method: The growth rate method was used.

[0103] (1) First, culture the 7 plant fungi on PDA plates at 25 °C for about 3 - 6 days for later use;

[0104] (2) Heat and melt the PDA medium, cool it to 45–50 °C, add 125 μL of the test compound at a concentration of 10 g / L to make a medium containing 50 mg / L of the liquid medicine, and pour it into petri dishes and cool. Boscalid was used as a positive control;

[0105] (3) Under aseptic conditions, use a punch to cut circular mycelial discs (diameter 0.50 cm) from the edges of the mycelia of each strain cultured for 6 days (with as consistent growth conditions as possible), then use an inoculation needle to pick them to the center of the drug-containing plate, and then place the petri dish upside down in an incubator (28 °C) for cultivation;

[0106] (4) Observe and measure the growth of the mycelia at different times after treatment, and use the cross method to measure the diameter and process the data to calculate the inhibition rate;

[0107] (5) Inhibition rate (%) = (control mycelial diameter - treated mycelial diameter) / (control mycelial diameter - 0.5) × 100;

[0108] (6) Each treatment is repeated 3 times.

[0109] Table 1 shows the test results of the inhibitory activities of norbornene carboxylic acid hydrazide compounds against seven agricultural pathogenic fungi

[0110]

[0111] Note: Each treatment in the experiment was set with three replicates, and the data in the table are the averages of the three replicates.

[0112] Table 2 shows the EC 50 values (mg / L)

[0113]

[0114] The bactericidal activity determination results of experimental groups I-1 to I-15 and the control agent boscalid are shown in Tables 1 and 2. As can be seen from the results of Tables 1 and 2, at a concentration of 25 mg / L, compounds I-1 to I-15 showed varying degrees of antibacterial activity against 7 plant fungi. Some compounds showed relatively good antibacterial activity against Sclerotinia sclerotiorum, Fusarium graminearum, and Botryosphaeria dothidea, and showed moderate to good inhibitory activity against Phytophthora capsici and Phytophthora nicotianae. The inhibition rates of some compounds were higher than those of the control agent boscalid.

[0115] In view of the fact that some target compounds have good inhibitory activity against Sclerotinia sclerotiorum, Fusarium graminearum, and Botryosphaeria dothidea, the EC 50 values of some compounds with higher inhibition rates were tested. As can be seen from Table 2, the EC50 value of compound I-2 against Sclerotinia sclerotiorum is 2.55 mg / L, which is higher than that of the positive control agent bixafen at 0.99 mg / L. The EC50 value of compound I-2 against Fusarium graminearum reached 2.03 mg / L, which is higher than that of the positive control agent boscalid. The EC 50 of the compound against Botryosphaeria dothidea is between 0.17 - 2.25 mg / L. In particular, the EC 50The value reached 0.17 mg / L, which was lower than that of the positive control boscalid at 0.20 mg / L.

[0116] Plate experiment ( Figure 2 ) showed that, compared with the blank control (0 mg / L), I-2 still had a strong inhibitory effect on the growth of Botryosphaeria dothidea at a concentration of 0.78 mg / L and had a good inhibitory effect on the hyphae of Botryosphaeria dothidea. This series of compounds had good inhibitory activity against Botryosphaeria dothidea and had the potential for developing fungicides.

[0117] Example 17

[0118] In vivo bactericidal experiment:

[0119] Apples with uniform texture, size and smooth surface were purchased from the market, washed with sterile water, then washed with 75% ethanol, and air-dried at room temperature.

[0120] An appropriate amount of compound I-2 was weighed and prepared into two concentrations of 200 mg / L and 100 mg / L with an aqueous solution of 0.2% Tween-80.

[0121] Protection activity test method: Spray each apple surface (spray volume is 5 mL, one concentration), spray evenly, and then air-dry naturally. After the fruit surface has no liquid, pierce the peel with an inoculation needle and inoculate Botryosphaeria dothidea agar discs (0.5 cm in diameter), three agar discs are inoculated on each fruit, the positive control is boscalid, and it is cultured under indoor conditions (25 ± 2 °C and 95% relative humidity) for 6 days, measure the lesion diameter, and calculate the inhibition rate.

[0122] The schematic diagram of the in vivo (apple) experiment of compound I-2 against Botryosphaeria dothidea is shown in Figure 3 .

[0123] Inhibition rate (%) = (lesion diameter of blank control - lesion diameter of test compound) / (lesion diameter of blank control - 0.5) × 100%.

[0124] Protection activity test method: Spray each apple fruit surface, (spray volume is 5 mL, one concentration), spray evenly, and then air-dry naturally. After the fruit surface has no liquid, pierce the peel with an inoculation needle and inoculate Botryosphaeria dothidea agar discs (0.5 cm in diameter), three agar discs are inoculated on each fruit, the positive control is boscalid, and it is cultured under indoor conditions (25 ± 2 °C and 95% relative humidity) for 6 days, measure the lesion diameter, and calculate the inhibition rate.

[0125] Protection activity inhibition rate (%) = (lesion diameter of blank control - lesion diameter of test compound) / (lesion diameter of blank control - 0.5) × 100%.

[0126] Therapeutic activity test method: Pierce the fruit peel with an inoculation needle, and inoculate a Botryosphaeria dothidea fungal cake (0.5 cm in diameter). Inoculate three fungal cakes on each fruit, and then spray the surface of each apple fruit (spray volume is 5 mL, one concentration, and the positive control is boscalid). Spray evenly and then air dry naturally. After the fruit surface has no liquid, incubate at indoor conditions (25 ± 2 °C and 95% relative humidity) for 6 days, measure the lesion diameter, and calculate the inhibition rate.

[0127] Protection activity inhibition rate (%) = (lesion diameter of blank control - lesion diameter of test compound) / (lesion diameter of blank control - 0.5) × 100%.

[0128] Table 3 In vivo biological activity of compound I-2 against Botryosphaeria dothidea (in vivo on apple fruits)

[0129]

[0130] At a concentration of 200 mg / L, the protection activity and therapeutic activity of compound I-2 were 92.6% and 85.0% respectively, both superior to 82.9% and 51.2% of the positive control boscalid. When the concentration was further reduced to 100 mg / L, the protection activity and therapeutic activity of compound I-2 were 86.8% and 78.9% respectively, also superior to 45.1% and 41.1% of the positive control boscalid. The results showed that compound I-2 has the potential value for developing antifungal pesticides.

[0131] Example 18

[0132] Under the conditions of Example 2, investigate the effect of the ratio of 5-norbornene-2-carboxylic acid to phenylhydrazine hydrochloride on the product yield. The conditions and results are shown in Table 4.

[0133] Table 4

[0134]

[0135]

[0136] It can be seen that the preferred range of the feeding ratio of 5-norbornene-2-carboxylic acid (mmol) to phenylhydrazine (mmol) is 1.1:1 - 1.3:1. Beyond this range, the yield of the obtained product decreases.

[0137] Example 19

[0138] Investigated the influence of three condensation conditions on the hydrazide reaction situation and yield, as shown in Table 5.

[0139] Table 5

[0140]

[0141] The effects of three condensation conditions on the hydrazide reaction situation and yield were investigated. Among them, using DMAP / EDCI as the condensation condition, the reaction yield was the highest (63.6%); using PyBoP as the condensation condition, the yield was slightly lower (51.2%); using HOBT / EDCI as the condensation condition, the yield was the lowest (35.1%). Therefore, it is best to use DMAP / EDCI as the condensing agent for this hydrazide reaction.

[0142] The norbornene formyl hydrazide compounds described in the present invention have obvious structural differences and distinct chemical structural characteristics, and show good effects against Sclerotinia sclerotiorum, Gibberella zeae, and Botryosphaeria dothidea. They can be used to control fungal diseases of agricultural or forestry plants. The preparation method of the compounds is simple, the yield is high, and the product properties are stable.

[0143] 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. A method for preparing norbornene carboxylic acid hydrazide compounds, characterized in that: Comprising, Reacting 5-norbornene-2-carboxylic acid with substituted phenylhydrazine to synthesize norbornene formylhydrazine compounds; Among them, the structural formula of the norbornene formylhydrazine compound is: I Among them, R is selected from the groups of H, 4-F, 3-F, 4-Cl, 3-Cl, 4-Br, 3-Br, 4-I, 4-CN, 4-CH3, 4-OCF3, 2,4-diF, 2,4-diCl, 2-Cl-4-F, 2,4,6-tri Cl.

2. The preparation method according to claim 1, characterized in that: Comprising dissolving the oily substance 5-norbornene-2-carboxylic acid in DCM, successively adding substituted phenylhydrazine hydrochloride, EDCI, 4-dimethylaminopyridine and triethylamine, after adding, reacting at room temperature, and detecting by TLC that the raw materials have completely reacted; Washing successively with water, saturated sodium bicarbonate, and saturated sodium chloride, rotating and concentrating the organic phase to remove most of the DCM to obtain an oily substance, and finally purifying the crude product by silica gel column chromatography with 200-300 mesh to obtain the target compound norbornene formylhydrazine compound, wherein the volume ratio of petroleum ether / ethyl acetate in the silica gel column chromatography purification process is 20∶1~5∶1.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the 5-norbornene-2-carboxylic acid, substituted phenylhydrazine hydrochloride, triethylamine, EDCI and 4-dimethylaminopyridine is 1.2∶1∶2∶1.2:0.

1.

4. The preparation method according to claim 3, characterized in that: The reaction temperature of the 5-norbornene-2-carboxylic acid and the substituted phenylhydrazine is 25 °C, and the reaction time is 1-5 h.

5. The norbornene formylhydrazine compound prepared by the preparation method according to any one of claims 1 to 4.

6. Use of the norbornene formyl hydrazide compounds as claimed in claim 5 in controlling plant fungi in agriculture or forestry, characterized in that: The plant fungi are Sclerotinia sclerotiorum, Botryosphaeria dothidea, Phytophthora capsici and Phytophthora nicotianae.

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