Preparation method and application of a class of phenylhydrazine carboxylic acid menthyl ester compounds

Abstract

The invention discloses a preparation method and application of a class of phenylhydrazinecarboxylic acid menthyl ester compounds, comprising: esterifying menthol to synthesize menthyl chloroformate, and then reacting menthyl chloroformate with substituted phenylhydrazine in one step to synthesize the phenylhydrazinecarboxylic acid menthyl ester compounds, wherein the compounds have a general formula I: wherein R is H, a halogen, or an alkyl selected from any group; the compounds have good preventive effects on wheat fusarium head blight, apple ring rot fungus, and rapeseed sclerotinia fungus under in vitro conditions, and can be used for preventing and controlling fungal diseases of agricultural or forestry plants. The preparation method of the invention is simple, has a high yield, and has stable product properties.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide synthesis, and specifically relates to a preparation method and application of a class of phenylhydrazine menthyl carboxylate compounds. Background Art

[0002] Crop diseases and insect pests are one of the important constraints that affect the sustainable and healthy development of agricultural products and forest resources. Pesticides, as a special commodity for controlling biological hazards such as pests and diseases of agricultural and forestry crops, 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 resistance. Therefore, the development of new pesticide varieties with targeted effects is crucial for the effective control of plant diseases.

[0003] The main structures of many antimicrobial agents that have been marketed contain amide groups, and amide bonds are also key components of many drugs or pesticides, such as fluopyram, penflufenpyram, flupyraclostrobin, etc. Therefore, when designing compounds, further replacing the amide structure with a hydrazide structure and searching for drug lead compounds with excellent antifungal activity have great theoretical and practical significance for the development of new antifungal pesticides and the prevention and control of agricultural and forestry crop diseases.

[0004] So far, there is no report on the use of phenylhydrazine carboxylic acid menthyl ester compounds as agricultural fungicides. Summary of the invention

[0005] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0006] In view of the above problems and / or the 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 class of phenylhydrazine carboxylic acid menthyl ester compounds having anti-plant pathogenic fungi activity, wherein the phenylhydrazine carboxylic acid menthyl ester compounds have the structural formula:

[0008]

[0009]

[0010] Wherein, R is selected from F, Cl, Br, I, CH 3 CF 3 and OCF 3 .

[0011] Another object of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing a class of menthyl phenylhydrazine carboxylate compounds having anti-plant pathogenic fungi activity.

[0012] In order to solve the above technical problems, the present invention provides the following technical solution: a method for preparing phenylhydrazine carboxylic acid menthyl ester compounds, characterized in that: a method for preparing a class of phenylhydrazine carboxylic acid menthyl ester compounds having anti-plant pathogenic fungi activity, comprising:

[0013] Menthol is esterified to synthesize menthyl chloroformate;

[0014] Menthyl chloroformate was reacted with various substituted phenylhydrazines to synthesize menthyl phenylhydrazine carboxylate compounds.

[0015] As a preferred embodiment of the method for preparing the phenylhydrazine carboxylic acid menthyl ester compound of the present invention, the synthesis of menthyl chloroformate comprises:

[0016] Take menthol and solid triphosgene in a single-necked bottle, add tetrahydrofuran as solvent, and stir at room temperature for 1 hour;

[0017] Then triethylamine was slowly added dropwise using a dropping funnel, and the reaction was carried out for 8 hours. After TLC detection, the reaction was completed, the white solid was removed by filtration, and the filtrate was concentrated by rotary evaporation to remove tetrahydrofuran to obtain a white liquid, which was menthyl chloroformate.

[0018] As a preferred embodiment of the method for preparing the menthyl phenylhydrazine carboxylate compounds of the present invention, the molar ratio of menthol, triphosgene and triethylamine reagent is 1:1.1:1.1.

[0019] As a preferred embodiment of the method for preparing the phenylhydrazine carboxylic acid menthyl ester compound of the present invention, wherein: the synthesis of phenylhydrazine carboxylic acid menthyl ester comprises:

[0020] Dissolve phenylhydrazine hydrochloride in DCM, cool on ice, then add N,N-diisopropylethylamine and stir for 10 minutes;

[0021] Then, menthyl chloroformate was dissolved in DMC, and slowly added to the mixed solution of phenylhydrazine hydrochloride through a dropping funnel, and the reaction was carried out for 3 hours. TLC detected that the reaction of the raw material was complete;

[0022] After the reaction, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotary centrifugation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography to obtain the target compound, menthyl phenylhydrazine.

[0023] As a preferred embodiment of the method for preparing the menthyl phenylhydrazine carboxylate compounds of the present invention, the molar ratio of the menthyl chloroformate, substituted phenylhydrazine hydrochloride and N,N-diisopropylethylamine is 1:1.1:1.2.

[0024] As a preferred embodiment of the method for preparing the menthyl phenylhydrazine carboxylate compounds of the present invention, the menthyl chloroformate reacts with each substituted phenylhydrazine to synthesize the menthyl phenylhydrazine carboxylate compounds, wherein the reaction time is 1 to 3 hours.

[0025] As a preferred embodiment of the method for preparing the phenylhydrazine carboxylic acid menthyl ester compounds of the present invention, the substituted phenylhydrazine includes 4-fluorophenylhydrazine, 4-methylphenylhydrazine, 4-bromophenylhydrazine, 4-trifluoromethylphenylhydrazine, 2-bromophenylhydrazine, 3-chlorophenylhydrazine, 3-fluorophenylhydrazine, 4-chlorophenylhydrazine, 4-trifluoromethoxyphenylhydrazine, 2,4-difluorophenylhydrazine, 2-difluorophenylhydrazine, 4-iodophenylhydrazine, 2,4-dichlorophenylhydrazine, 4-methoxyphenylhydrazine and 3-bromophenylhydrazine.

[0026] Another object of the present invention is to overcome the deficiencies in the prior art and provide the use of the phenylhydrazine carboxylic acid menthyl ester compound product in preventing and controlling plant fungi in agriculture or forestry.

[0027] As a preferred embodiment of the application of the present invention, the plant fungi include potato late blight, pepper phytophthora, tomato gray mold, wheat fusarium, rapeseed sclerotinia and apple ring rot.

[0028] Beneficial effects of the present invention:

[0029] (1) The compound described in the present invention is a derivative of phenylhydrazine formate containing menthyl ester, which has a novel molecular structure, is a new compound, and has distinct chemical structure characteristics. The structural formula contains menthyl formate and phenylhydrazine groups, wherein phenylhydrazine and menthyl formate are connected by a hydrazide bond; the preparation method of the compound described in the present invention is simple, the raw materials are easily available, and the reaction conditions are mild and easy to control.

[0030] (2) The compound described in the present invention is an agent for preventing and controlling plant fungi in the field of agriculture or forestry. This agent shows good effects in preventing and controlling wheat fusarium sclerotinia, rapeseed sclerotinia and apple ring rot. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0032] Figure 1 The figure is a schematic diagram of the preparation method of the phenylhydrazine carboxylic acid menthyl ester compounds in the present invention.

[0033] Figure 2 The figure is a comparison of the treatment effects of different concentrations of I-1 and fluopyram on living apples in the present invention. DETAILED DESCRIPTION

[0034] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0035] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0036] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0037] The schematic diagram of the preparation method of phenylhydrazine carboxylic acid menthyl ester compounds of the present invention is shown in Figure 1 , including the following steps:

[0038] (1) Menthol (CAS: 2216-51-5, purchased from Shanghai Bid Pharmaceutical Co., Ltd.) was esterified to synthesize menthyl chloroformate;

[0039] (2) Menthyl chloroformate is reacted with various substituted phenylhydrazines to synthesize menthyl phenylhydrazine.

[0040] The specific steps are:

[0041] (1) Preparation of Menthyl Chloroformate

[0042] Take menthol (1g, 6.4mmol) and solid triphosgene (2.08g, 7.1mmol) in a 150ml single-mouth bottle, add 20ml tetrahydrofuran to dissolve, and stir for 1h. Slowly add 975μL of triethylamine with a dropping funnel at room temperature, react for 8h, and detect by TLC. After the reaction is complete, filter to remove the white solid, and concentrate the filtrate by rotary evaporation to remove tetrahydrofuran. The yellow-white liquid obtained is menthyl chloroformate;

[0043] (2) Preparation of Menthyl Phenylhydrazine

[0044] 4-Fluorophenylhydrazine, 4-methylphenylhydrazine, 4-bromophenylhydrazine, 4-trifluoromethylphenylhydrazine, 2-bromophenylhydrazine, 3-chlorophenylhydrazine, 3-fluorophenylhydrazine, 4-trifluoromethoxyphenylhydrazine, 2,4-difluorophenylhydrazine, 2-difluorophenylhydrazine, 4-iodophenylhydrazine, 2,4-dichlorophenylhydrazine, 3-bromophenylhydrazine, 2-chlorophenylhydrazine (0.92mmol) were added to 5mL DCM solution, and N,N-diisopropylethylamine (1mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (1.01mmol) was dissolved in 2ml DMC, added to a dropping funnel, and slowly dripped into the mixed solution of phenylhydrazine hydrochloride. The reaction was carried out for 3h. TLC detected that the reaction of the raw material was complete. After the reaction, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotary centrifugation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate was 20:1 to 15:1, to obtain the target compound menthyl phenylhydrazinecarboxylate.

[0045] Example 1

[0046] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-1):

[0047]

[0048] 2-Fluorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-1) was obtained: light yellow solid; yield, 59.5%, mp103.2–104.3℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.07–6.97(m,2H),6.92(t,J=8.0Hz,1H),6.86–6.77(m,1H),6.56(s,1H),5.92(s,1H),4.60(s,1H),2. 23–1.81(m,2H),1.65(s,2H),1.46(s,1H),1.36(s,1H),1.02(s,2H),0.95–0.84(m,6H),0.82–0.57(m,4H). 13 C NMR (150 MHz, CDCl 3): δ156.86, 151.29 (d, J = 238.5Hz), 136.41, 124.58 (d, J = 3.5Hz), 120.82 (d, J = 6.9Hz), 115.18 (d,J=17.2Hz),114.20,76.34,47.40,41.30,34.27,31.47,26.51,23.61,22.10,20.85,16.52.

[0049] Example 2

[0050] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-2):

[0051]

[0052] 3-Fluorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-2) was obtained: white solid; yield, 58.5%, mp114.3–115.9℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.15(td,J=8.2,6.3Hz,1H),6.64–6.46(m,4H),5.71(m,1H),4.61(s,1H),2.12–1.84(m,2H),1.67 (d,J=12.7Hz,2H),1.52–1.42(m,1H),1.35(s,1H),1.03(m,2H),0.96–0.84(m,6H),0.83–0.51(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ164.00(d,J=242.7Hz),156.95,150.33,130.54(d,J=9.6Hz),108.65,107.51(d,J=21.4Hz) ,100.30(d,J=25.9Hz),76.43,47.43,41.35,34.29,31.51,26.50,23.56,22.12,20.86,16.54.

[0053] Example 3

[0054] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-3):

[0055]

[0056] 4-Fluorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC detected that the raw material had reacted completely. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1 to obtain the target menthyl phenylhydrazine formate derivative (I-3): light yellow solid; yield, 58.2%, mp89.2-90.7℃; 1 H NMR (600 MHz, CDCl 3 ): δ6.96–6.91(m,2H),6.77(dd,J=8.6,4.3Hz,2H),6.59–6.21(m,2H),4.59(s,2H),2.07–1.84(m,2H),1.67 (d,J=10.4Hz,2H),1.49–1.43(m,1H),1.35(s,1H),1.09–0.96(m,2H),0.95–0.86(m,6H),0.80–0.55(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ160.04(d,J=242.7Hz),156.06,138.94(d,J=2.8Hz),125.52(d,J=8.2Hz),115.04( d, J=22.37Hz),77.09,47.22,41.35,34.23,31.48,26.49,23.54,22.07,20.82,16.49.

[0057] Example 4

[0058] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-4):

[0059]

[0060] 2-Chlorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-4) was obtained: white solid; yield, 59.6%, mp 91.4–92.5℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.26(dd,J=7.9,1.3Hz,1H),7.19–7.15(m,1H),6.92(d,J=7.6Hz,1H),6.82(td,J=7.8,1.5Hz,1H),6.51(s,1H),6.22(s,1H) 4.59(s,1H),2.23–1.81(m,2H),1.65(s,2H),1.50–1.42(m,1H),1.35(s,1H),1.03(s,2H),0.96–0.84(m,6H),0.82–0.51(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ156.69,144.23,129.52,127.80,121.18,119.13,113.42,76.49,47.37,41.32,34.31,31.50,26.49,23.62,22.11,20.87,16.59.

[0061] Example 5

[0062] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-5):

[0063]

[0064] 3-Chlorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-5) was obtained: light yellow solid; yield, 59.8%, mp107.8–108.7℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.14(t,J=8.0Hz,1H),6.85(dd,J=7.9,1.9Hz,1H),6.81(s,1H),6.68(d,J=8.0Hz,1H),6.44(s,1H),5.75(m,1H),4.61(s,1H ),2.11–1.84(m,2H),1.67(d,J=11.0Hz,2H),1.51–1.45(m,1H),1.35(s,1H),1.03(m,2H),0.97–0.84(m,6H),0.83–0.57(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ157.01,149.61,135.13,130.28,120.81,113.02,111.25,76.40,47.39,41.33,34.25,31.48,26.48,23.51,22.10,20.85,16.38.

[0065] Example 6

[0066] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-6):

[0067]

[0068] 2-Bromophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-6) was obtained: white solid; yield, 58.3%, mp104.8–105.2℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.42(dd,J=7.9,1.3Hz,1H),7.19(t,J=7.3Hz,1H),6.89(s,1H),6.84–6.68(m,2H),6.23(s,1H),4.60(s,1H ),2.13–1.83(m,2H),1.65(s,2H),1.45(s,1H),1.35(s,1H),1.02(s,2H),0.94–0.84(m,6H),0.81–0.55(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ156.71,145.08,132.62,128.41,121.62,113.41,108.57,76.38,47.29,41.23,34.22,31.42,26.44,23.57,22.07,20.84,16.51.

[0069] Example 7

[0070] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-7):

[0071]

[0072] 3-Bromophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-7) was obtained: white solid; yield, 58.3%, mp 97.4–98.9℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.07(t,J=8.0Hz,1H),7.00(ddd,J=7.9,1.7,0.9Hz,1H),6.96(t,J=2.0Hz,1H),6.72(d,J=8.0Hz,1H),6.46(s,1H),4.61(s ,1H),2.11–1.84(m,2H),1.74–1.61(m,2H),1.52–1.44(m,1H),1.37(s,1H),1.03(s,2H),0.96–0.85(m,6H),0.83–0.61(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ156.97,149.70,130.58,123.76,123.25,115.91,111.74,76.44,47.44,41.34,34.26,31.49,26.40,23.58,22.11,20.88,16.48.

[0073] Example 8

[0074] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-8):

[0075]

[0076] 4-Bromophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-8) was obtained: white solid; yield, 58.9%, mp133.5–134.2℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.31(d,J=8.8Hz,2H),6.67(d,J=8.4Hz,2H),6.58(s,1H),4.59(s,1H),2.20–1.79(m,2H),1.67( d,J=12.7Hz,2H),1.50–1.42(m,1H),1.35(s,1H),1.02(s,2H),0.96–0.84(m,6H),0.82–0.59(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ157.01,147.46,132.03,114.71,112.82,76.35,47.38,41.32,34.24,31.45,26.48,23.56,22.10,20.83,16.52.

[0077] Example 9

[0078] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-9):

[0079]

[0080] 4-Iodophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw materials was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-9) was obtained: light yellow solid; yield, 59.1%, mp 139.8–140.3℃ 1 H NMR (600 MHz, CDCl 3 ): δ7.59–7.40(m,2H),6.59(d,J=8.6Hz,2H),6.48(s,1H),4.59(s,1H),2.13–1.83(m,2H),1.72–1. 60(m,2H),1.51–1.42(m,1H),1.35(s,1H),1.13–0.96(m,2H),0.94–0.84(m,6H),0.82–0.60(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ156.97,148.36,137.90,115.20,82.53,76.36,47.34,41.33,34.23,31.44,26.45,23.58,22.11,20.85,16.57.

[0081] Example 10

[0082] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-10):

[0083]

[0084] 4-Methylphenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-10) was obtained: white solid; yield, 56.8%, mp108.5–109.6℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.03(d,J=7.8Hz,2H),6.79–6.59(m,3H),5.11(s,1H),4.61(s,1H),2.27(s,3H),2.12–1.89(m,2 H),1.67(s,2H),1.51–1.44(m,1H),1.37(s,1H),1.02(s,2H),0.95–0.86(m,6H),0.83–0.60(m,4H). 13 CNMR (150MHz, CDCl 3 ): δ157.06,145.92,130.19,129.69,113.27,75.94,47.38,41.35,34.27,31.42,26.45,23.57,22.08,20.82,20.60,16.52.

[0085] Embodiment 11

[0086] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-11):

[0087]

[0088] 4-Trifluoromethylphenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-11) was obtained as a light yellow solid. The yield was 57.1%, and the mp was 116.2.8–117.3℃. 1 H NMR (600 MHz, CDCl 3 ): δ7.03(d,J=7.8Hz,2H),6.71(d,J=7.8Hz,2H),6.67(s,1H),5.89(s,1H),4.61(s,1H),2.12–1.89(m,2H),1 .67(s,2H),1.51–1.44(m,1H),1.37(s,1H),1.04(s,2H),0.91(s,3H),0.97–0.86(m,6H),0.82–0.52(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ156.94,151.14,126.68(d,J=3Hz),124.65(q,J=269.3Hz),122.71(q,J=32.2H z),112.38,76.65,47.44,41.35,34.25,31.50,26.57,23.60,22.10,20.81,16.54.

[0089] Example 12

[0090] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-12):

[0091]

[0092] 4-Trifluoromethoxyphenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC detected that the raw material had reacted completely. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-12) was obtained: light yellow solid; yield, 55.1%, mp 97.1–97.9℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.07(d,J=8.5Hz,2H),6.89–6.59(m,3H),5.68(m,1H),4.61(s,1H),2.13–1.83(m,2H),1.67(d, J=12.7Hz,2H),1.51–1.42(m,1H),1.36(s,1H),1.03(s,2H),0.95–0.83(m,6H),0.82–0.55(m,4H). 13 CNMR (150MHz, CDCl 3 ): δ157.14,147.05,143.06,122.32,120.71(q,J=254.3Hz),113.69,76.47,47.42,41.37,34.26,31.48,26.51,23.57,22.07,20.79,16.54.

[0093] Example 13

[0094] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-13):

[0095]

[0096] 2,4-Difluorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-13) was obtained: light yellow solid; yield, 59.5%, mp101.3–102.3℃; 1 H NMR (600 MHz, CDCl 3 ): δ6.90(td,J=9.0,5.4Hz,1H),6.86–6.76(m,2H),6.61(s,1H),5.84(m,1H),4.61(s,1H),2.12–1.87(m,2 H),1.73–1.63(m,2H),1.53–1.44(m,1H),1.37(s,1H),1.04(s,2H),0.96–0.86(m,6H),0.83–0.60(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ156.90(dd,J=239.8,10.78Hz),156.84,150.92(dd,J=241.8,13.10Hz),132.99(dd,J=15.6,6.2Hz),115.13,111. 04(dd,J=22.0,3.6Hz),103.96(t,J=47.49Hz),76.55,47.40,41.33,34.29,31.51,26.46,23.62,22.09,20.84,16.50.

[0097] Embodiment 14

[0098] Prepare phenylhydrazine carboxylic acid menthyl ester derivative (I-14):

[0099]

[0100] 2,4-Dichlorophenylhydrazine (1.01mmol) was added to 5mL DCM solution, and then N,N-diisopropylethylamine (1.2mmol) was added and stirred in an ice bath for 10min. Then, menthyl chloroformate (0.92mmol) was dissolved in 2ml DMC and slowly added to the mixed solution of phenylhydrazine hydrochloride. The reaction was continued for 3h. TLC showed that the reaction of the raw material was complete. After the reaction was completed, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography. The volume ratio of petroleum ether / ethyl acetate was 20:1 to 15:1. The target menthyl phenylhydrazine formate derivative (I-14) was obtained: light yellow solid; yield, 58.6%, mp75.5–76.7℃; 1 H NMR (600 MHz, CDCl 3 ): δ7.28(d,J=2.3Hz,1H),7.15(dd,J=8.7,2.3Hz,1H),6.86(d,J=8.4Hz,1H),6.45(s,1H),6.20(s,1H),4.58(s,1H),2.1 4–1.82(m,2H),1.67(d,J=9.7Hz,2H),1.50–1.43(m,1H),1.35(s,1H),1.03(s,2H),0.95–0.85(m,6H),0.82–0.48(m,4H). 13 C NMR (150 MHz, CDCl 3 ): δ157.42,143.75,128.40,125.80,119.97,114.65,77.16,47.92,41.89,34.82,32.04,27.09,24.19,22.70,21.43,17.12.

[0101] Embodiment 15

[0102] Bactericidal activity (in vitro) experiment:

[0103] All the test strains in this experiment were purchased from the official website of China Agricultural Microbial Culture Collection (ACCC) and China Forestry Microbial Culture Collection (CFCC), including wheat fusarium sphaeroides (ACCC 31060), apple ring rot (ACCC 36164), tomato gray mold (ACCC 36027), rapeseed sclerotinia (ACCC 30096), pepper phytophthora (ACCC 36279) and potato late blight (ACCC 36164). MYA-1113 TM). The culture medium used is potato agar glucose medium (PDA for short). PDA culture medium formula: 200g potato (peeled), 20g glucose, 15g agar, 1000mL distilled water, preparation method: wash and peel the potato, weigh 200g and cut into small pieces, add water and cook until soft (boil for 20-30 minutes, until it can be pierced by a glass rod), filter into a beaker with eight layers of gauze, add 15-20g agar according to experimental needs, add 20g glucose, stir evenly, cool slightly after fully dissolved, add water to 1000mL, sterilize at 121℃ for 15 minutes after packaging, and set aside after cooling.

[0104] Experimental method: Growth rate method was used.

[0105] (1) First, culture the seven plant fungi on a PDA plate at 25°C for about 3-6 days for later use;

[0106] (2) Heat and melt the PDA medium, cool it to 45-50°C, add 50 mg / L of the test compound to prepare a medium containing 50 mg / L of the drug solution, and pour it into a culture dish to cool, with fluopyrabendazim (fluopyrabendazim) as a positive control;

[0107] (3) Using aseptic operation procedures, use a cork puncher to punch a round bacterial cake (0.50 cm in diameter) at the edge of the hyphae of each strain after 6 days of culture (the growth conditions should be as consistent as possible), then use an inoculation needle to pick it to the center of the drug-containing plate, and then place the culture dish upside down in an incubator (28°C) for culture;

[0108] (4) Observe and measure the growth of mycelium at different times after treatment, measure the diameter using the cross method, process the data, and calculate the inhibition rate;

[0109] Inhibition rate (%) = (control mycelium diameter - treated mycelium diameter) / (control mycelium diameter - 0.5) × 100;

[0110] Each treatment was repeated 3 times.

[0111] Table 1. Results of the inhibitory activity test of phenylhydrazine carboxylic acid menthyl ester compounds against seven agricultural pathogenic fungi

[0112]

[0113] Note: Each treatment was repeated three times in the experiment, and the data in the table are the average values ​​of the three repetitions.

[0114] Table 2. EC values ​​of some compounds 50 Value (mg / L)

[0115]

[0116]

[0117] The results of the fungicidal activity determination of the experimental groups I-1 to I-14 and the control agent fluopyram are shown in Tables 1 and 2. As can be seen from Tables 1 and 2, at a concentration of 50 mg / L, compounds I-1 to I-14 showed different degrees of antibacterial activity against 6 plant fungi, some of which showed relatively good antibacterial activity against apple ring rot fungus, and moderate to good inhibitory activity against wheat fusarium and rapeseed sclerotinia fungus. The inhibition rate of some compounds against apple ring rot fungus was higher than that of the control agent fluopyram.

[0118] Considering that some target compounds have good inhibitory activity against wheat fusarium, apple ring rot and rapeseed sclerotinia, the EC of some compounds with higher inhibition rate was tested. 50 As can be seen from Table 2, the EC values ​​of the target compounds against wheat fusarium 50 The activity of compound I-13 against Sclerotinia sclerotiorum EC 50 The value reached 0.565 mg / L, close to the positive control drug fluopyram 0.281 mg / L. The target compounds were all less than 1.0 mg / L for apple ring rot fungus. Among them, the EC value of compound I-1 for apple ring rot fungus was 50 The value is 0.465 mg / L, which is close to the positive control drug fluopyram 0.322 mg / L. This shows that the inhibitory activity of these three compounds against wheat fusarium and apple ring rot is comparable to that of the positive control drug fluopyram, and has the potential to develop antifungal agents.

[0119] Example 16

[0120] In vivo antibacterial assay

[0121] Apple fruits with uniform texture and size purchased from the market were washed with sterile water, then washed with 75% ethanol, and dried in the shade at room temperature. Compound I-1 and fluopyrab were weighed and dissolved in 0.2% Tween-80 aqueous solution to prepare two concentrations of 200 mg / L and 100 mg / L.

[0122] Then spray the surface of the apple (spray volume is 3ml, one concentration), spray evenly, and then dry naturally in the shade. After there is no liquid on the leaf surface, scratch the leaf epidermis with a blade, the scratch area is 3mm, and inoculate the apple ring rot fungus cake (0.5mm diameter). Inoculate 9 cakes of each concentration and average them on three apples respectively. The positive control is flupyraclostrobin, and the blank control is DMSO. After the plants are placed in (25±2℃ and 95% relative humidity) for 7 days, the diameter of the lesions is measured and the inhibition rate is calculated. The calculation formula of the inhibition rate (%) is: (blank control lesion diameter-test compound lesion diameter) / (blank control lesion diameter-0.5)×100.

[0123] Table 3 Biological activities of compound I-1 and trifloxystrobin against apple ring rot pathogen

[0124]

[0125] As shown in Table 3 and Figure 2 As shown, at a concentration of 200 mg / L, the protective activity and therapeutic activity of compound I-1 were 94.7% and 74.1%, respectively, which were superior to the positive control fluopyrab 86.2% and 73.3%.

[0126] When the concentration was further reduced to 100 mg / L, the protective activity and therapeutic activity of compound I-1 were 74.6% and 45.3%, respectively, which were also better than the positive control flupyraclostrobin of 69.3% and 34.0%. The results showed that compound I-1 has potential value in the development of antifungal pesticides.

[0127] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing menthyl phenylhydrazine compounds, Features: include, Menthol is esterified to synthesize menthyl chloroformate; Menthyl chloroformate reacts with various substituted phenylhydrazines to synthesize menthyl phenylhydrazine formate compounds; The substituted phenylhydrazine includes 2-fluorophenylhydrazine, 3-fluorophenylhydrazine, 4-fluorophenylhydrazine, 2-bromophenylhydrazine, 3-bromophenylhydrazine, 4-bromophenylhydrazine, 4-iodophenylhydrazine, 4-methylphenylhydrazine, 4-trifluoromethylphenylhydrazine, 4-trifluoromethoxyphenylhydrazine, 2,4-difluorophenylhydrazine, and 2,4-dichlorophenylhydrazine; The phenylhydrazine carboxylic acid menthyl ester compound has the structural formula: Among them, R is 2-fluoro, 3-fluoro, 4-fluoro, 2-bromo, 3-bromo, 4-bromo, 4-iodo, 4-methyl, 4-trifluoromethyl, 4-trifluoromethoxy, 2,4-difluoro and 2,4-dichloro.

2. The method for preparing the menthyl phenylhydrazine compound according to claim 1, Features: The synthesis of menthyl chloroformate comprises: Take menthol and solid triphosgene in a single-necked bottle, add tetrahydrofuran as solvent, and stir at room temperature for 1 hour; Then triethylamine was slowly added dropwise using a dropping funnel, and the reaction was carried out for 8 hours. After TLC detection, the reaction was completed, the white solid was removed by filtration, and the filtrate was concentrated by rotary evaporation to remove tetrahydrofuran to obtain a white liquid, which was menthyl chloroformate.

3. The method for preparing the menthyl phenylhydrazine compound according to claim 2, Features: The molar ratio of the menthol, triphosgene and triethylamine reagent is 1:1.1:1.

1.

4. A method for preparing the menthyl phenylhydrazine carboxylate compound as claimed in any one of claims 1 to 3, Features: The synthetic menthyl phenylhydrazine carboxylate comprises: Dissolve phenylhydrazine hydrochloride in DCM, cool on ice, then add N,N-diisopropylethylamine and stir for 10 minutes; Then, menthyl chloroformate was dissolved in DMC, and slowly added to the mixed solution of phenylhydrazine hydrochloride through a dropping funnel, and the reaction was carried out for 3 hours. TLC detected that the reaction of the raw material was complete; After the reaction, the mixture was extracted with water and dichloromethane and washed with saturated sodium chloride. The organic phase was concentrated by rotary centrifugation to remove most of the DCM to obtain an oily substance. Finally, the crude product was separated and purified by 200-300 mesh silica gel column chromatography to obtain the target compound, menthyl phenylhydrazine.

5. The method for preparing the menthyl phenylhydrazine compound according to claim 4, Features: The molar ratio of menthyl chloroformate, substituted phenylhydrazine hydrochloride and N,N-diisopropylethylamine is 1:1.1:1.

2.

6. The method for preparing the menthyl phenylhydrazine compound according to claim 1, Features: The menthyl chloroformate reacts with each substituted phenylhydrazine to synthesize menthyl phenylhydrazine carboxylate compounds, wherein the reaction time is 1 to 3 hours.

7. Application of the menthyl phenylhydrazine carboxylate compounds prepared by the preparation method according to claim 1 in preventing and controlling plant fungi in agriculture or forestry. Features: The plant fungi are wheat fusarium rust, rapeseed sclerotinia sclerotium and apple ring rot.

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