A pleuromutilin derivative containing an ester group, and its preparation method and use

Abstract

The present application relates to a truncated pleuromutilin derivative containing an ester group, and a preparation method and use thereof. The structural formula is shown in Formula T: By testing the antibacterial activity of the truncated pleuromutilin derivative containing an ester group, it is proved that it has good antibacterial activity against plant bacterial diseases and is superior to truncated pleuromutilin. It can be used to prepare a plant pathogen control agent, and its preparation method is simple and the production cost is low.

Description

Technical Field

[0001] The present application relates to the technical field of pesticides, and in particular to an ester-containing pleuromutilin derivative, a preparation method and use thereof. Background Art

[0002] Plant bacterial diseases cause serious harm to agricultural production due to their frequent, intermittent and regional outbreaks. Among them, rice bacterial leaf blight and bacterial leaf streak caused by Xanthomonas oryzae pv.oryzae (Xoo) and Xanthomonas oryzae pv.oryzicola (Xoc) usually reduce rice production by 10-40%, seriously affecting rice yield and safety. Methods for preventing and controlling the two diseases include using plant host resistance or cultivating less susceptible varieties, and adopting chemical and biological control measures. Among them, chemical control is the main prevention and control method at present. At present, copper-containing fungicides are mainly used to control bacterial diseases, but the dependence on copper-containing fungicides leads to copper resistance in the soil and copper accumulation reaching toxic levels and potential toxicity in human endocrine. In addition, the long-term use of traditional pesticides such as zinc thiazole, chlorothiazide and thiophanate-methyl leads to the risk of increased resistance of plant bacterial diseases and excessive pesticide residues, making it difficult to effectively control bacterial diseases in a short period of time once they break out. Therefore, finding new, efficient, low-risk and safe agricultural fungicides is an important research direction in the field of pesticide creation.

[0003] Pleuromutulin, isolated and extracted from the basidiomycetes Pleurotus mutilus (Fr.) Sacc. and Pleurotus Passeckerianus Pilat, has become one of the hot spots in the current bactericidal research due to its novel antibacterial mechanism and slow drug resistance. The mode of action of pleuromutilin is to form an induced fit effect with the peptidyl transferase center (PTC) of the bacterial ribosome 50S subunit, causing its subunits to rearrange, interfering with the binding of tRNA to the P-site and A-site, thereby inhibiting protein synthesis. So far, commercial drugs containing pleuromutilin structure have been developed, including Tiamulin and Valnemulin, which are antibacterial drugs for treating livestock and poultry diseases caused by Gram-positive bacteria, mycoplasmas and spirochetes, as well as Retapamulin and Lefamulin, which are used to treat Staphylococcus aureus. However, the research on pleuromutilin and its derivatives is mainly concentrated in the fields of veterinary drugs and medicine, and there are few related reports in the field of pesticides. In 2023, our research team applied for invention patents for "a pleuromutilin suspension and its preparation method" and "a pleuromutilin wettable powder and its preparation method". Its preparations have a high control effect on various agricultural diseases such as rice bacterial blight. The field trials of pesticide registration for the control of rice bacterial blight, rice bacterial streak and citrus canker were carried out in Hunan, Guizhou, Guangxi, Hainan, Jiangsu, Zhejiang and Anhui. The test results showed that the average control effect of 20% pleuromutilin suspension-300g / hectare was 63.40%, which was better than or equivalent to the control effect of the control agent 20% zinc thiazole suspension. Therefore, the structural modification of pleuromutilin has broad prospects for application in agricultural antibacterial. We used pleuromutilin as a guide for derivative design, in order to screen out new pleuromutilin derivatives with higher activity. Summary of the invention

[0004] One of the purposes of the present invention is to provide a preparation method and application of ester-containing pleuromutilin derivatives, and to introduce an ester structure into the C14 side chain as a flexible chain for splicing to synthesize ester-containing pleuromutilin derivatives.

[0005] Another object of the present invention is to provide an intermediate compound for preparing the above-mentioned compound or its stereoisomer, or its salt or solvate and a preparation method thereof.

[0006] Another object of the present invention is to provide a composition containing the above compound or its stereoisomer, or its salt or solvate.

[0007] Another object of the present invention is to provide the use of the above compound or its stereoisomer, or its salt or solvate, or the composition.

[0008] Another object of the present invention is to provide a method for controlling agricultural pests and diseases using the above-mentioned compound or its stereoisomer, or its salt or solvate, or the composition.

[0009] To achieve the above objectives, this application provides the following technical solutions:

[0010] A pleuromutilin derivative containing an ester group, or a salt thereof, or a solvate thereof, the general structural formula of which is as follows:

[0011]

[0012] In the formula: R is selected from an optionally substituted or unsubstituted alkyl or alkylene group, an optionally substituted or unsubstituted alkenyl group, an optionally substituted or unsubstituted aromatic group, an optionally substituted or unsubstituted heteroaromatic group, an optionally substituted or unsubstituted alkoxy group, or an optionally substituted or unsubstituted ester group.

[0013] Preferably, R is selected from hydrogen, methyl, ethyl, propyl, butyl, chloromethyl, bromomethyl, fluoromethyl, dichloromethyl, dibromomethyl, difluoromethyl, trichloromethyl, tribromomethyl, trifluoromethyl, dichloroethyl, dibromoethyl, difluoroethyl, trichloroethyl, tribromoethyl, trifluoroethyl, dichloropropyl, dibromopropyl, difluoropropyl, trichloropropyl, tribromopropyl, trifluoropropyl, dichlorobutyl, dibromobutyl, difluorobutyl, trichlorobutyl, tribromobutyl, trifluorobutyl, vinyl, phenyl, benzyl, NCCH2-, thienyl, pyridyl, furanyl, HOOC(CH2)2-, HOOC(CH2)3-, CH3(CH2)2O-, CH3OC(O)-, CH3C(O)OCH2-.

[0014] More preferably, it is selected from the following specific compounds:

[0015] Compound T1: (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-acetoxyacetate;

[0016] Compound T2: (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-chloroacetoxy)acetate;

[0017] Compound T3: (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-bromoacetoxy)acetate;

[0018] Compound T4: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-2,2-dichloroacetate;

[0019] Compound T5: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-2,2,2-trichloroacetate;

[0020] Compound T6: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-3-chloropropionate;

[0021] Compound T7: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-4-chlorobutyrate;

[0022] Compound T8: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-5-chlorovalerate;

[0023] Compound T9: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl propionate;

[0024] Compound T10: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl butyrate;

[0025] Compound T11: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl benzoate;

[0026] Compound T12: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-phenylethoxy)acetate;

[0027] Compound T13: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethylthiophene-2-carboxylate;

[0028] Compound T14: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl isonicotinate;

[0029] Compound T15: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl acrylate;

[0030] Compound T16: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]an-5-yl-2-(2-cyanoacetoxy)acetate;

[0031] Compound T17: 4-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethoxy)-4-oxysuccinic acid;

[0032] Compound T18: 5-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethoxy)-5-oxopentanoic acid;

[0033] Compound T19: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-((propyloxycarbonyl)oxy)acetate;

[0034] Compound T20: methyl 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxoethyl oxalate;

[0035] Compound T21: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]an-5-yl-2-(2-acetoxyacetoxy)acetate;

[0036] Compound T22: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-(1H-1,2,4-triazol-1-yl)acetoxy)acetate;

[0037] Compound T23: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-(5-amino-1,3,4-thiadiazol-2-yl)thio)ethoxy)acetate;

[0038] Compound T24: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]an-5-yl-2-(2-morpholinoacetoxy)acetate;

[0039] Compound T25: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]an-5-yl-2-(2-thiomorpholinoacetoxy)acetate;

[0040] Compound T26: tert-butyl-4-(2-(2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy-2-oxoacetyl)-2-oxoacetyl)piperazine-1-carboxylate;

[0041] Compound T27: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-(piperazin-1-yl)acetoxy)acetate;

[0042] Compound T28: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]an-5-yl-2-((2-thiomorpholin-4-thiocarbonyl)thio)acetoxy)acetate;

[0043] Compound T29: (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(diethylglycyloyl)oxyacetate;

[0044] Compound T30: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-acetoxy-3-(1H-1,2,4-triazol-1-yl)propanoate;

[0045] Compound T31: 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-acetoxy-3-thiomorpholinylpropanoate.

[0046] The present application also provides a method for preparing a pleuromutilin derivative containing an ester group, comprising the following steps:

[0047] (1) Using pleuromutilin and substituted acyl chloride as raw materials, adding a solvent and an acid-binding agent, reacting at room temperature, adding water and ethyl acetate for extraction after the reaction, removing the solvent by rotary evaporation, and separating by column chromatography to obtain a pleuromutilin derivative containing an ester group.

[0048]

[0049] (2) Using pleuromutilin and substituted acid or anhydride as raw materials, adding a solvent, a condensing agent and an acid binding agent, reacting at room temperature, adding water and ethyl acetate for extraction after the reaction, removing the solvent by rotary evaporation, and separating by column chromatography to obtain a pleuromutilin derivative containing an ester group.

[0050]

[0051] (3) Using T2 or T6 as a raw material, adding a substituted amine and an acid-binding agent, reacting at room temperature, removing the solvent by rotary evaporation after the reaction, adding water and ethyl acetate for extraction, removing ethyl acetate by rotary evaporation, and separating by column chromatography to obtain ester-containing pleuromutilin derivatives T22-T31.

[0052] BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 is the therapeutic activity of T2 and pleuromutilin against rice bacterial leaf streak at 50 and 10 μg / mL;

[0054] Figure 2 is the protective activity of T2 and pleuromutilin against rice bacterial leaf streak at 50 and 10 μg / mL;

[0055] Figure 3 is the therapeutic activity of compound T2 against rice bacterial blight at 10 μg / mL;

[0056] Figure 4 is the protective activity of compound T2 against rice bacterial blight at 50 μg / mL;

[0057] Figure 5 It is the protective activity of compound T2 against citrus canker;

[0058] Figure 6 The figures are the effect diagrams of compound T2 in controlling citrus canker in the field, wherein (a) is a control diagram before and after CK, and its disease index increased from 3.52 to 12.83; (b) is a picture taken 7 days after 750 times of 20% chloroacetyl truncated pleuromutilin (T2); (c) is a picture taken 7 days after 1000 times of 20% chloroacetyl truncated pleuromutilin (T2), and its disease index decreased from 3.68 to 2.71. Example

[0059] Now describe in detail various exemplary embodiments of the present application, this detailed description should not be considered as a limitation of the present application, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present application. It should be understood that the terms described in the present application are only for describing a particular embodiment and are not intended to limit the present application. Unless otherwise stated, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art described in the present application. Although the present application only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present application. All raw materials and solvents used in the examples are commercially available products of corresponding purity.

[0060] Example 1

[0061] Preparation of compound T1 ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-acetoxyacetate):

[0062] Pleuromutilin (0.50 g, 1.29 mmol) and acetyl chloride (0.13 g, 1.55 mmol) were dissolved in DMF by stirring, and triethylamine (0.16 g, 1.55 mmol) was slowly added dropwise. The reaction was carried out at room temperature. The developing solvent was ethyl acetate (v): petroleum ether (v) = 3:2. Potassium permanganate was used for color development. After the reaction, the reaction solution was added into water, extracted with ethyl acetate, dried, and the ethyl acetate was removed by rotary evaporation. Compound T1 was obtained by column chromatography.

[0063] Example 2

[0064] The preparation method of compound T2 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-chloroacetoxy)acetate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of chloroacetyl chloride.

[0065] Example 3

[0066] The preparation method of compound T3 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-bromoacetoxy)acetate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of bromoacetyl bromide.

[0067] Example 4

[0068] Preparation of compound T4 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-2,2-dichloroacetate):

[0069] Pleuromutilin (1.00 g, 2.59 mmol) and DMAP (31.90 mg, 0.26 mmol) were dissolved in dichloromethane, and dichloroacetic acid (0.44 g, 3.37 mmol) was added followed by slow addition of DCC (0.57 g, 2.72 mmol). The reaction was carried out at room temperature. The developing solvent was ethyl acetate (v): petroleum ether (v) = 3:2. Potassium permanganate was used for color development. After the reaction, the reaction solution was added to water, extracted with dichloromethane, dried, and the solvent was removed by rotary evaporation. Compound T4 was obtained by column chromatography.

[0070] Example 5

[0071] The preparation method of compound T5 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-2,2,2-trichloroacetate) is as in Example 4, except that dichloroacetic acid is replaced by an equimolar amount of trichloroacetic acid.

[0072] Example 6

[0073] The preparation method of compound T6 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-3-chloropropionate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of chloropropionyl chloride.

[0074] Example 7

[0075] The preparation method of compound T7 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-4-chlorobutyrate) is as in Example 1, except that acetyl chloride is replaced by an equal molar amount of chlorobutyryl chloride.

[0076] Example 8

[0077] The preparation method of compound T8 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl-5-chlorovalerate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of chlorovaleryl chloride.

[0078] Example 9

[0079] The preparation method of compound T9 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl propionate) is the same as that in Example 1, except that acetyl chloride is replaced by an equimolar amount of propionyl chloride.

[0080] Example 10

[0081] The preparation method of compound T10 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethylbutyrate) is the same as that in Example 1, except that acetyl chloride is replaced by an equimolar amount of butyryl chloride.

[0082] Embodiment 11

[0083] The preparation method of compound T11 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl benzoate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of benzoyl chloride.

[0084] Example 12

[0085] The preparation method of compound T12 (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-phenylethoxy) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of phenylacetyl chloride.

[0086] Embodiment 13

[0087] The preparation method of compound T13 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethylthiophene-2-carboxylate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of thiophenecarbonyl chloride.

[0088] Embodiment 14

[0089] The preparation method of compound T14 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl isonicotinate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of picolinoyl chloride.

[0090] Embodiment 15

[0091] The preparation method of compound T15 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethyl acrylate) is the same as that in Example 1, except that acetyl chloride is replaced by an equal molar amount of acryloyl chloride.

[0092] Example 16

[0093] The preparation method of compound T16 (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-cyanoacetoxy)acetate) is the same as that in Example 4, except that dichloroacetic acid is replaced by an equal molar amount of cyanoacetic acid.

[0094] Embodiment 17

[0095] The preparation method of compound T17 (4-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethoxy)-4-oxysuccinic acid) is the same as that in Example 4, except that dichloroacetic acid is replaced by an equimolar amount of succinic anhydride.

[0096] Embodiment 18

[0097] The preparation method of compound T18 (5-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxyethoxy)-5-oxopentanoic acid) is the same as that in Example 4, except that dichloroacetic acid is replaced by an equal molar amount of glutaric anhydride.

[0098] Embodiment 19

[0099] The preparation method of compound T19 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-((propyloxycarbonyl)oxy)acetate) is the same as that in Example 4, except that dichloroacetic acid is replaced by an equimolar amount of propyl chloroformate.

[0100] Embodiment 20

[0101] The preparation method of compound T20 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-oxoethyl methyl oxalate) is the same as that in Example 4, except that dichloroacetic acid is replaced by an equimolar amount of methyl oxalyl chloride.

[0102] Embodiment 21

[0103] The preparation method of compound T21 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-acetoxyacetoxy)acetate) is as in Example 4, except that dichloroacetic acid is replaced by an equal molar amount of acetoxyacetyl chloride.

[0104] Embodiment 22

[0105] Preparation of compound T22 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-(1H-1,2,4-triazol-1-yl)acetoxy)acetate):

[0106] T2 (1.00 g, 2.20 mmol) and triazole (0.17 g, 2.42 mmol) were dissolved in acetonitrile by stirring, and potassium carbonate (0.91 g, 6.59 mmol) was added. The reaction was carried out at room temperature. The developing solvent was ethyl acetate (v): petroleum ether (v) = 1:1. Potassium permanganate was used for color development. After the reaction, the solvent was removed by rotary evaporation, and water and ethyl acetate were added for extraction. The ethyl acetate was removed by rotary evaporation, and compound T22 was obtained by column chromatography.

[0107] Embodiment 23

[0108] The preparation method of compound T23 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-(5-amino-1,3,4-thiadiazol-2-yl)thio)ethoxy)acetate) is the same as that in Example 22, except that the triazole is replaced by an equimolar amount of aminothiadiazolthiol.

[0109] Embodiment 24

[0110] The preparation method of compound T24 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-morpholinoacetoxy)acetate) is the same as that in Example 22, except that triazole is replaced by an equimolar amount of morpholine.

[0111] Embodiment 25

[0112] The preparation method of compound T25 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-thiomorpholinoacetoxy)acetate) is the same as that in Example 22, except that triazole is replaced by an equimolar amount of thiomorpholine.

[0113] Embodiment 26

[0114] The preparation method of compound T26 (tert-butyl-4-(2-(2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy-2-oxoacetyl)-2-oxoacetyl)piperazine-1-carboxylate) is the same as that in Example 22, except that triazole is replaced by an equimolar amount of Boc-piperazine.

[0115] Embodiment 27

[0116] Preparation of compound T27 ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(2-(piperazin-1-yl)acetoxy)acetate):

[0117] 0.50 g of T26 was dissolved in dichloromethane, and trifluoroacetic acid was added for deprotection for 20 h. T27 was obtained after rotary evaporation and column chromatography.

[0118] Embodiment 28

[0119] The preparation method of compound T28 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-((2-thiomorpholine-4-thiocarbonyl)thio)acetoxy)acetate) is as in Example 22, except that triazole is replaced by an equal molar amount of thiomorpholine and an equal molar amount of carbon disulfide.

[0120] Embodiment 29

[0121] The preparation method of compound T29 ((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl-2-(diethylglycylglycyl)oxyacetate) is the same as that in Example 22, except that triazole is replaced by an equimolar amount of diethylamine.

[0122] Embodiment 30

[0123] The preparation method of compound T30 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-acetoxy-3-(1H-1,2,4-triazol-1-yl)propanoate) is as in Example 22, except that T2 is replaced by an equal molar amount of T6, and triazole is replaced by an equal molar amount of triazole.

[0124] Embodiment 31

[0125] The preparation method of compound T31 (2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propylcyclopenta[8]alkane-5-yl)oxy)-2-acetoxy-3-thiomorpholinylpropanoate) is as in Example 22, except that T2 is replaced by an equal molar amount of T6, and triazole is replaced by an equal molar amount of thiomorpholine.

[0126] Example 1-31 Preparation of ester-containing pleuromutilin derivatives The physicochemical properties are shown in Table 1, and the nuclear magnetic resonance spectroscopy ( 1 HNMR) and carbon spectra ( 13 C NMR) data are shown in Table 2.

[0127] Table 1 Physicochemical properties of ester-containing pleuromutilin derivatives prepared in Examples 1-31

[0128]

[0129]

[0130] Table 2 Nuclear magnetic resonance spectrum data of ester-containing pleuromutilin derivatives prepared in Examples 1-31

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142] Activity Test Example 1

[0143] In vitro antimicrobial activity test:

[0144] (1) Test method

[0145] The in vitro bioactivity of the target compound against rice bacterial leaf streak pathogen, rice bacterial leaf blight pathogen, citrus canker pathogen, kiwi canker pathogen, and peach punch pathogen was determined by turbidity method, and 5 corresponding concentration gradients were set for EC50 value determination, and the results were repeated three times. The specific operation is as follows:

[0146] Preparation of nutrient agar medium (NA): Add 3 g beef extract, 5 g peptone, 1 g yeast powder, and 10 g glucose to a beaker, dilute to 1000 mL with secondary water, stir to dissolve, adjust the pH to 7.0-7.2 with 5% NaOH solution, add 18 g agar, sterilize at 121°C for 20 min, and store at room temperature for use.

[0147] Preparation of nutrient broth (NB): Add 3 g beef extract, 5 g peptone, 1 g yeast powder, and 10 g glucose to a beaker, dilute to 1000 mL with secondary water, stir to dissolve, adjust pH to 7.0-7.2 with 5% NaOH solution, sterilize at 121°C for 20 min, and store at room temperature for use.

[0148] Activation of bacteria: Seal the sterile culture dish inoculated with the NA medium by inoculation loop streaking, and place it upside down in a 28°C incubator for growth. Add a single colony from the NA medium to the NB medium, and culture at 28°C and 180 rpm with shaking until the growth logarithmic phase.

[0149] Preparation of the drug: Weigh 2.0 mg of the target compound, add 100 μL of DMSO to dissolve, take different volumes of the solution and add them to centrifuge tubes, add DMSO to 100 μL, add 3.9 mL of Tween 20 (0.1%), take 1 mL of the prepared drug and add it to a sterilized 4 mL NB medium test tube, three parallels for each concentration, take 50 μL of the bacterial solution and add it to the test tube, shake and culture in a constant temperature shaker (28°C, 180 rpm) for 24 to 48 hours until the logarithmic growth phase, and measure the absorbance (OD 595 ), the inhibition rate is calculated as follows:

[0150] Corrected absorbance = culture absorbance - sterile drug absorbance

[0151]

[0152] Table 3 In vitro biological activity of the compounds of the examples against Xoc

[0153]

[0154]

[0155] The in vitro biological activity of the compounds against Xoc was determined by turbidity assay. The test results in Table 3 show that the EC values ​​of the compounds against Xoc 50 The values ​​all showed excellent antibacterial activity. Among them, the EC values ​​of compounds T2, T16, T22, and T23 50 The values ​​were 0.35, 0.22, 0.31, and 0.17 μg / mL, respectively, which were significantly better than the control agents thiophanate-methyl (42.6 μg / mL) and thiothiazide zinc (22.6 μg / mL) and the lead compound pleuromutilin (1.23 μg / mL).

[0156] Table 4 In vitro biological activity of the compounds of the examples against Xoo

[0157]

[0158]

[0159] The in vitro biological activity of the compounds against Xoo was determined by turbidity method. The test results in Table 4 show that the target compounds in this series have excellent antibacterial activity against Xanthomonas oryzae. Among them, the EC values ​​of compounds T2, T3, T4, and T6 are 50 The values ​​were 0.24, 0.24, 0.14, and 0.09 μg / mL, respectively, which were better than the control agents thiophanate-methyl (65.88 μg / mL) and thiothiazide zinc (19.85 μg / mL) and the lead compound pleuromutilin (1.33 μg / mL).

[0160] Table 5 In vitro biological activity of the compounds of the examples against citrus canker

[0161]

[0162] The in vitro biological activity of the compounds against citrus canker bacteria was determined by turbidity method. The test results in Table 5 show that the EC values ​​of compounds T2 and T6 are 50 The values ​​were 0.75 and 0.16 μg / mL, respectively, which were significantly better than the control agents zinc thiazole (64.59 μg / mL) and thiophanate-methyl (87.71 μg / mL) and the lead compound pleuromutilin (0.89 μg / mL).

[0163] Table 6 In vitro biological activity of the compounds of the examples against kiwifruit canker pathogens

[0164]

[0165] The in vitro biological activity of the compounds against kiwifruit canker pathogen was determined by turbidity method. The test results in Table 6 show that the EC values ​​of compounds T2 and T6 are 50 The values ​​were 6.19 and 14.10 μg / mL, respectively, which were significantly better than the control agents zinc thiazole (51.15 μg / mL) and copper thiazole (133.20 μg / mL).

[0166] Table 7 In vitro biological activity of the compounds of the examples against peach borer pathogen

[0167]

[0168] The in vitro biological activity of the compounds against peach perforator pathogen was determined by turbidity method. The test results in Table 7 show that the EC 50 The value was 24.31 μg / mL, which was better than the control agents zinc thiazole (94.16 μg / mL) and thiophanate-methyl (43.17 μg / mL).

[0169] Test Example 2: Pot test of highly active compounds against rice bacterial leaf streak

[0170] The protective activity of highly active compounds against rice bacterial leaf streak at concentrations of 50 and 10 μg / mL was determined by pressure osmosis. The compound and control agent zinc thiazole were dissolved in DMSO, respectively, and prepared with 0.2% Tween-80 solution to make agents at concentrations of 50 and 10 μg / mL, and evenly sprayed on rice leaves until liquid dripped. One day later, a syringe containing logarithmic phase Xoc bacterial solution (without the needle tip) was used to pressure infiltrate the 1 / 3 to 1 / 2 of the tip of the rice leaf. At the same time, a clear water control without the agent was set. Each treatment was performed on more than 10 leaves, and repeated 3 times. The length of the lesions on the rice leaves was measured 14 days after the application, and its protective activity was calculated based on the length of the lesions. The therapeutic activity is to first use a syringe (without the needle tip) containing a logarithmic phase Xoc bacterial solution to infiltrate the 1 / 3 to 1 / 2 of the tip of the rice leaf. One day later, the compound and zinc thiazole at concentrations of 50 and 10 μg / mL are evenly sprayed on the rice leaves. At the same time, a clear water control without the agent is set up, and each treatment has more than 10 leaves, and repeated 3 times. The length of the lesions on the rice leaves is counted 14 days after the application of the drug, and the therapeutic activity is calculated based on the length of the lesions.

[0171] Control effect (%) = (lesion length of control group - lesion length of treatment group) ÷ lesion length of control group × 100

[0172] Test Example 3: Pot test of highly active compounds against rice bacterial blight

[0173] The protective activity of compound T2 against rice bacterial blight at a concentration of 10 or 50 μg / mL was determined by the leaf cutting method. Thiazole zinc was used as the control agent, and DMSO was added to dissolve it, and a 0.2% Tween-80 solution was used to prepare the agent at a concentration of 10 or 50 μg / mL, which was evenly sprayed on the rice leaves until liquid dripped. One day later, the 2-3 cm part of the rice leaf tip was cut off with scissors containing logarithmic phase Xoo bacterial solution, and a clear water control without the agent was set at the same time. Each treatment had more than 10 leaves and was repeated 3 times. The length of the lesions on the rice leaves was counted 14 days after the application of the drug, and the protective activity was calculated based on the length of the lesions. The therapeutic activity was to first cut off the 2-3 cm part of the rice leaf tip with scissors containing logarithmic phase Xoo bacterial solution, and one day later, the agent at a concentration of 10 or 50 μg / mL was evenly sprayed on the rice leaves until liquid dripped. At the same time, a clear water control without pesticide was set up, with more than 10 leaves for each treatment, and repeated 3 times. The length of the lesions on the rice leaves was counted 14 days after the application of the pesticide, and the protective activity was calculated based on the length of the lesions.

[0174] Control effect (%) = (lesion length of control group - lesion length of treatment group) ÷ lesion length of control group × 100

[0175] Test Example 4: Pot test of highly active compounds against citrus canker

[0176] The compound, control agent zinc thiazole and thiophanate-methyl were dissolved in DMSO, and the required concentration of the agent was prepared with 0.2% Tween-80 solution, and evenly sprayed on the citrus leaves until liquid dripped. One day later, 20 holes were pierced on each citrus leaf with a syringe, and paper soaked with logarithmic phase Xac bacteria solution was covered on the pinholes for 24 hours, with more than 15 leaves treated each time. At the same time, a clear water control was set up, and the length of the lesions on the citrus leaves was measured 30 days after the application of the drug, and its protective activity was calculated based on the length of the lesions.

[0177] Table 8 The therapeutic activity of chloroacetyl pleuromutilin (T2) and pleuromutilin against rice bacterial leaf streak at 50 and 10 μg / mL

[0178]

[0179]

[0180] The results of the therapeutic activity of T2 and pleuromutilin against rice bacterial leaf streak at 50 and 10 μg / mL are shown in Table 8 and Figure 1As shown: at 50 μg / mL, T2 and pleuromutilin have comparable therapeutic activities against rice bacterial leaf streak, with therapeutic activities of 88.0% and 86.3%, respectively, both better than the control agent zinc thiazole (21.3%). When the test concentration is reduced to 10 μg / mL, T2 still has a therapeutic activity of 77.5%, better than the therapeutic activity of the control agent pleuromutilin (45.4%).

[0181] Table 9 Protective activity of chloroacetyl pleuromutilin (T2) and pleuromutilin against rice bacterial leaf streak at 50 and 10 μg / mL

[0182]

[0183] The protective activity results of chloroacetyl pleuromutilin (T2) and pleuromutilin against rice bacterial leaf streak disease at 50 and 10 μg / mL are shown in Tables 9 and Figure 2 As shown: at 50 μg / mL, T2 and pleuromutilin had comparable antibacterial activity against rice bacterial leaf streak, with protective activities of 73.2% and 63.9%, respectively, both superior to the control agents thiazole zinc (21.3%) and thiophanate-methyl (34.6%). When the test concentration was reduced to 10 μg / mL, T2 still had a protective activity of 70.9%, superior to the protective activity of pleuromutilin (59.9%).

[0184] Table 10 The therapeutic activity of chloroacetyl pleuromutilin (T2) against rice bacterial blight at 10 μg / mL

[0185]

[0186] The therapeutic activity of chloroacetyl pleuromutilin (T2) against rice bacterial blight was tested at 10 μg / mL. The test results are shown in Table 10 and Figure 3 As shown: at a concentration of 10 μg / mL, chloroacetyl pleuromutilin (T2) exhibited excellent therapeutic activity against rice bacterial blight, with a therapeutic activity of 57.0%, which was superior to the therapeutic activity of the control agents zinc thiazole (21.3%) and pleuromutilin (31.1%).

[0187] Table 11 Protective activity of chloroacetyl pleuromutilin (T2) against rice bacterial blight at 50 μg / mL

[0188]

[0189] The test results are shown in Table 11 and Figure 4 As shown: at 50 μg / mL, chloroacetyl pleuromutilin (T2) exhibited good antibacterial activity, with a protective activity against rice bacterial blight of 50.2%, which was significantly better than the protective activities of thiabendazole zinc (18.7%) and thiophanate-methyl (18.4%).

[0190] Table 12 Protective activity of chloroacetyl pleuromutilin (T2) against citrus canker

[0191]

[0192] The test results are shown in Table 12 and Figure 5 As shown: At 100 μg / mL, chloroacetyl pleuromutilin (T2) showed good protective activity against citrus canker, with a protective activity of 42.3%, which was significantly better than the protective activities of zinc thiazole (200 μg / mL, 32.0%) and thiophanate-methyl (200 μg / mL, 10.2%). At 50 μg / mL, chloroacetyl pleuromutilin (T2) showed good protective activity against citrus canker, with a protective activity of 33.7%, which was comparable to the protective activity of zinc thiazole (32.0%) and better than the protective activity of thiophanate-methyl (10.2%).

[0193] Test Example 5: Field test on the efficacy of highly active compounds against citrus canker

[0194] Test point ①

[0195] The citrus orchard of Xinglongyuan Ecological Agriculture Development Cooperative in Fengting Town, Luodian County, has medium soil fertility and is located in a mountainous area. The test variety is navel orange, 4 years old, with a plant spacing of 3.0m×4.0m and an average plant height of 2.5m. The test area has a warm climate and abundant rainfall, and citrus canker often occurs.

[0196] Test point ②

[0197] The citrus orchard of Rongjiang Furong Ecological Agriculture Co., Ltd. in Wangling Village, Zhongcheng Town, Rongjiang County has medium soil fertility and is located in a mountainous area. The test variety is a 2-year-old navel orange grafted with a 12-year-old tree, with a plant spacing of 3.0m×2.5m and an average plant height of 2.0m. The test area has a warm climate and abundant rainfall, and citrus canker often occurs.

[0198] Test point ①

[0199] 1. Test area: 3 mu

[0200] 2. Comparative test of the efficacy of different pesticides in the field

[0201] The experiment has a total of 5 treatments and 1 control. The specific treatment conditions are shown in Table 13. Each treatment was repeated 3 times, with 2 navel orange trees in each repeat. The treatment plots were randomly arranged, totaling 20 test plots. The pesticide was sprayed 3 times in total. If it rained after spraying, it was necessary to spray again in time. The first spray was on April 28, 2024, and then sprayed every 7 to 10 days. The control group did not use drugs to control ulcer disease, and other pest control and fertilization management were consistent with the whole garden.

[0202] Table 13 Treatment of citrus canker in field control trial (Luodian)

[0203]

[0204]

[0205] 3. Disease investigation and result statistics

[0206] Before the first treatment, investigate the disease base number on the spring shoots of the same year, and investigate the control effect 21 days after the last application of the pesticide. During the investigation, investigate one tree for each treatment and each repeat, and investigate each tree in five directions: east, west, south, north, and center. In each direction, investigate 50 spring shoot leaves and 25 fruits, and record the number of diseased leaves and fruits at each level. The grading standards for the disease of citrus canker leaves (fruits) are as follows: Level 0: No disease; Level 1: 1 to 5 lesions on each leaf (fruit); Level 3: 6 to 10 lesions on each leaf (fruit); Level 5: 11 to 15 lesions on each leaf (fruit); Level 7: 16 to 20 lesions on each leaf (fruit); Level 9: More than 21 lesions on each leaf (fruit).

[0207] The incidence rate and disease index were calculated according to the following formula, and the significance of the difference was analyzed using SPSS software.

[0208] Disease index = [∑(number of diseased leaves at each level × relative level value) / total number of leaves investigated × 9)] × 100

[0209] Control effect (%) = [(disease index in blank control area - disease index in treated area) / disease index in blank control area] × 100

[0210] 4. Test results

[0211] Table 14 Field efficacy of different pesticide treatments on citrus canker (Luodian)

[0212]

[0213] Note: Different lowercase letters after the data in the same column indicate significant differences (p<0.05).

[0214] The field control results of T2 pesticide treatment on citrus canker in Luodian test site are shown in Table 14. As can be seen from Table 14, the disease index of each pesticide treatment was significantly different from that of the control area 21 days after the third application. Among the five treatments, the average control effect of each treatment on citrus canker leaves (spring shoots) was 58.65-84.85%, with the best control effect of 20% chloroacetyl pleuromutilin suspension at 500 times, followed by 20% chloroacetyl pleuromutilin suspension at 750 times and 20% chloroacetyl pleuromutilin suspension at 1000 times. The control effects of 20% zinc thiazole suspension at 1000 times and 25% oligosaccharide ethionine microemulsion at 500 times were relatively low, at 63.05% and 58.65%, respectively, and were significantly lower than the control effects of each concentration of 20% chloroacetyl pleuromutilin suspension.

[0215] The average protective effect of each treatment on citrus canker fruit was 52.98-91.20%. There was no significant difference among the three treatments with 500-fold, 750-fold and 1000-fold dilutions of 20% chloroacetyl pleuromutilin suspension, with the protective effects being 85.38%, 82.41% and 82.41% respectively. The protective effects of 1000-fold dilution of 20% zinc thiazole suspension and 500-fold dilution of 25% oligosaccharide ethionyl microemulsion were lower, at 55.88% and 52.98% respectively, which were lower than the protective effects of each concentration of 20% chloroacetyl pleuromutilin suspension.

[0216] Test point ②

[0217] 1. Test area: 3 mu

[0218] 2. Comparative test of the efficacy of different pesticides in the field

[0219] The experiment has 6 treatments and 1 control. The specific treatments are shown in Table 15. Each treatment was repeated 3 times, with 2 navel orange trees in each repeat. The treatment plots were randomly arranged, totaling 18 test plots. The pesticide was sprayed 3 times in total. If it rained after spraying, it was necessary to spray again in time. The first spray was on May 21, 2024, and then sprayed every 7 to 10 days. The control group did not use drugs to control ulcer disease, and other pest control and fertilization management were consistent with the whole garden.

[0220] Table 15 Treatment of citrus canker in field control trial (Rongjiang)

[0221]

[0222] 3. Disease investigation and result statistics

[0223] Before the first treatment, investigate the disease base on the spring shoots of that year.

[0224] Before each subsequent treatment, the disease index was investigated. During the investigation, one tree was investigated for each treatment and each replicate. Each tree was investigated in five directions: east, west, south, north, and center. The number of diseased leaves at each level was recorded, and the damage growth rate was calculated.

[0225] The control effect was investigated 12 days after the last application of the pesticide. During the investigation, one tree was investigated for each treatment and each replicate. Each tree was investigated in five directions: east, west, south, north and center. Fifty spring shoots were investigated in each direction, and the number of diseased leaves at each level was recorded. The grading standard, calculation of disease index and control effect of citrus canker leaf (fruit) disease were the same as those of Luodian.

[0226] 4. Test results

[0227] The field control results of different pesticides against citrus canker in the Rongjiang test site are shown in Tables 16 and Figure 6 As can be seen from Table 16, 12 days after the third application of pesticides, the disease index of each pesticide treatment was significantly different from that of the control area. Among the six treatments, the average protective effect of each treatment on citrus canker leaves (spring shoots) was 28.51-65.36%. The protective effects of 500 times diluted 20% chloroacetyl pleuromutilin suspension, 1000 times diluted 20% chloroacetyl pleuromutilin suspension, and 750 times diluted 20% chloroacetyl pleuromutilin suspension were 65.36%, 61.99% and 62.57% respectively. The poor protective effects were 400 times diluted 12% copper rosinate sustained-release agent, 750 times diluted 20% zinc thiazole suspension, and 1000 times diluted 25% oligosaccharide ethionyl acetate microemulsion. The protective effect of 1000 times diluted 25% oligosaccharide ethionyl acetate microemulsion was 28.51%, the protective effect of 750 times diluted 20% zinc thiazole suspension was 39.12%, and the protective effect of 400 times diluted 12% copper rosinate sustained-release agent was 48.62%. The above three treatments were significantly lower than the treatments with each concentration of 20% chloroacetyl pleuromutilin suspension concentrate.

[0228] Table 16 Field efficacy of different pesticide treatments on citrus canker (Rongjiang)

[0229]

[0230] Note: Different lowercase letters after the data in the same column indicate significant differences (p<0.05).

[0231] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pleuromutilin derivative containing an ester group or a salt thereof, wherein the pleuromutilin derivative containing an ester group has a structural formula as shown in Formula T: ； Wherein: R is selected from chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, ClCH2CH2-, ClCH2CH2CH2-, ClCH2CH2CH2CH2-, ethyl, propyl, benzyl, thienyl, pyridyl, vinyl, NCCH2-, HOOC(CH2)3-, CH3(CH2)2O-, CH3OC(O)-, CH3C(O)OCH2-, 、 、 、 、 、 、 、 、 、 。 2. The method for preparing the ester-containing pleuromutilin derivative or its salt according to claim 1, characterized in that Including steps a and b: Step a: ； or step b: 。 3. A composition, characterized in that A composition comprising the ester-containing pleuromutilin derivative or its salt as claimed in claim 1, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide.

4. The composition according to claim 3, characterized in that The dosage form of the composition is selected from emulsifiable concentrate, powder, granule, aqueous solution, suspension, ultra-low volume spray, microcapsule, smoke agent, aqueous emulsion, and water-dispersible granule.

5. Use of the ester-containing pleuromutilin derivative or its salt according to claim 1 or the composition according to claim 3 in the preparation of drugs for controlling agricultural pests and diseases, wherein the agricultural pests and diseases are plant bacterial diseases; the plant bacterial diseases are rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, peach bacterial punch hole disease, and kiwifruit canker.

6. A method for preventing and controlling agricultural pests and diseases, characterized in that: The ester-containing pleuromutilin derivative or its salt as described in claim 1, or the composition as described in claim 3 is allowed to act on harmful substances or their living environment; the agricultural pests and diseases are plant bacterial diseases; the plant bacterial diseases are rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, peach bacterial punch hole disease, and kiwi fruit canker.

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