Modified cyclodextrin derivatives capable of inclusion of agricultural actives, and methods of making and using the same

Abstract

This invention provides a modified cyclodextrin derivative and its preparation method. The modified cyclodextrin derivative of this invention improves the migration ability of macrolide active substances in soil. This invention also relates to an inclusion complex comprising the modified cyclodextrin derivative and macrolide active substances and its application in the control of soil pests.

Description

Technical Field

[0001] This invention relates to a modified cyclodextrin derivative and its preparation method; this invention also relates to an inclusion complex comprising the modified cyclodextrin derivative and a macrolide active ingredient and its application in controlling soil root-knot nematodes. Background Technology

[0002] Root-knot nematodes are among the most destructive plant nematodes globally, infecting 2,000-3,000 plant species. Infection with root-knot nematodes causes stunted growth of the above-ground parts of the plant, and in severe cases, growth stagnation, leading to reduced yield and quality. Currently, control of root-knot nematodes mainly relies on pesticides, with abamectin being the most widely used nematicide, and the most common formulation being abamectin emulsifiable concentrate (EC). Before application, the infected soil needs to be dug up, and the soil soaked or the roots drenched with abamectin emulsion diluted with water. This method of application drastically increases labor costs and can lead to delayed control.

[0003] Avermectin, a highly effective nematode control agent, typically achieves significant killing effects at concentrations as low as ppm. However, the current common application method is hole or furrow application. Firstly, avermectin is a lipophilic macromolecule with extremely low water solubility (7.8 ppb). Direct spraying of water containing macrolide pesticides results in its easy adsorption and gradual decomposition by organic matter in the top 1-2 cm of soil. Secondly, soil particles have small gaps between them; research shows that only particles smaller than 100 nm that do not interact with the soil can penetrate these gaps. Since root-knot nematodes are active at depths of 3-30 cm, direct application without excavating the soil will not allow for effective contact and killing of the nematodes. Therefore, there is a need to develop formulations that increase the water solubility of avermectin and other macrolide pesticides with nematode-killing capabilities, thereby enhancing their soil migration ability, to effectively control root-knot nematodes.

[0004] US2013 / 0231299 describes the use of chelating agents in metallized form to improve the control of pesticides against soil-dwelling pests.

[0005] In response to the shortcomings of existing technologies, this invention unexpectedly discovered that a modified cyclodextrin derivative can be used to encapsulate macrolide active ingredients to obtain modified cyclodextrin inclusion complexes. These inclusion complexes can improve the water solubility of macrolide agricultural active ingredients, thereby greatly increasing the migration ability of active components in the soil and effectively controlling soil pests. Summary of the Invention

[0006] In view of the problems existing in the prior art, in order to solve the migration properties of macrolide drugs in soil, the present invention ingeniously links cyclodextrin molecules through cross-linking technology and introduces active groups to obtain a series of modified cyclodextrin derivatives.

[0007] Surprisingly, some of the modified cyclodextrin derivatives showed significant advantages in encapsulating macrolide actives, such as enhanced encapsulation ability and increased water solubility, thus giving them stronger soil permeability.

[0008] A first aspect of the present invention is to provide a modified cyclodextrin derivative having a structure as shown in general formula I, wherein each glucose molecule in the cyclodextrin has three substitution positions, and cyclodextrin derivatives with different substituent groups and degrees of substitution can be obtained by modifying the hydroxyl groups.

[0009]

[0010] Wherein A is a straight-chain or branched alkyl group of C6-C15 (e.g., C6, C7, C8, C9, C10, C11, C12, C13, C14, C15), covalently bonded to the 2, 3, or 6 position of the cyclodextrin; preferably A is a straight-chain or branched alkyl group of C9-C15.

[0011] R1 and R2 are each independently an alkyl carboxylic acid of C1-C5 (e.g., C1, C2, C3, C4, C5) and its salt or a sulfonic acid of C1-C6 (e.g., C1, C2, C3, C4, C5, C6) and its salt; R3 is an alkyl carboxylic acid of C1-C5 (e.g., C1, C2, C3, C4, C5) and its salt or a alkyl sulfonic acid of C1-C6 (e.g., C1, C2, C3, C4, C5, C6) and its salt;

[0012] m can be 5, 6 or 7, with m being 6 being preferred;

[0013] * indicates a connection key (all * have the same meaning below).

[0014] Each polymer molecule represented by Formula I contains 3-50 cyclodextrin structural units.

[0015] Each cyclodextrin polymer monomer has a molecular weight between 3,000 and 60,000.

[0016] The modified cyclodextrin derivative of Formula I described in this invention preferably has R3 as a C1-C5 alkyl carboxylic acid and its salt, a C1-C6 alkyl sulfonic acid and its salt, or a hydroxypropyl group.

[0017] A second aspect of the present invention provides a method for preparing the modified cyclodextrin derivative of Formula I, comprising a crosslinking reaction and a modification reaction.

[0018] This invention provides a method for preparing a modified cyclodextrin derivative of Formula I (R3 being a C1-C5 alkyl carboxylic acid and its salt), comprising the following steps:

[0019] a) In the presence of an acid-binding agent, the cyclodextrin shown in Formula II is cross-linked with the haloalkane shown in Formula III to convert it into the cross-linked product shown in Formula IV.

[0020]

[0021] Where X is F, Cl, Br or I; n is an integer from 6 to 15 (e.g. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15), preferably an integer from 9 to 15; A and m are defined in the same way as in Equation I;

[0022] b) React the halocarbonyl compounds shown in Formula IV and Formula V to convert them into cyclodextrin polymerized carbonyl compounds shown in Formula VI;

[0023]

[0024] Wherein R4 is an alkyl group of H, Li, Na, K or C1-C5 (e.g., C1, C2, C3, C4, C5); X is F, Cl, Br or I; Y is a straight-chain or branched alkane of C1-C5 (e.g., C1, C2, C3, C4, C5); Ra, Rb and Rc are alkyl carboxylic acids of H, C1-C5 (e.g., C1, C2, C3, C4, C5) or alkyl esters of C1-C5 (e.g., C1, C2, C3, C4, C5); A and m are defined as in Formula I;

[0025] It should be noted that after the reaction of formula IV and formula V, the number of H atoms substituted depends on the molar ratio of the two reactants and steric hindrance; multiple H atoms can be substituted simultaneously. The greater the degree of substitution, the greater the water solubility of the final product.

[0026] and

[0027] c) Using an inorganic base to convert a compound of formula VI into a compound of formula VII;

[0028]

[0029] Where M is H, Li, Na or K; Y is a straight-chain or branched alkane of C1-C5 (e.g., C1, C2, C3, C4, C5); Rd, Re and Rf are alkyl carboxylates of H, C1-C5 (e.g., C1, C2, C3, C4, C5); A and m are defined as in Formula I.

[0030] On the other hand, the present invention also provides a method for preparing the modified cyclodextrin derivative of Formula I (R3 being a C1-C6 alkyl sulfonic acid and its salt), comprising the following steps:

[0031] a) In the presence of an acid-binding agent, the cyclodextrin shown in Formula II is cross-linked with the haloalkane shown in Formula III to convert it into the cross-linked product shown in Formula IV.

[0032]

[0033] Where X is F, Cl, Br, or I; n is an integer from 6 to 15 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15), preferably an integer from 9 to 15; A and m are defined the same as in Equation I.

[0034] b) React the haloalkyl sulfonates shown in Formula IV and Formula VIII to convert them into cyclodextrin polymer sulfonic acid and its salts shown in Formula IX.

[0035]

[0036] Where X is F, Cl, Br or I; Y is a straight-chain or branched alkane of C1-C5 (e.g., C1, C2, C3, C4, C5); M is H, Li, Na or K; Rg, Rh and Ri are H or alkyl sulfonates of C1-C5 (e.g., C1, C2, C3, C4, C5); A and m are defined as in Formula I;

[0037] If, in step b), Y is specifically an integer between 3 and 4, the following steps will be performed:

[0038] b') React the sulfonyl lactone shown in Formula IV with Formula X to convert it into the cyclodextrin polymer sulfonic acid and its salt shown in Formula XI.

[0039]

[0040] Where Z is a C3-C4 straight-chain alkyl group; M is H, Li, Na or K; Rj, Rk and Rl are H or C3-C4 (e.g. C1, C2, C3, C4) alkyl sulfonates; A and m are defined as in Formula I.

[0041] Furthermore, the present invention also provides a method for preparing the modified cyclodextrin derivative (R3 being hydroxypropyl) of Formula I, comprising the following steps:

[0042] a) In the presence of an acid-binding agent, the cyclodextrin shown in Formula II is cross-linked with the haloalkane shown in Formula III to convert it into the cross-linked product shown in Formula IV.

[0043]

[0044] Where X is F, Cl, Br, or I; n is an integer from 6 to 15 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15), preferably an integer from 9 to 15; A and m are defined in the same way as in Equation I.

[0045] b) Under alkaline conditions, the crosslinking product shown in Formula IV is condensed with propylene oxide, and after concentration and drying, product XI is obtained.

[0046]

[0047] Where R5 is CH2CH(OH)CH3; Rn, Ro and Rp are H or -CH2CH(OH)CH3; A and m are defined the same as in Formula I.

[0048] A third aspect of the present invention is to provide an inclusion complex comprising the modified cyclodextrin derivative and the macrolide active ingredient described in the present invention, wherein the macrolide active ingredient and the modified cyclodextrin derivative are in a weight ratio of 1:1 to 1:20, preferably 1:5 to 1:15.

[0049] The present invention relates to the application of modified cyclodextrin derivatives to enhance the migration ability of macrolide actives in soil.

[0050] The application of the inclusion complex of modified cyclodextrin derivatives and macrolide actives described in this invention in the control of soil pests.

[0051] The application of the inclusion complex of modified cyclodextrin derivatives and macrolide actives described in this invention in the control of soil nematodes.

[0052] The present invention also provides a pesticide composition comprising an inclusion complex of a modified cyclodextrin derivative and a macrolide active ingredient.

[0053] The present invention also provides an application of the pesticide composition described herein in the control of soil pests.

[0054] The present invention also provides the application of the pesticide composition described herein in the control of soil nematodes.

[0055] The present invention also provides the application of the pesticide composition described above in the control of soil root-knot nematodes.

[0056] The following is a detailed description of the present invention.

[0057] Cyclodextrin (CD) is a collective term for a series of cyclic oligosaccharides formed from amylose by cyclodextrin glucosyltransferase produced by Bacillus. They typically contain 6–12 D-glucan units. Molecules containing 6, 7, and 8 glucose units are more frequently studied and are referred to as alpha-, beta-, and gama-cyclodextrins, respectively. Their specific structures are shown below:

[0058]

[0059] The structural formula of glucose, the most basic structural unit that makes up different types of cyclodextrins, is shown below:

[0060]

[0061] Because cyclodextrins have a hydrophilic outer edge and a hydrophobic inner lumen, they can provide a hydrophobic binding site, similar to enzymes, to encapsulate various suitable host molecules, such as organic molecules, inorganic ions, and gas molecules. Therefore, cyclodextrins have received considerable attention and widespread application in catalysis, separation, food, and pharmaceutical fields. However, natural cyclodextrins have some drawbacks, including low solubility in water and poor inclusion ability. Therefore, modifying natural cyclodextrins to alter their physicochemical properties from a practical application perspective has become a research hotspot.

[0062] There are many reports on cyclodextrin modification in the prior art. For example, Chinese patent CN106512004B discloses a fully methylated β-cyclodextrin-modified nanographene / porphyrin supramolecular assembly. This supramolecular assembly exhibits good DNA cleavage performance under light irradiation and has good application prospects in the field of photodynamics.

[0063] Chinese patent CN103642190B discloses a polyethylene glycol-modified cyclodextrin. The modified cyclodextrin is added to waterborne polyurethane, and a film sample is obtained through film formation, drying and other processes. The test results show that it can greatly improve the tensile strength of the film.

[0064] Because cyclodextrin molecules can have a wide variety of substituents, the effects of different types of substituents and different degrees of substitution on the physical and chemical properties of the derivatized products are uncertain, and the fields in which they can be applied are unpredictable for those skilled in the art.

[0065] A first aspect of the present invention is to provide a modified cyclodextrin derivative having a structure as shown in general formula I, wherein each glucose molecule in the cyclodextrin has three substitution positions, and cyclodextrin derivatives with different substituent groups and degrees of substitution can be obtained by modifying the hydroxyl groups.

[0066]

[0067] The substituents in Formula I are the same as those defined above.

[0068] The modified cyclodextrin derivative of Formula I described in this invention preferably has R3 as a C1-C5 alkyl carboxylic acid and its salt, a C1-C6 alkyl sulfonic acid and its salt, or a hydroxypropyl group.

[0069] Specifically, the present invention also provides the following crosslinking products:

[0070] The crosslinked product shown in Formula IV:

[0071]

[0072] The definitions of A and m are the same as those mentioned above.

[0073] The modified cyclodextrin derivative shown in Formula VII:

[0074]

[0075] Where M is H, Li, Na, or K; Y is a C1-C5 straight-chain or branched alkane; Rd, Re, and Rf are H, C1-C5 alkyl carboxylates; A and m are defined as described above.

[0076] The modified cyclodextrin derivative shown in Formula IX:

[0077]

[0078] Where M is H, Li, Na or K; Y is a C1-C5 straight-chain or branched alkane; Rg, Rh and Ri are H, C1-C5 alkyl sulfonates; A and m are defined as described above.

[0079] The modified cyclodextrin derivative shown in Formula XI:

[0080]

[0081] Where R5 is CH2CH(OH)CH3; Rn, Ro and Rp are H or -CH2CH(OH)CH3; A and m are defined as described above.

[0082] A second aspect of the present invention is to provide a method for preparing the modified cyclodextrin derivative of formula I described in the present invention.

[0083] Numerous methods have been reported in the literature for modifying cyclodextrin parent compounds, generally employing chemical synthesis. The preparation of the modified cyclodextrin derivative shown in Formula I of this invention mainly involves two key steps: cross-linking reaction and modification reaction. Depending on the structure of the modified intermediate, such as the ester group, the ester group needs to be hydrolyzed with an inorganic base to obtain the corresponding final carboxylic acid and its salt. Then, appropriate post-processing is performed, such as multiple dialysis operations, followed by concentration and drying to obtain the final modified cyclodextrin polymer.

[0084] The crosslinking and modification reactions are the key steps in the entire reaction process, and their preparation can be carried out in a conventional reactor or a microreactor. Since the above reactions involve highly toxic reagents, preparation in a microreactor using a continuous flow method offers certain advantages over conventional reactors and is therefore a preferred option.

[0085] Conventional reactors are those used in contrast to microchannel reactors. They typically include laboratory glass reaction flasks and industrial stainless steel and enamel-lined reactors, and are all intermittent in operation.

[0086] The modified cyclodextrin derivative of Formula I described in this invention is preferably a C1-C5 alkyl carboxylic acid and its salt, a C1-C6 alkyl sulfonic acid and its salt, or a hydroxypropyl group.

[0087] The modified cyclodextrin derivative of Formula I described in this invention, when R3 is a C1-C5 alkyl carboxylic acid or its salt, is prepared by the following method, specifically including the following steps:

[0088] a) In the presence of an acid-binding agent, the cyclodextrin shown in Formula II is cross-linked with the haloalkane shown in Formula III to convert it into the cross-linked product shown in Formula IV.

[0089]

[0090] Where X is F, Cl, Br or I; n is an integer from 6 to 15, preferably an integer from 9 to 15; A and m are defined in the same way as in Equation I;

[0091] b) React the halocarbonyl compounds shown in Formula IV and Formula V to convert them into cyclodextrin polymerized carbonyl compounds shown in Formula VI;

[0092]

[0093] Wherein R4 is an alkyl group of H, Li, Na, K or C1-C5 (e.g., C1, C2, C3, C4, C5); X is F, Cl, Br or I; Y is a straight-chain or branched alkane of C1-C5 (e.g., C1, C2, C3, C4, C5); Ra, Rb and Rc are alkyl carboxylic acids of H, C1-C5 (e.g., C1, C2, C3, C4, C5) or alkyl esters of C1-C5 (e.g., C1, C2, C3, C4, C5); A and m are defined as in Formula I;

[0094] and

[0095] c) Using an inorganic base to convert VI into a compound of formula VII;

[0096]

[0097] Where M is H, Li, Na or K; Y is a straight-chain or branched alkane of C1-C5 (e.g., C1, C2, C3, C4, C5); Rd, Re and Rf are alkyl carboxylates of H, C1-C5 (e.g., C1, C2, C3, C4, C5); A and m are defined as in Formula I.

[0098] For step a) the crosslinking reaction, the cyclodextrin II used as the starting material is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin when m is 5, 6, or 7, respectively; the crosslinking agent, dihaloalkane III, has the following structural formula:

[0099] X-CnH2n-X III

[0100] Where X is a halogen, such as F, Cl, Br or I; n is an integer from 6 to 15, preferably an integer from 9 to 15.

[0101] Cyclodextrin II and dihaloalkane III are typically carried out at 0-80°C, preferably 20°C to 60°C.

[0102] Suitable reaction solvents are protic solvents, such as DMF and DMSO.

[0103] Suitable acid-binding agents are organic or inorganic bases, among which inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydride, etc., and organic bases include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP), with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP) being particularly preferred.

[0104] The ratio of cyclodextrin II to dihaloalkane III has a significant impact on the degree of polymer substitution. A cyclodextrin molecule has 6-8 glucose molecules, each with 3 substitution sites, therefore a single cyclodextrin molecule has 18-24 substitution sites.

[0105] In this invention, cyclodextrin II and dihaloalkane III are typically fed in a molar ratio of 1:1.2 to 1:3 to control the degree of substitution of the cyclodextrin derivative between 2 and 4, so as to avoid excessive or insufficient crosslinking, which would result in the final polymer's physical and chemical properties failing to meet the requirements of this invention.

[0106] For the modification reaction in step b), the reaction mechanism is the same as in step a), therefore the solvent and catalyst can be the same as in step a). The crosslinking product IV obtained in the previous step is reacted with the halocarbonyl compound V shown in the following formula.

[0107]

[0108] X, Y, and R4 are defined as described above.

[0109] The crosslinking product IV and the halocarbonyl compound V are usually carried out at 0-80°C, preferably 20°C to 60°C.

[0110] Suitable reaction solvents are protic solvents, such as DMF and DMSO.

[0111] Suitable acid-binding agents are organic or inorganic bases, among which inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydride, etc., and organic bases include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP), with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP) being particularly preferred.

[0112] The crosslinking product IV and the halogenated carbonyl compound V are fed in a ratio of 1:5 to 15 (relative to the molar amount of the starting cyclodextrin), preferably 1:8 to 1:12.

[0113] For step c) of the hydrolysis reaction, the solvent in product VI obtained in the previous step is removed by vacuum distillation. After the solvent is completely removed, water and an inorganic base are added to the reactor, and the mixture is heated and stirred for several hours. After cooling, the pH of the system is adjusted to 5-9 with an inorganic acid, and the reaction is terminated. The inorganic base can be an alkali metal hydroxide, such as NaOH, KOH, or LiOH; or an alkali metal carbonate, such as Na₂CO₃, K₂CO₃, or Li₂CO₃.

[0114] The amount of inorganic base used is equal to or in excess of the amount of the halocarbonyl compound of formula V.

[0115] Finally, the reaction solution obtained in the previous step was placed into a dialysis bag with a molecular weight cutoff of 500-1000, and dialyzed with deionized water under stirring to remove small molecule salts and alcohols. The dialysate in the bag was then concentrated under reduced pressure and thoroughly dried in a vacuum drying oven to obtain the final polymer VII.

[0116] In another embodiment of the present invention, the modified cyclodextrin derivative of Formula I according to the present invention, when R3 is a C1-C6 alkyl sulfonic acid or its salt, is prepared by the following method, specifically including the following steps:

[0117] a) In the presence of an acid-binding agent, the cyclodextrin shown in Formula II is cross-linked with the haloalkane shown in Formula III to convert it into the cross-linked product shown in Formula IV.

[0118]

[0119] Where X is F, Cl, Br, or I; n is an integer from 6 to 15, preferably an integer from 9 to 15; A and m are defined the same as in Equation I.

[0120] b) React the haloalkyl sulfonates shown in Formula IV and Formula VIII to convert them into cyclodextrin polymer sulfonic acid and its salts shown in Formula IX.

[0121]

[0122] Where X is F, Cl, Br or I; Y is a straight-chain or branched alkane of C1-C5 (e.g., C1, C2, C3, C4, C5); M is H, Li, Na or K; Rg, Rh and Ri are H or alkyl sulfonates of C1-C5 (e.g., C1, C2, C3, C4, C5); A and m are defined as in Formula I;

[0123] For the crosslinking reaction in step a), the reaction route and conditions (such as reaction solvent, catalyst and reaction temperature) are consistent with the crosslinking reaction in step a) when R3 is the aforementioned C1-C5 alkyl carboxylate, and are carried out with reference to its preparation process, and will not be repeated here.

[0124] For the preparation of alkyl sulfonic acids and their salts in step b), the crosslinking product IV is reacted with the haloalkyl sulfonate shown in formula VIII.

[0125]

[0126] Where X, Y, and M are the same as defined above.

[0127] The crosslinking product IV and the halogenated carbonyl compound VIII are typically carried out at 20-90°C, preferably 50-80°C.

[0128] Suitable reaction solvents are protic solvents, such as DMF and DMSO.

[0129] Suitable acid-binding agents are organic or inorganic bases, among which inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydride, etc., and organic bases include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP), with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP) being particularly preferred.

[0130] The crosslinking product IV and the halocarbonyl compound VIII are fed in a ratio of 1:5 to 15 (relative to the initial molar amount of cyclodextrin), preferably 1:8 to 1:12. The sodium salt is obtained directly after the reaction, without the need for a hydrolysis step.

[0131] In a more specific embodiment of the present invention, when R3 is an alkyl sulfonic acid or its salt, and when the value of Y in step b) is specifically an integer from 3 to 4, it can also be prepared by the following method:

[0132] b') The intermediate product IV obtained in step a) is reacted with the sulfonyl lactone shown in formula X to convert it into the cyclodextrin polymer sulfonic acid and its salt shown in formula IX.

[0133]

[0134] In the above reaction formula, the sulfonyl lactone structure shown in formula X is as follows:

[0135]

[0136] In the formula: Z is a straight-chain alkane of C3-C4 (e.g., C3 or C4), as defined above.

[0137] The reaction conditions and molar amounts of the feed are the same as those of the halocarbonyl compound of formula V. The only difference is that the sulfonyl lactone shown in formula X is used to directly generate the sodium salt without the need for a hydrolysis step.

[0138] Finally, the obtained reaction solution was placed in a dialysis bag with a molecular weight cutoff of 500-1000, and dialyzed with deionized water under stirring to remove salts and small organic molecules from the system. The dialysate in the bag was then concentrated under reduced pressure and thoroughly dried in a vacuum drying oven to obtain the final polymer IX.

[0139] In another embodiment of the present invention, the modified cyclodextrin derivative of Formula I according to the present invention, when R3 is hydroxypropyl, is prepared by the following method, specifically including the following steps:

[0140] a) In the presence of an acid-binding agent, the cyclodextrin shown in Formula II is cross-linked with the haloalkane shown in Formula III to convert it into the cross-linked product shown in Formula IV.

[0141]

[0142] Where X is F, Cl, Br, or I; n is an integer from 6 to 15, preferably an integer from 9 to 15; A and m are defined the same as in Equation I.

[0143] b) Under alkaline conditions, the crosslinking product shown in Formula IV is condensed with propylene oxide, and after concentration and drying, product XI is obtained.

[0144]

[0145] For this reaction, a suitable reaction solvent is a protic solvent, such as DMF or DMSO.

[0146] Suitable acid-binding agents are organic or inorganic bases, among which inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydride, etc., and organic bases include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP), with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP) being particularly preferred.

[0147] After the reaction is complete, the resulting reaction solution is placed in a dialysis bag with a molecular weight cutoff of 500-1000 and dialyzed with deionized water under stirring to remove salts and small organic molecules from the system. The dialysate in the bag is then concentrated under reduced pressure and thoroughly dried in a vacuum drying oven to obtain the final polymer XI. Alternatively, desalination can be performed using a strong acid ion exchange resin or nanofiltration equipment.

[0148] This invention uses straight-chain or branched dihaloalkanes of varying lengths to crosslink dispersed cyclodextrin monomers, forming a network to obtain polymers with more cavities. This provides more space for active molecules to enter, significantly improving their inclusion capacity. Therefore, by modifying natural cyclodextrin, the cyclodextrin derivatives of this invention significantly enhance the inclusion capacity for macrolide actives. Compared to natural cyclodextrin and substances obtained by derivatizing only the hydroxyl groups on a single cyclodextrin, the modified cyclodextrin derivatives of this invention improve the water solubility of macrolide actives, thereby greatly increasing their migration ability in soil.

[0149] Therefore, the present invention provides the application of the modified cyclodextrin derivatives in improving the migration ability of macrolide actives in soil.

[0150] A third aspect of the present invention is to provide an inclusion complex comprising a derivative of the modified cyclodextrin described herein and a macrolide active ingredient.

[0151] Existing technologies have also reported on the derivatization of natural cyclodextrin monomers, such as methylation, ethylation, and hydroxypropylation, to obtain a series of modified derivatives. However, studies have found that these derivatives suffer from reduced water solubility.

[0152] The modified cyclodextrin derivatives of this invention, due to the network structure composed of 6-15 carbon hydrophobic straight-chain or branched alkanes, exhibit a tendency for avermectin to enter the network. Avermectin entering the network can be further fixed by the cyclodextrin cavities, thus significantly enhancing the inclusion capacity compared to a single cyclodextrin molecule. Furthermore, the hydrophilic carboxylic acid and its salts, or alkyl sulfonic acid and its salt groups, located on the outer side of the polymer, do not affect the entry of macrolide active ingredients into the cavity. Therefore, in an optimal configuration, the nanocavities achieve a solubility factor exceeding 30,000. Consequently, the modified cyclodextrin derivatives provided by this invention exhibit greater water solubility and stronger inclusion capacity for macrolide active ingredients compared to natural cyclodextrin or methylated, ethylated, and hydroxypropylated modified cyclodextrins.

[0153] In the inclusion complex of modified cyclodextrin derivatives and macrolide actives described in this invention, the solid macrolide active molecules and the modified cyclodextrin derivatives are in a weight ratio of 1:1 to 1:20, preferably 1:5 to 1:15.

[0154] The preparation methods for the inclusion complexes of modified cyclodextrin derivatives and macrolide actives described in this invention commonly include grinding, ultrasonication, and organic solvent methods, which can be referred to in existing technology reports.

[0155] The specific procedure involves dissolving the modified cyclodextrin derivative obtained above in water to prepare a 10% (w / w) aqueous solution. Then, solid macrolide active molecules and the cyclodextrin derivative are added to the solution at a weight ratio of 1:1-1:20 (preferably 1:5-1:15). The solution is ultrasonically vibrated at room temperature for 0.5-8 hours. If necessary, unencapsulated macrolide active molecules are removed using a filter membrane. After the cyclodextrin inclusion complex is formed, the solvent is removed, and the mixture is dried to obtain the macrolide cyclodextrin inclusion complex.

[0156] The modified cyclodextrin derivatives obtained by this invention are suitable for all types of hydrophobic pesticide active ingredients, especially macrolide active molecules, including at least one of abamectin, ivermectin, emamectin bezoate, eprinomectin, doramectin, moxidectin, spinosad, ethyl spinosad, and milbemycin.

[0157] The present invention also provides a pesticide composition comprising an inclusion complex of a modified cyclodextrin derivative and a macrolide active ingredient.

[0158] The inclusion complexes of the above-mentioned modified cyclodextrin derivatives and macrolide actives are mixed with at least one agriculturally acceptable additive to prepare pesticide compositions of different formulations and contents. The agriculturally acceptable additives include liquid diluents or carriers, solid diluents or carriers, emulsifiers, dispersants, thickeners, and stabilizers.

[0159] When applying pesticide compositions containing the modified cyclodextrin derivatives and macrolide active ingredients described in this invention, or pesticide compositions containing the modified cyclodextrin derivatives and macrolide active ingredients, the macrolide active ingredients can penetrate deeper into the soil without tilling the soil, resulting in better control of soil pests, especially root-knot nematodes, and reducing labor and machinery costs.

[0160] Therefore, the present invention also provides the application of the inclusion complex of the modified cyclodextrin derivative and macrolide active ingredients in the control of soil pests.

[0161] The present invention also provides the application of the inclusion complex of the modified cyclodextrin derivative and macrolide active ingredients in the control of soil nematodes.

[0162] The present invention also provides an application of the pesticide composition described herein in the control of soil pests.

[0163] The present invention also provides the application of the pesticide composition described herein in the control of soil nematodes.

[0164] The present invention also provides the application of the pesticide composition described above in the control of soil root-knot nematodes.

[0165] The present invention also provides a method for controlling soil pests, wherein a pesticide composition containing a modified cyclodextrin derivative and a macrolide active ingredient as described in the present invention, or a pesticide composition containing a modified cyclodextrin derivative and a macrolide active ingredient as described in the present invention, is applied to the soil inhabited by the pests, either diluted or undiluted.

[0166] The application methods of the modified cyclodextrin derivative and macrolide active ingredient inclusion complex or pesticide composition containing the modified cyclodextrin derivative and macrolide active ingredient inclusion complex of the present invention can be exemplified by soil mixing treatment, spot application treatment, strip application treatment, or irrigation treatment.

[0167] Compared with the prior art, the beneficial effects of this application are as follows:

[0168] First, by modifying natural cyclodextrin, the resulting cyclodextrin derivatives exhibit significantly improved inclusion capacity for macrolide actives. Compared to substances obtained by derivatizing only the hydroxyl groups on a single cyclodextrin, this invention uses linear or branched dihaloalkanes of varying lengths to crosslink dispersed cyclodextrin monomers into a network, resulting in polymers containing more cavities. This provides more space for active molecules to enter, thereby significantly improving their inclusion capacity.

[0169] Secondly, the cyclodextrin derivatives obtained by this invention have excellent hydrophilic properties. After encapsulation of macrolide active components, they can penetrate deeper into the soil without tilling and applying pesticides, thus providing better control of root-knot nematodes and reducing labor and machinery costs. Attached Figure Description

[0170] Figure 1 The infrared spectrum is a comparison between β-cyclodextrin and the β-cyclodextrin polymer obtained in Example 1 (corresponding to the polymer in the attached figure);

[0171] Figure 2 The image shows a comparison of the 1H-NMR spectra of β-cyclodextrin and the β-cyclodextrin polymer obtained in Example 1 (corresponding to the polymer in the attached figure). Detailed Implementation

[0172] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0173] Example 1: Preparation of β-cyclodextrin-modified carboxylate polymers (chain length 12)

[0174] 1.1 Crosslinking reaction

[0175] 6 g (0.0053 mol) of dried β-cyclodextrin (pre-vacuum dried to remove moisture from the cyclodextrin cavity) was dissolved in 100 g of N,N-dimethylformamide (DMF) with stirring. Then, 13.7 g (0.09 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added and mixed thoroughly to obtain phase A. 2.6 g (0.0079 mol) of 1,12-dibromododecane was dissolved in 80 g of DMF to obtain phase B. Phases A and B were mixed using a T-type PEEK tee and reacted at room temperature in a PFA microtube with an inner diameter of 1.0 mm and an outer diameter of 1.6 mm. The residence time was set to 1 hour by adjusting the flow rate of the syringe pump while maintaining a fixed reaction tube volume. The consumption of 1,12-dibromododecane in the system was monitored by gas chromatography. The reaction was considered complete when the conversion rate was greater than 95%, which took approximately 1 hour.

[0176] 1.2 Modification reaction

[0177] 8.1 g (0.0742 mol) of methyl chloroacetate was dissolved in 30 g of DMF to obtain phase C. This phase C was mixed with the reactants of phases A and B through a T-type PEEK tee and reacted at room temperature in a PFA microtube with an inner diameter of 1.0 mm and an outer diameter of 1.6 mm. The reaction tube volume was kept constant, and the residence time was set to 2 hours by adjusting the flow rate of the syringe pump. The product was collected in a round-bottom flask. The consumption of methyl chloroacetate in the system was monitored by gas chromatography. The reaction was considered complete when its peak completely disappeared in the chromatogram, which took approximately 2 hours.

[0178] 1.3 Hydrolysis reaction

[0179] The product obtained in the previous step was concentrated and distilled under reduced pressure to remove DMF. The oil pump pressure was 1 mmHg, and the bath temperature was 50°C. After the solvent was completely removed, 120 g of water and 3 g of sodium hydroxide were added to the flask, and the mixture was stirred at 60°C for 2 hours. After cooling, the pH of the system was adjusted to 7-8 with hydrochloric acid. The pH value of the system was monitored with a pH meter, and the reaction was terminated when the pH value no longer decreased.

[0180] 1.4 Dialysis

[0181] The reaction solution obtained in the previous step was placed into a dialysis bag with a molecular weight cutoff of 500-1000 and dialyzed with deionized water while stirring. The water was changed approximately every 5 hours, for a total of three water changes. The dialysate in the bag was then concentrated under reduced pressure and thoroughly dried in a vacuum drying oven to obtain 5.7 grams of the final polymer.

[0182] The polymer obtained above was subjected to infrared and nuclear magnetic resonance analysis to obtain infrared and nuclear magnetic resonance spectra, such as... Figure 1 and Figure 2 As shown.

[0183] Depend on Figure 1 As can be seen, compared with β-cyclodextrin, the polymer obtained in this example has a higher viscosity at 2853 cm⁻¹. -1 A new absorption peak appeared at 2924 cm⁻¹. -1 The absorption peaks at these two points are enhanced. These two peaks are attributed to the symmetric and antisymmetric stretching vibrations of -CH2-, respectively, indicating an increase in the -CH2- content in the product and suggesting the occurrence of a cross-linking reaction. The most significant increase in the product is 1588 cm⁻¹. -1 This absorption peak is attributed to the antisymmetric absorption of -CO2-, and 1417 cm⁻¹ -1 This absorption peak belongs to -CO 2 The symmetrical absorption of - indicates that the carboxyl group has been successfully attached to the polymer.

[0184] Depend on Figure 2It can be seen that the increased peaks of the polymer obtained in this embodiment at high fields, such as 1.6 ppm and 2.8 ppm, are the -CH2- peaks in long-chain alkanes. The polymer shows a significant increase in peaks at 3.0-4.0 ppm compared to β-cyclodextrin, indicating an increase in ether bonds; these peaks belong to -O-CH2-. The appearance or increase of these peaks indicates that the polymer has been successfully synthesized. Calculations from the hydrogen atoms in the 1.6 ppm and 2.8 ppm peaks show that an average of three dodecane atoms are attached to each cyclodextrin molecule. The peak of sodium acetate (-CH2-COONa) is masked by the water peak in the solvent D2O.

[0185] Therefore, infrared and nuclear magnetic resonance analyses showed that the modified β-cyclodextrin acetic acid polymer was prepared in this embodiment.

[0186] By adjusting the feeding ratio of β-cyclodextrin to 1,12-dibromododecane and the reaction temperature, β-cyclodextrin polymers with different degrees of polymerization can be obtained.

[0187] Following a similar preparation method as in Example 1 above, modified α-cyclodextrin and γ-cyclodextrin carboxylic acids and their salt polymers were obtained.

[0188] Example 2: Preparation of β-cyclodextrin-modified carboxylate polymers (chain length 6)

[0189] In Example 1, 1,12-dibromododecane was replaced with 1,6-dibromohexadecane, and the modified β-cyclodextrin polymer with a chain length of 6 carbons was prepared according to the steps of crosslinking reaction, modification reaction, hydrolysis reaction and dialysis in Example 1.

[0190] Following a similar preparation method as in Example 2 above, β-cyclodextrin carboxylic acid polymers with chain lengths of 7-11 were obtained.

[0191] Example 3: Preparation of cyclodextrin polymers modified with carboxylic acid groups of different lengths

[0192] Referring to a similar preparation method as in Example 2 above, methyl chloroacetate was replaced with C2-C5 haloalkyl groups to obtain polymers of β-cyclodextrin carboxylic acids and their salts of different lengths.

[0193] Example 4: Preparation of β-cyclodextrin-modified alkyl sulfonic acid polymer (chain length 12)

[0194] 1.1 Crosslinking reaction

[0195] The β-cyclodextrin crosslinked polymer was prepared according to step 1.1 of Example 1.

[0196] 6 g (0.0053 mol) of dried β-cyclodextrin (pre-vacuum dried to remove moisture from the cyclodextrin cavity) was dissolved in 100 g of N,N-dimethylformamide (DMF) with stirring. Then, 13.7 g (0.09 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added and mixed thoroughly to obtain phase A. 2.6 g (0.0079 mol) of 1,12-dibromododecane was dissolved in 80 g of DMF to obtain phase B. Phases A and B were mixed using a T-type PEEK tee and reacted at room temperature in a PFA microtube with an inner diameter of 1.0 mm and an outer diameter of 1.6 mm. The residence time was set to 1 hour by adjusting the flow rate of the syringe pump while maintaining a fixed reaction tube volume. The consumption of 1,12-dibromododecane in the system was monitored by gas chromatography. The reaction was considered complete when the conversion rate was greater than 95%, which took approximately 1 hour.

[0197] 1.2 Modification reaction

[0198] The cross-linking intermediate reaction solution obtained in the previous step was placed into a three-necked flask. Then, 3.0 g of solid NaOH (0.0745 mol) was added to the reactor, controlling the molar ratio of β-cyclodextrin to NaOH in the cross-linking product to be 1:14. The mixture was refluxed at 76 °C for 4 h for dehydration. After dehydration was completed, 12.4 g of C2H4C1SO3Na (sodium 2-chloroethylsulfonate) (0.0742 mol, 166.56 g) was added to the three-necked flask in three portions. The reaction was carried out at the above temperature for about 5 hours until the pH reached 9 and no longer decreased, at which point the reaction was terminated. After cooling, the pH of the system was adjusted to 7-8 with hydrochloric acid.

[0199] 1.3 Dialysis

[0200] The reaction solution obtained in the previous step was placed into a dialysis bag with a molecular weight cutoff of 500-1000 and dialyzed with deionized water while stirring. The water was changed approximately every 5 hours, for a total of three water changes. The dialysate in the bag was then concentrated under reduced pressure and thoroughly dried in a vacuum drying oven to obtain 6.2 grams of the final polymer.

[0201] Infrared and nuclear magnetic resonance analyses were performed on the polymers obtained above, and the results showed that β-cyclodextrin sulfonic acid and its salt polymers were obtained.

[0202] Example 5: Preparation of β-cyclodextrin-modified alkyl sulfonic acid polymers (chain length 6)

[0203] In Example 4, 1,12-dibromododecane was replaced with 1,6-dibromohexadecane, and the modified β-cyclodextrin alkyl sulfonic acid polymer with a chain length of 6 carbons was prepared by following the steps of crosslinking reaction, modification reaction and dialysis in Example 4.

[0204] Following the preparation method of Example 5 above, β-cyclodextrin alkyl sulfonic acid and its salt polymers with crosslinked carbon chain lengths of 7-11 were obtained.

[0205] Example 6: Preparation of cyclodextrin polymers modified with sulfonic acid groups of different lengths

[0206] Referring to the preparation method of Example 5, the product obtained from the crosslinking step was reacted with a C2-C5 haloalkyl sulfonate to obtain a modified alkyl sulfonate polymer with a length of 2-5 carbons.

[0207] Example 7: Preparation of β-cyclodextrin-modified hydroxypropyl polymer (chain length 6)

[0208] 1.1 Crosslinking reaction

[0209] 6 g (0.0053 mol) of dried β-cyclodextrin (pre-vacuum dried to remove moisture from the cyclodextrin cavity) was dissolved in 100 g of N,N-dimethylformamide (DMF) with stirring. Then, 13.7 g (0.09 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added and mixed thoroughly. 2.6 g (0.0079 mol) of 1,12-dibromododecane was dissolved in 80 g of DMF and then added dropwise to the above reaction system. The mixture was stirred at room temperature for about 1 hour. The consumption of 1,12-dibromododecane was monitored by gas chromatography. The reaction was considered complete when the conversion rate was greater than 95%, which took about 1.5 hours.

[0210] 1.2 Modification reaction

[0211] Add 3.0 g of solid NaOH and 10 g of distilled water to the reaction solution of the crosslinking product shown in Formula IV obtained in step 1.1, cool to 15 °C and slowly add 4.35 g of propylene oxide to the system, maintain the temperature at 15 °C-20 °C for 2 hours.

[0212] Molecular weight of propylene oxide: 58 (0.075 mol)

[0213] 1.3 Dialysis

[0214] The reaction solution obtained in the previous step was placed into a dialysis bag with a molecular weight cutoff of 500-1000 and dialyzed with deionized water while stirring. The water was changed approximately every 5 hours, for a total of three water changes. The dialysate in the bag was then concentrated under reduced pressure and thoroughly dried in a vacuum drying oven to obtain 5.3 grams of the final hydroxypropyl-modified cyclodextrin polymer.

[0215] Cyclodextrin inclusion complex

[0216] Application Example 1: Preparation of the inclusion complex of avermectin and modified β-cyclodextrin carboxylic acid polymer

[0217] The modified β-cyclodextrin carboxylic acid polymer obtained in Example 1 was dissolved in deionized water to prepare a 10% aqueous solution. 0.15 times the weight of the polymer solid avermectin was added to the solution, and the mixture was sonicated at room temperature for 1 hour. The solution was then filtered through a 0.4 μm filter to remove unencapsulated avermectin. The filtrate was evaporated to dryness and then thoroughly dried in a vacuum desiccator to obtain the inclusion complex.

[0218] Following the same method as in this application example, the modified β-cyclodextrin polymer aqueous solution was mixed with ivermectin, emamectin bezoate, eprinomectin, doramectin, moxidectin, spinosad, ethyl spintoram, and milbemycin, and then sonicated to obtain target inclusion complexes of different macrocyclic lactone active components.

[0219] Application Example 2: Preparation of inclusion complex of avermectin and modified β-cyclodextrin alkyl sulfonic acid polymer

[0220] The modified β-cyclodextrin alkyl sulfonic acid polymer obtained in Example 4 was dissolved in deionized water to prepare a 10% aqueous solution. 0.15 times the weight of the polymer solid avermectin was added to the solution, and the mixture was sonicated at room temperature for 1 hour. The solution was then filtered through a 0.4 μm filter to remove unencapsulated avermectin. The filtrate was evaporated to dryness and then thoroughly dried in a vacuum desiccator to obtain the inclusion complex.

[0221] Following the same method as in this application example, the modified β-cyclodextrin alkyl sulfonic acid polymer aqueous solution was mixed with the macrocyclic lactone surfactant described in this invention and then subjected to ultrasonication to obtain the target inclusion complex.

[0222] Application Example 3: Preparation of inclusion complex of avermectin and modified β-cyclodextrin hydroxypropyl polymer

[0223] The modified β-cyclodextrin hydroxypropyl polymer obtained in Example 7 was dissolved in deionized water to prepare a 10% aqueous solution. 0.15 times the weight of the polymer solid avermectin was added to the solution, and the mixture was sonicated at room temperature for 1 hour. The solution was then filtered through a 0.4 μm filter to remove unencapsulated avermectin. The filtrate was evaporated to dryness and then thoroughly dried in a vacuum desiccator to obtain the inclusion complex.

[0224] Following the same method as in this application example, the modified β-cyclodextrin hydroxypropyl polymer aqueous solution was mixed with the macrocyclic lactone surfactant described in this invention and then subjected to ultrasound to obtain the target inclusion complex.

[0225] Comparative Application Example 1: Preparation of the inclusion complex of avermectin and methylated β-cyclodextrin

[0226] Natural β-cyclodextrin was dissolved in deionized water to prepare a 10% aqueous solution. 0.15 times the weight of the polymer's avermectin solid was added to the solution, and the mixture was sonicated at room temperature for 1 hour. Unencapsulated avermectin was then removed by filtration through a 0.4 μm membrane. The filtrate was evaporated to dryness and then thoroughly dried in a vacuum desiccator to obtain the inclusion complex.

[0227] Following the same method as in this comparative application example, natural α-cyclodextrin, γ-cyclodextrin, and methylated, ethylated, and hydroxypropylated modified cyclodextrin were prepared into aqueous solutions. These solutions were then mixed with ivermectin, emamectin benzoate, eprinomectin, doramectin, moxidectin, spinosad, ethyl spinosad, and milbemycin, and subjected to ultrasonic oscillation. The filtrate was then evaporated to dryness and thoroughly dried in a vacuum desiccator to obtain the target inclusion complex.

[0228] Comparison of solubilization effects and soil leaching test

[0229] I. Solubilization effect test

[0230] Avermectin molecules encapsulated by cyclodextrin polymers are in a dissolved state in aqueous solution, so the solubility factor can be used to test the inclusion capacity of cyclodextrin polymers.

[0231] All cyclodextrin samples tested were prepared into a 10% aqueous solution. Inclusion complexes were obtained according to the microcapsule preparation method described above. The content of avermectin was then quantitatively analyzed by liquid chromatography (the samples were filtered before entering the liquid phase to remove insoluble avermectin).

[0232] As a control, the solubilizing effect of three natural cyclodextrins and two commonly used modified cyclodextrins on avermectin was also tested.

[0233] Table 1. Comparison of the solubilizing effects of different modified cyclodextrins on avermectin compared with natural and commercially available cyclodextrins.

[0234]

[0235] Literature value: The water solubility of avermectin is 0.0000078 g / L.

[0236] As shown in Table 1, the modified cyclodextrin obtained in this invention exhibits a significantly higher solubility for avermectin compared to natural cyclodextrin. Compared to commercially available methylated β-cyclodextrin, most show comparable or even better solubility, far exceeding that of hydroxypropyl-β-cyclodextrin.

[0237] II. Soil Leaching Test

[0238] The column leaching method was used to test the samples according to the national standard method (GB31270.5-2014). Soil that had passed through a 2mm sieve was prepared, and then soil was added to a glass column (6cm inner diameter, with the bottom end of the glass column sealed with a 200-mesh filter) to a height of 30cm. The soil column was then saturated with water by reverse osmosis using a 0.01mol / L calcium chloride solution from top to bottom, thus removing any air present in the soil column.

[0239] 1.0 mg of the test substance was mixed with 0.5 g of soil and evenly applied to the upper layer of a soil column. The top of the soil column was covered with a 0.5 cm thick layer of quartz sand to prevent damage to the soil layer during water addition. Simulated rainfall was then conducted at a rate of 200 mm / 48 h, completed over 12 h. The mixture was then leached with a 0.01 mol / L calcium chloride solution, and the leachate was collected. After leaching, the soil column was evenly cut into three sections, and the content of the test substance in the soil and leachate of each section was determined.

[0240] The test compound is a modified cyclodextrin inclusion complex prepared according to an application example of this invention.

[0241] For comparison, this experiment tested two modified monomeric cyclodextrin derivatives; meanwhile, the commercially available 0.18% avermectin EC for nematode control was used as a control group.

[0242] Based on the content of the tested substances in each section of soil and leachate, calculate its percentage of the total price adjustment according to the national standard method:

[0243]

[0244] In the formula:

[0245] R i - The percentage of the test substance in each soil section and leachate, %;

[0246] mi - the mass of the test substance in each soil section and leachate, in milligrams (mg);

[0247] Note: i = 1, 2, 3, 4, representing the soil and leachate components at depths of 0cm to 10cm, 10cm to 20cm, and 20cm to 30cm, respectively.

[0248] m o -Total amount of test substance added, in milligrams (mg).

[0249] Press R i The value is used to classify the mobility of pesticides in the soil into four levels, as shown in Table 2.

[0250] Table 2. Classification of pesticide leaching performance in soil

[0251] grade <![CDATA[R i / %]]> Leachable I <![CDATA[R4>50]]> Easy to leach II <![CDATA[R3+R4>50]]> Leachable III <![CDATA[R2+R3+R4>50]]> Difficult to leach IV <![CDATA[R1>50]]> Difficult to leach

[0252] Following the above operations and evaluation methods, the leaching effects of the samples in each treatment group are shown in Table 3 below:

[0253] Table 3. Comparison of the leaching ability of abamectin encapsulated by various modified cyclodextrins with that of natural and commercially available cyclodextrins.

[0254]

[0255]

[0256] Table 3 shows that the modified cyclodextrin derivative of the present invention significantly improved the leaching performance of avermectin compared with natural cyclodextrin, commercially available modified derivatives, and the control group.

Claims

1. The use of a modified cyclodextrin derivative to improve the mobility of a macrolide active in soil, characterized in that, The modified cyclodextrin derivative has a structure shown in Formula I: Formula I wherein A is a C6-C15 linear or branched alkyl group covalently bonded at the 2, 3 or 6 position of the cyclodextrin; R1and R2are each independently H, hydroxypropyl, C1-C5 alkyl carboxylic acid and its salt or C1-C6 alkyl sulfonic acid and its salt; R3is hydroxypropyl, C1-C5 alkyl carboxylic acid and its salt or C1-C6 alkyl sulfonic acid and its salt; m is 5, 6 or 7; * represents a connecting bond.

2. Use according to claim 1, characterized in that, wherein A is a C9-C15 linear or branched alkyl group; m is 6.

3. Use according to claim 1, characterized in that, Each polymer molecule shown in Formula I contains 3-50 cyclodextrin structural units.

4. Use according to claim 1, characterized in that, The modified cyclodextrin derivative has a structure shown in Formula VII: ； wherein M is H, Li, Na or K; Y is a C1-C5 linear or branched alkane; Rd, Reand Rfare H, C1-C5 alkyl carboxylic acid salt; A and m are defined as the same as defined in Claim 1.

5. The use according to claim 1, characterized in that, The modified cyclodextrin derivative has a structure shown in Formula IX: ； wherein M is H, Li, Na or K; Y is a C1-C5 linear or branched alkane; Rg, Rhand Ri are H, C1-C5 alkyl sulfonic acid salt; A and m are defined as the same as defined in Claim 1.

6. Use according to claim 1, characterized in that, The modified cyclodextrin derivative has a structure shown in Formula XI: ； wherein R5is CH2CH(OH)CH3; Rn, Roand Rpare H or -CH2CH(OH)CH3; A and m are defined as the same as defined in Claim 1.

7. Use according to claim 1, characterized in that, The preparation method of the modified cyclodextrin derivative having a structure shown in Formula I comprises a cross-linking reaction and a modification reaction.

8. The use according to claim 1, characterized in that, When R3is C1-C5 alkyl carboxylic acid and its salt, the method comprises the following steps: a) converting Formula II cyclodextrin and Formula III haloalkane into Formula IV cross-linking product by cross-linking reaction in the presence of an acid binding agent; ； wherein X is F, Cl, Br or I; n is an integer of 6-15; A and m are defined as the same as defined in Claim 1; b) converting Formula IV and Formula V haloformyl compound into Formula VI cyclodextrin polymer formyl compound; ； wherein R4is H, Li, Na, K or C1-C5 alkyl; X is F, Cl, Br or I; Y is C1-C5 linear or branched alkane; Ra, Rband Rc are H, C1-C5 alkyl carboxylic acid or C1-C5 alkyl ester; A and m are defined as the same as defined in Claim 1; and c) converting Formula VI into Formula VII compound using inorganic base; wherein M is H, Li, Na or K; Y is C1-C5 linear or branched alkane; Rd, Reand Rfare H, C1-C5 alkyl carboxylic acid salt; A and m are defined as the same as defined in Claim 1.

9. Use according to claim 8, characterized in that, In step a), n is an integer of 9-15.

10. Use according to claim 8, characterized in that, In step a), the Formula II cyclodextrin and Formula III haloalkane are fed in a molar ratio of 1:1.2~1:

3.

11. Use according to claim 8, characterized in that, In step b), the Formula IV and Formula V haloformyl compound are fed in a molar ratio of 1:5~1:15 relative to the molar amount of the starting cyclodextrin.

12. Use according to claim 11, characterized in that, The halocarbonyl compound of formula IV and formula V is fed at a molar ratio of 1:8 to 1:12 relative to the starting cyclodextrin.

13. The use according to claim 8, characterized in that, In step a), the reaction solvent is DMF or DMSO; the acid binding agent is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene or 4-dimethylaminopyridine; In step b), the reaction solvent is DMF or DMSO; the catalyst is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene or 4-dimethylaminopyridine.

14. The use according to claim 8, characterized in that, Steps a) and b) are carried out in a conventional reactor or in a microreactor.

15. The use according to claim 1, characterized in that, When R3 is C1-C6 alkylsulfonic acid and salts thereof, the following steps are included: a) cross-linking reaction of the cyclodextrin of formula II with a haloalkane of formula III in the presence of an acid binding agent to convert into a cross-linking product of formula IV; ； wherein X is F, Cl, Br or I; n is an integer from 6 to 15; A and m are defined as in claim 1, b) reaction of IV with a haloalkylsulfonate of formula VIII to convert into a cyclodextrin polymer sulfonic acid of formula IX and salts thereof; ； wherein X is F, Cl, Br or I; Y is a linear or branched C1-C5 alkane; M is H, Li, Na or K; Rg, Rh and Ri are H or a C1-C5 alkylsulfonate; A and m are defined as in claim 1; or b') reaction of IV with a sulfonic acid lactone of formula X to convert into a cyclodextrin polymer sulfonic acid of formula IX and salts thereof; ； wherein Z is a linear C3-C4 alkyl; M is H, Li, Na or K; Rj, Rk and Rl are H or a C3-C4 alkylsulfonate; A and m are defined as in claim 1.

16. Use according to claim 15, characterized in that, In step a), n is an integer from 9 to 15.

17. The use according to claim 15, characterized in that, In step a), the cyclodextrin of formula II and the haloalkane of formula III are fed at a molar ratio of 1:1.2 to 1:

3.

18. The use according to claim 15, characterized in that, In step b) or b'), the cross-linking product IV and the haloalkylsulfonate of formula VIII or the sulfonic acid lactone of formula X are fed at a molar ratio of 1:5 to 1:15 relative to the starting cyclodextrin.

19. Use according to claim 18, characterized in that, The cross-linking product IV and the haloalkylsulfonate of formula VIII or the sulfonic acid lactone of formula X are fed at a molar ratio of 1:8 to 1:12 relative to the starting cyclodextrin.

20. The use according to claim 15, characterized in that, In step a), the reaction solvent is DMF or DMSO; the acid binding agent is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene or 4-dimethylaminopyridine (DMAP). The reaction solvent in step b) is DMF or DMSO; the catalyst is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene or 4-dimethylaminopyridine (DMAP); The reaction solvent in step b') is DMF or DMSO; the catalyst is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide, potassium hydroxide or sodium hydride; the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 4-dimethylaminopyridine (DMAP).

21. An inclusion complex comprising the modified cyclodextrin derivative of Formula I and a macrolide active ingredient.

22. The clathrate of claim 21, wherein, The weight ratio of the macrolide active ingredient to the modified cyclodextrin derivative is 1:1-1:

20.

23. The clathrate of claim 22, wherein, The weight ratio of the macrolide active ingredient to the modified cyclodextrin derivative is 1:5-1:

15.

24. The clathrate of claim 21, wherein, The macrolide active ingredient is at least one of abamectin, ivermectin, emamectin benzoate, eprinomectin, doramectin, moxidectin, spinosad, spinetoram or milbemycins.

25. Use of the inclusion complex comprising the modified cyclodextrin derivative and the macrolide active ingredient of claim 21 for controlling soil nematodes.

26. A pesticidal composition, characterized by, The inclusion complex comprising the modified cyclodextrin derivative and the macrolide active ingredient of claim 21.

27. Use of the pesticide composition of claim 26 for controlling soil nematodes.

28. Use of the pesticide composition of claim 26 for controlling soil nematodes.

29. Use of the pesticide composition of claim 26 for controlling soil nematodes.

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