Aldehyde-based insect pheromone derivative, preparation method therefor, and use thereof

Abstract

The present invention provides an aldehyde-based insect pheromone derivative. A compound containing at least one primary amine group is used as a carrier, and an aldehyde-based insect pheromone forms an imine derivative with the carrier by means of a chemical reaction. The present invention further provides a preparation method and use of the aldehyde-based insect pheromone derivative, and a release method. By means of the treatment of the aldehyde-based insect pheromone in a chemical reaction, the aldehyde-based insect pheromone derivative provided by the present invention can exhibit significantly improved stability and can also realize the sustained release and controlled release of the pheromone. The carrier material has a wide range of sources, diverse choices, convenience, and economy. In addition, the aldehyde-based insect pheromone derivative provided by the present invention can also realize the combined fixation and release of multiple pheromones, thereby enabling the trapping, prevention and control of multiple insects.

Description

An aldehyde insect pheromone derivative, its preparation method and uses Technical Field

[0001] This invention relates to the field of insect pheromone pesticides, specifically to an aldehyde insect pheromone derivative, its preparation method, and its uses. Background Technology

[0002] Pheromones are a collective term for compounds that play a role in chemical communication between organisms. They are compounds used by insects to express various information such as gathering, foraging, mating, and alarm. In other words, they are the chemical molecular language of insect communication. Common pheromones include: altruistic pheromones, egoistic pheromones, synergistic pheromones, aggregation pheromones, tracking pheromones, alarm pheromones, dispersal pheromones, and sex pheromones.

[0003] In recent years, the overuse of pesticides has posed a serious threat to the environment, agricultural product safety, and human health. The increasing resistance of pests to pesticides has also presented new challenges to their control. With the improvement of people's environmental and ecological awareness, new pest control technologies that use sex pheromones to interfere with mating, such as sex mating techniques, to reduce the reproduction rate of pest populations and control pest damage are receiving more and more attention.

[0004] Insect sex pheromones are compounds that regulate the attraction behavior of male and female insects. They are both sensitive and specific, with a long range of action and strong attraction. Sex pheromones are biomimetic high-tech products that mimic natural insect sex pheromones and are released into the field through a releaser to lure and kill pests of the opposite sex. This technology kills pests without contacting plants or agricultural products, eliminating concerns about pesticide residues, and is one of the preferred methods for ecological pest control in modern agriculture.

[0005] Typically, insect sex pheromones used for pest monitoring and control are processed into slow-release formulations using physical methods. The carrier materials are often synthetic materials such as rubber, polyethylene, and polyvinyl chloride. These carriers are not easily degraded in the environment, easily becoming agricultural waste and causing farmland pollution. In recent years, researchers have also developed chemical methods to process insect sex pheromones. However, products obtained through chemical processing generally require light exposure for pheromone release, limiting their application.

[0006] For aldehyde insect pheromones (such as cis-9-hexadecenal, cis-11-hexadecenal, etc.), their stability is generally poor, they evaporate quickly and are prone to deterioration. Physical processing alone is difficult to significantly improve their stability. Existing chemical methods mainly achieve slow release through light, and the light source is mostly ultraviolet light, which has high requirements for the application environment. Moreover, aldehyde pheromones are not stable under ultraviolet light, so the application of pheromones is also quite limited.

[0007] Therefore, there is an urgent need to develop a chemical-based processing method for aldehyde insect pheromones that is simple to process and has low application requirements, in order to improve their stability and expand their application range. Summary of the Invention

[0008] To overcome the shortcomings of the existing technology, one object of the present invention is to provide an aldehyde insect pheromone derivative that improves the stability of aldehyde insect pheromones through chemical reactions. Under certain conditions, the derivative can achieve the slow release and controlled release of aldehyde insect pheromones, and therefore has great potential as an insect trapping and control product.

[0009] Another object of the present invention is to provide a method for preparing, using and releasing the aldehyde insect pheromone derivative.

[0010] The first aspect of the present invention provides an aldehyde insect pheromone derivative, which uses a compound containing at least one primary amine group as a carrier, with which the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the structure shown in formula (I).

[0011] Wherein, R represents the compound containing at least one primary amino group with x primary amino group residues removed;

[0012] a represents an integer from 1 to 20 (for example, it can be any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0013] b represents an integer from 0 to 20 (for example, it can be any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0014] c represents an integer from 0 to 2 (for example, it can be any integer of 0, 1 or 2);

[0015] d represents an integer from 0 to 20 (for example, it can be any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0016] x represents an integer that is at least 1.

[0017] Unlike common physical processing methods, the aldehyde insect pheromone derivatives provided by this invention use a compound containing at least one primary amine group as a carrier. The primary amine group reacts chemically with the aldehyde group in the insect pheromone to generate an imine substance, thereby linking the aldehyde insect pheromone to the carrier. This significantly improves its stability. Depending on the number of primary amine groups participating in the reaction, one or more pheromones can be linked to the carrier, forming a novel "keychain"-like structure. The imine derivatives can undergo controlled, slow hydrolysis under certain conditions (e.g., in air or water), thereby enabling the sustained and controlled release of insect pheromones. The reaction route is shown below:

[0018] The aldehyde insect pheromone derivatives provided by this invention can use any primary amine compound commonly found in the chemical field as a carrier material. Preferably, these are substances that are easily degradable under natural conditions, have low pollution, and are inexpensive and readily available. They can be small molecules or large molecules such as polymers, peptides, and proteins. For example, the carrier materials that can be used in this invention include, but are not limited to, amino acids, peptides, hydrazides, acylhydrazides, anilines, hydroxylamines, hydrazones, and other carrier materials.

[0019] In the aldehyde insect pheromone derivatives provided by this invention, amino acid esters can be used as carriers. In this case, the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the structure shown in formula (I-1).

[0020] Wherein, R1 represents C1-C16 alkyl, C0-C8 alkylene, C6-C20 aryl, or -CH2-(CH2). a1 -(CH=CH)-(CH2) b1 -(CH=CH) c1 -(CH2) d1 -CH3;

[0021] R2 represents the residues of the amino acid ester after removing the ester group and amino group;

[0022] a, b, c, and d are each independently defined as in equation (Ⅰ);

[0023] a1 represents an integer from 1 to 20 (for example, it can be any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0024] b1 represents an integer from 0 to 20 (for example, it can be any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0025] c1 represents an integer from 0 to 2 (for example, it can be any integer of 0, 1 or 2);

[0026] d1 represents an integer from 0 to 20 (for example, it can be any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).

[0027] In the aldehyde insect pheromone derivatives provided by this invention, polypeptide esters can also be used as carriers. In this case, the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the structure shown in formula (I-2).

[0028] Wherein, R1 represents C1-C16 alkyl, C0-C8 alkylene, C6-C20 aryl, or -CH2-(CH2). a1 -(CH=CH)-(CH2) b1 -(CH=CH) c1 -(CH2) d1 -CH3;

[0029] P represents the residues of the polypeptide ester after removing the ester group and amino group;

[0030] a, b, c, and d are each independently defined as in equation (Ⅰ);

[0031] a1 represents an integer from 1 to 20 (for example, it can be any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0032] b1 represents an integer from 0 to 20 (for example, it can be any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20);

[0033] c1 represents an integer from 0 to 2 (for example, it can be any integer of 0, 1 or 2);

[0034] d1 represents an integer from 0 to 20 (for example, it can be any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).

[0035] The alcohols that form amino acid esters and polypeptide esters can be common fatty alcohols (such as methanol, ethanol, lauryl alcohol, etc.), aromatic alcohols, etc., or they can be insect pheromones of alcohols. In this case, different kinds of insect pheromones can be linked to a single carrier, thereby enabling the combined application of pheromones to achieve the goal of joint control of multiple insects.

[0036] In some embodiments, the amino acid ester or polypeptide ester can be a C1-C16 alkyl ester or benzyl ester of an amino acid or polypeptide, thus eliminating the need for a combination of multiple pheromones. In some preferred embodiments, the amino acid ester or polypeptide ester can be a methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, lauryl ester, etc.

[0037] In other embodiments, the amino acid ester or polypeptide ester may be an ester formed by an amino acid or polypeptide and an alcoholic insect pheromone or its stereoisomer as shown in Formula (II);

[0038] HO-CH2-(CH2) a1 -(CH=CH)-(CH2) b1 -(CH=CH) c1 -(CH2) d1 -CH3

[0039] Formula (II)

[0040] Among them, a1, b1, c1, and d1 are each independently defined as in equations (I-1) and (I-2).

[0041] In some preferred embodiments, a1 represents an integer from 1 to 12, b1 represents an integer from 0 to 12, c1 represents an integer from 0 to 2, and d1 represents an integer from 0 to 10. In some more preferred embodiments, a1 represents an integer from 3 to 12, b1 represents an integer from 0 to 6, c1 represents an integer of 0 or 1, and d1 represents an integer from 0 to 8. In some further preferred embodiments, a1 represents an integer from 6 to 10, b1 represents 0, c1 represents an integer of 0 or 1, and d1 represents an integer from 0 to 6. In some most preferred embodiments, the alcohol-based insect pheromone may be cis-11-hexadecenol or E8E10-dodecadien-1-ol.

[0042] In some embodiments, the amino acid used to form the amino acid ester can be a common natural or non-natural amino acid, wherein the amino group removed is the amino acid residue represented by R2. For example, amino acids that can be used in this invention include, but are not limited to, phenylalanine, alanine, glycine, leucine, and γ-aminobutyric acid. In some more preferred embodiments, the amino acid can be phenylalanine, in which case the amino acid residue R2 is represented as:

[0043] In some preferred embodiments, the amino acid ester used as the carrier can be

[0044] In some embodiments, the polypeptide used to form the polypeptide ester can be a polypeptide formed from any number of common natural and non-natural amino acids, wherein the polypeptide residue represented by P is the portion excluding the carboxyl and amino groups at both ends. In some preferred embodiments, the polypeptide can be a polypeptide formed from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) natural or non-natural amino acids. In some more preferred embodiments, the polypeptide can be a polypeptide formed from 2 to 20 natural amino acids, for example, a polypeptide formed from 3 to 16 natural amino acids, and more particularly, a polypeptide formed from 3 to 8 natural amino acids. In some preferred embodiments, the polypeptide may be Ala-phe-leu-Trp-gly, Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly, Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly or Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly.

[0045] In the aldehyde insect pheromone derivatives provided by this invention, compounds with the structure shown in formula (I-3) can also be used as carriers. In this case, the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the structure shown in formula (I-4).

[0046] R'-LY-NH2

[0047] Equation (Ⅰ-3)

[0048] Wherein, R' represents C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, C3-C20 cycloalkyl, 3-20 heterocyclic, C6-C20 aryl or 5-20 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, carboxyl, 3-8 heterocyclic, C3-C8 cycloalkyl, C6-C12 aryl or 5-12 heteroaryl;

[0049] L indicates a C0-C8 alkylene group;

[0050] Y represents -C(O)NH-, -NHC(O)-, -C(O)-, -NH-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NH- or not present;

[0051] a, b, c, and d are each independently defined as in equation (Ⅰ).

[0052] In some embodiments, in formulas (I-3) and (I-4), R' may represent a C6-C12 aryl or a 5-12 heteroaryl, such as phenyl, naphthyl, biphenyl, furanyl, thiophene, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or indolyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, and carboxyl; L may represent a C0-C6 alkylene, such as a C0-C4 straight-chain or branched alkylene; Y may represent -C(O)NH-, -NH-, -O-, or be absent.

[0053] In some preferred embodiments, the compound (i.e., the support) with the structure shown in formula (I-3) can be one of the following compounds:

[0054] In the aldehyde insect pheromone derivatives provided by this invention, compounds with the structure shown in formula (I-5) can also be used as carriers. In this case, the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the structure shown in formula (I-6).

[0055] Wherein, R3 and R4 each independently represent C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, C3-C20 cycloalkyl, 3-20 heterocyclic, C6-C20 aryl or 5-20 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, carboxyl, 3-8 heterocyclic, C3-C8 cycloalkyl, C6-C12 aryl or 5-12 heteroaryl groups;

[0056] a, b, c, and d are each independently defined as in equation (Ⅰ).

[0057] In some embodiments, in formulas (I-5) and (I-6), R3 and R4 can each independently represent a C6-C12 aryl or a 5-12 heteroaryl group, for example, phenyl, naphthyl, biphenyl, furanyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or indolyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, and carboxyl.

[0058] In some preferred embodiments, the compound (i.e., the support) with the structure shown in formula (I-5) can be

[0059] The aldehyde insect pheromone derivatives provided by this invention can be of any type commonly found in the art, and may contain an aldehyde group and at least one double bond. In some preferred embodiments, in formula (I), a represents an integer from 1 to 12, b represents an integer from 0 to 12, c represents an integer from 0 to 2, and d represents an integer from 0 to 10. In some more preferred embodiments, a represents an integer from 3 to 12, b represents an integer from 0 to 6, c represents an integer of 0 or 1, and d represents an integer from 0 to 8. In some further preferred embodiments, a represents an integer from 6 to 10, b represents 0, c represents 0, and d represents an integer from 2 to 6. In some most preferred embodiments, the aldehyde insect pheromone is cis-9-hexadecenal, cis-11-hexadecenal, or cis-13-octadecenal.

[0060] In some embodiments, the aldehyde insect pheromone derivatives provided by the present invention can be the following compounds:

[0061] A second aspect of the present invention provides a method for preparing an aldehyde insect pheromone derivative as described in any of the above technical solutions. The method may be: reacting a compound containing at least one primary amine group with an aldehyde insect pheromone containing at least one primary amine group as shown in formula (III) in an optional organic solvent to prepare the imine derivative.

[0062] CHO-(CH2) a -(CH=CH)-(CH2) b -(CH=CH) c -(CH2) d -CH3

[0063] Formula (Ⅳ)

[0064] Among them, R, a, b, c, d, and x are each independently defined as in any of the above technical solutions.

[0065] In the preparation method provided by the present invention, the reaction can be carried out in different reaction media (e.g., water, organic solvent or the reaction raw materials themselves) according to the different carrier materials selected, so as to prepare the imine derivative. The reaction temperature and reaction time can also be adjusted by those skilled in the art according to different reaction media and actual reaction conditions. The purification method of the product can also be selected by those skilled in the art according to different product types and actual reaction conditions, such as extraction, crystallization, column chromatography, etc.

[0066] In some embodiments, the compound containing at least one primary amine group reacts with aldehyde insect pheromones in an optional organic solvent at a temperature of 10–150°C, for example, at about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, or any temperature range. In some preferred embodiments, the reaction temperature can be 25–105°C.

[0067] In some embodiments, the organic solvent may be aliphatic hydrocarbons (such as n-pentane, n-hexane, etc.), alicyclic hydrocarbons (such as cyclopentane, cyclohexane, etc.), aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), heterocyclic hydrocarbons (such as tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, etc.), halogenated aliphatic hydrocarbons (such as dichloromethane, trichloromethane, dichloroethane, etc.), halogenated aromatic hydrocarbons (such as chlorobenzene, bromobenzene, chlorotoluene, bromotoluene, etc.), alcohols (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.), ketones (such as acetone, butanone, etc.), esters (such as methyl acetate, ethyl acetate, etc.), ethers (such as diethyl ether, diethyl ether, etc.), nitriles (such as acetonitrile, etc.), alkyl sulfoxides (such as dimethyl sulfoxide, etc.), alkyl amides (such as dimethyl imide, etc.), and other solvents commonly used in the art.

[0068] In some embodiments, the weight of the organic solvent can be 1 to 100 times the weight of the aldehyde insect pheromone, for example, about 2 times, about 5 times, about 8 times, about 10 times, about 12 times, about 15 times, about 18 times, about 20 times, about 22 times, about 25 times, about 28 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or any multiple range.

[0069] In some embodiments, the molar ratio of the compound containing at least one primary amino group, as shown in formula (III), to the aldehyde insect pheromone can be 1 to 5:1, for example, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.2:1, about 2.5:1, about 2.8:1, about 3:1, about 3.2:1, about 3.5:1, about 3.8:1, about 4:1, about 4.2:1, about 4.5:1, about 4.8:1, about 5:1, or any molar ratio range. In some preferred embodiments, the molar ratio of the amino acid ester or polypeptide ester to the aldehyde insect pheromone can be 1 to 3:1, for example, 1.2 to 2:1.

[0070] In some embodiments, when the compound containing at least one primary amine group is an amino acid ester or polypeptide ester, it can be prepared by esterification of the amino acid or polypeptide with an alcohol (e.g., methanol or alcoholic insect pheromones), which can be carried out in the presence of a protic acid catalyst (e.g., p-toluenesulfonic acid) commonly used in the art.

[0071] A third aspect of the present invention provides the use of any of the aldehyde insect pheromone derivatives described in the above-described technical solutions in the preparation of sustained-release and / or controlled-release formulations of insect pheromones. As mentioned above, the aldehyde insect pheromone derivatives provided by the present invention have the advantages of good stability and sustained-release and controlled-release capabilities, and are therefore very suitable for use in the preparation of sustained-release and controlled-release formulations of insect pheromones or other insect pheromone products with similar functions.

[0072] A fourth aspect of the present invention provides a method for releasing an aldehyde insect pheromone derivative as described in any of the above technical solutions, wherein the method comprises: hydrolyzing the aldehyde insect pheromone derivative in water or in air in the presence of an optional enzyme to release the aldehyde insect pheromone.

[0073] In some embodiments, when the aldehyde insect pheromone derivative is released into the air, the humidity of the air can be 1 to 100% (relative humidity, RH), for example, it can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, or any humidity range.

[0074] In some embodiments, when the aldehyde insect pheromone derivative is released into the air, the air temperature can be 10 to 60°C, for example, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, or any temperature range.

[0075] In some embodiments, when the aldehyde insect pheromone derivative is released in water, its mass percentage concentration in water can be 0.1% to 50%, for example, it can be about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or any mass percentage range.

[0076] In some embodiments, when the aldehyde insect pheromone derivative is released in water, the temperature of the water can be room temperature, i.e., 25±5℃.

[0077] In some embodiments, the enzyme may be a common enzyme in the art that promotes ester hydrolysis, including but not limited to Y200 enzyme, Novozym435, LVK-40G, etc.

[0078] In some preferred embodiments, the aldehyde insect pheromone derivative can be hydrolyzed in air at a temperature of 10–60°C (e.g., 25–50°C) and a relative humidity (RH) of 10–100% (e.g., 60–90%) to release the aldehyde insect pheromone.

[0079] The release method provided by this invention can adjust the release rate and amount of aldehyde insect pheromones by various means such as adjusting the concentration of aldehyde insect pheromone derivatives in water, air humidity, temperature, and using different enzymes, thereby achieving sustained release and controlled release.

[0080] The technical solution provided by this invention has the following advantages:

[0081] (1) The aldehyde insect pheromone derivatives provided by the present invention can significantly improve the stability of aldehyde insect pheromones by chemical reaction, and can also realize the slow release and controlled release of pheromones. The carrier materials are widely available, with many choices, convenient and economical. Some carrier materials are easily degraded in the environment after releasing pheromones, making them green and environmentally friendly.

[0082] (2) The aldehyde insect pheromone derivatives provided by the present invention can also achieve the combined release of multiple pheromones and regulate the release rate and amount of different pheromones, thereby enabling the control of multiple insects in multiple scenarios.

[0083] (3) The aldehyde insect pheromone derivatives provided by the present invention have a simple preparation process, the carrier materials are widely available and inexpensive, the synthesis and release processes are mild and easy to control, and they are highly operable. Therefore, they have good industrial applicability and are suitable for large-scale production and application. Attached Figure Description

[0084] Figure 1 shows the experimental results of the hydrolysis experiment in Example 36;

[0085] Figure 2 shows the experimental results of the hydrolysis experiment in Example 37;

[0086] Figure 3 shows the experimental results of the hydrolysis experiment in Example 38;

[0087] Figure 4 shows the experimental results of the hydrolysis experiment in Example 39;

[0088] Figure 5 shows the experimental results of the hydrolysis experiment in Example 40;

[0089] Figure 6 shows the experimental results of the hydrolysis experiment in Example 41;

[0090] Figure 7 is a graph showing the experimental results of the hydrolysis experiment in Example 42. Detailed Implementation

[0091] the term

[0092] Unless otherwise defined, the terminology used in this invention should be considered to have the ordinary meaning that can be understood by those skilled in the art. Some common terms are introduced and explained below:

[0093] The singular forms used in this article, such as “a,” “an,” “the,” “the,” “the above,” etc., contain both singular and plural referents.

[0094] The use of "include" or "include" in this article is open-ended rather than restrictive, meaning that it does not exclude unlisted types, elements, or methods or steps.

[0095] As used herein, "one embodiment" specifically refers to the particular feature, structure, or property of the described subject when the phrase appears. Therefore, "one embodiment" appearing in different places herein does not necessarily refer to the same embodiment. On the other hand, some specific embodiments may include some features of other embodiments but not all features of other embodiments. In such cases, combinations of embodiments with different features, although not listed herein, should be assumed to be included in the claims and statements herein.

[0096] As used herein, "C1-Cn" includes C1-C2, C1-C3, ..., C1-Cn. For example, the term "C1-C16" refers to a group having 1 to 16 carbon atoms, meaning the group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon atoms. Therefore, for example, "C1-C16 alkyl" refers to an alkyl group containing 1 to 16 carbon atoms.

[0097] The term "alkyl" as used alone or in combination herein refers to a saturated aliphatic hydrocarbon with optional substituted straight or optional substituted branched chains. Preferably, it may have 1 to 16 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc.

[0098] As used alone or in combination herein, the term "alkylene" refers to an optionally substituted saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably C1-C8 alkylene, more preferably C1-C6 alkylene. Non-limiting examples of alkylene include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Furthermore, when alkylene is "C0", it means that alkylene is absent.

[0099] As used alone or in combination herein, the term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. It can be straight-chain or branched, preferably C2-C8 alkenyl, more preferably C2-C6 alkenyl. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. wait.

[0100] The term "alkynyl" as used alone or in combination herein refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. It can be straight-chain or branched, preferably C2-C8 alkynyl, and more preferably C2-C6 alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0101] The term "cycloalkyl" as used alone or in combination herein refers to an optionally substituted non-aromatic saturated carbocyclic ring, which may include a monocyclic (having one ring), a bicyclic (having two rings), or a polycyclic (having more than two rings), and the ring type includes fused rings, bridged rings, and spirocyclic rings. Preferably, the cycloalkyl group may have 3 to 10 cyclic carbon atoms, for example, 3 to 6 cyclic carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0102] The term "heterocyclic group" as used alone or in combination herein refers to a non-aromatic, 5- to 20-membered monocyclic, bicyclic, or polycyclic ring, including fused rings, bridged rings, and spirocyclic rings, wherein the cyclic atoms may comprise 1 to 4 (e.g., 1, 2, 3, or 4) atoms selected from nitrogen, oxygen, and / or sulfur. Preferably, the heterocyclic group may have 5 to 12 cyclic atoms, for example, 5 to 10 cyclic atoms, or 5 to 8 cyclic atoms, or 5 to 6 cyclic atoms. Non-limiting examples of heterocyclic groups include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine, etc.

[0103] The term "aryl" as used alone or in combination herein refers to an optionally substituted aromatic hydrocarbon group having 6 to 20, such as 6 to 12 or 6 to 10 cyclic carbon atoms, which can be monocyclic, bicyclic, or polycyclic. Bicyclic or multiple cyclic aryl groups can be a monocyclic aryl group fused with other independent rings, such as alicyclic or aromatic rings. Non-limiting examples of monocyclic aryl groups include, but are not limited to, phenyl; non-limiting examples of bicyclic aryl groups include naphthyl; non-limiting examples of polycyclic aryl groups include, but are not limited to, phenanthryl, anthracene, fluorenyl, azulel, etc.

[0104] The term "heteroaryl" as used alone or in combination herein refers to an optionally substituted aromatic 5- to 20-membered monocyclic, bicyclic, or polycyclic ring, including fused rings, bridged rings, and spirocyclic rings, wherein the cyclic atoms may comprise 1 to 4 (e.g., 1, 2, 3, or 4) atoms selected from nitrogen, oxygen, and / or sulfur. Preferably, the heteroaryl group may have 5 to 12 cyclic atoms, for example, 5 to 10 cyclic atoms, 5 to 8 cyclic atoms, or 5 to 6 cyclic atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, inzolyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 - Triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl, etc.

[0105] The term "alkoxy" as used alone or in combination herein refers to an "alkyl-O-" group. Alkyl groups are defined herein. Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0106] The term "nitro" as used alone or in combination in this article refers to the -NO2 group.

[0107] The term "hydroxyl group" as used alone or in combination in this article refers to the -OH group.

[0108] The term “halogen” as used alone or in combination in this article refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0109] The term "amino" as used alone or in combination in this article refers to -NH2.

[0110] The term "cyano" as used alone or in combination in this article refers to -CN.

[0111] The term "carboxyl group" as used alone or in combination in this article refers to -COOH.

[0112] The term “benzyl” as used alone or in combination in this article refers to -CH2-phenyl.

[0113] The term “natural amino acid” as used alone or in combination herein includes the following amino acids having the α-configuration: glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile I), proline (Pro), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), serine (Ser), threonine (Thr), cysteine ​​(Cys), methionine (Met), asparagine (Asn), glutamine (Gln), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), and histidine (His), as well as non-protein natural amino acids such as γ-aminobutyric acid.

[0114] The term “non-natural amino acid” as used alone or in combination in this article refers to amino acids other than natural amino acids, such as citrulline.

[0115] The term "stereoisomer" as used alone or in combination herein includes all isomeric forms, such as R and S configurations arising from one or more asymmetric centers, (Z) and (E) double bond isomers (geometric isomers), (Z) and (E) conformational isomers, trans-restricted isomers, etc. Similarly, the invention can also exist as a mixture of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers), representative examples of which include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is contemplated that the scope of this invention covers all such isomers or mixtures thereof in any proportion.

[0116] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0117] Unless otherwise specified, all raw materials or reagents used in the embodiments of the present invention are commercially available products, and all percentages used are mass percentages unless otherwise specified.

[0118] In the embodiments of the present invention, room temperature (or normal temperature) refers to 25±5℃.

[0119] In embodiments of the present invention, the hydrolysis of imine derivatives is monitored by HPLC detection.

[0120] Example 1: Preparation of imine derivative 1 using phenylalanine dodecyl ester as a carrier

[0121] 10g of phenylalanine was weighed into 50g of toluene, and 11.3g of dodecanol and 7.3g of concentrated sulfuric acid were added. The mixture was refluxed at 120°C to remove water. After the reaction was completed, the mixture was washed with sodium carbonate aqueous solution until it was weakly alkaline. The mixture was extracted three times with DCM (200mL×3). After standing and separating the organic phase, it was washed with water (100mL) and separated again. The organic phase was then evaporated under reduced pressure to obtain crude phenylalanine dodecanol. The crude product was purified by column chromatography with EA:PE = 3:1 (v / v) as the eluent. A 25g silica gel column was used. After concentration, 15g of phenylalanine dodecanol was obtained.

[0122] 1 g (90%, 1.0 eq) of cis-11-hexadecenal was dissolved in 5 g of DCM, and then 1.3 g (98%, 1.0 eq) of phenylalanine dodecyl ester was added. The mixture was stirred at room temperature for 1 h, centrifuged to remove water, and the reaction was monitored by GC. The conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 2.1 g of imine derivative 1.

[0123] 1 H NMR (400MHz, CDCl3) δ7.28-7.20(m,3H),7.18-7.12(m,2H),5.37-5.32(m,2H),4.14-4.07(m,1H),2 .20-2.15(m,1H),2.05-1.98(m,4H),1.63-1.58(m,2H),1.38-1.19(m,40H),0.88(t,J=6.6Hz,6H).

[0124] Example 2: Preparation of imine derivative 2 using phenylalanine dodecyl ester as a carrier

[0125] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 1.3 g (98%, 1.0 eq) of phenylalanine dodecyl ester (prepared according to the method of Example 1) was added. The reaction was carried out at room temperature for 1 h, and the water was separated by centrifugation. The reaction was monitored by GC and the conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 2.1 g of imine derivative 2.

[0126] 1 H NMR (400MHz, CDCl3) δ7.31-7.13(m,5H),5.37-5.31(m,2H),4.14-4.08(m,1H),2.20-2.14(m,1H) ),2.05-1.98(m,4H),1.67(s,2H),1.61-1.56(m,2H),1.34-1.26(m,38H),0.89(q,J=6.9Hz,6H).

[0127] Example 3: Preparation of imine derivative 3 using benzoyl hydrazine as a carrier

[0128] Weigh 1 g (90%, 1.0 eq) of cis-11-hexadecenal and dissolve it in 5 g of DCM. Then add 0.5 g (98%, 1.0 eq) of benzoylhydrazine and react at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC and the conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 3.

[0129] 1 H NMR (400MHz, CDCl3) δ7.86-7.78(m,2H),7.46-7.36(m,3H),5.37-5.32(m,2H),2.35-2. 28(m,1H),2.04-1.95(m,4H),1.52-1.43(m,2H),1.38–1.26(m,19H),0.91-0.88(m,3H).

[0130] Example 4: Preparation of imine derivative 4 using benzoyl hydrazine as a carrier

[0131] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.5 g (98%, 1.0 eq) of benzoylhydrazine was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 4.

[0132] 1 H NMR (400MHz, CDCl3) δ7.81-7.79(m,2H),7.53-7.64(m,1H),7.44-7.40(m,2H),5.39-5.30(m,2H) ,2.42-2.35(m,1H),2.04-1.95(m,4H),1.57-1.50(m,2H),1.37-1.25(m,19H),0.90-0.86(m,3H).

[0133] Example 5: Preparation of imine derivative 5 using phenylhydrazine as a carrier

[0134] 1 g (90%, 1.0 eq) of cis-11-hexadecenal was dissolved in 5 g of DCM, and then 0.4 g (98%, 1.0 eq) of phenylhydrazine was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.3 g of imine derivative 5.

[0135] 1 H NMR (400MHz, CDCl3) δ7.27-7.20(m,2H),7.08-7.02(m,1H),6.99-6.96(m,1H),6.87-6.79(m,1H),5.39-5. 31(m,2H),2.32-2.27(m,1H),2.05-1.97(m,4H),1.64-1.49(m,3H),1.40-1.28(m,18H),0.91-0.88(m,3H).

[0136] Example 6: Preparation of imine derivative 6 using phenylhydrazine as a carrier

[0137] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.4 g (98%, 1.0 eq) of phenylhydrazine was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.3 g of imine derivative 6.

[0138] 1 H NMR (400MHz, CDCl3) δ7.28-6.77(m,5H),5.36-5.31(m,2H),2.05-1.97(m,5H),1.62-1.49(m,3H),1.40-1.26(m,18H),0.90-0.88(m,3H).

[0139] Example 7: Preparation of imine derivative 7 using o-benzylhydroxylamine as a carrier

[0140] Weigh 1 g (90%, 1.0 eq) of cis-11-hexadecenal and dissolve it in 5 g of DCM. Then add 0.5 g (98%, 1.0 eq) of o-benzylhydroxylamine to the solution. React at room temperature for 1 h. After centrifugation to remove water, the reaction was monitored by GC. The conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 7.

[0141] 1H NMR (400MHz, CDCl3) δ7.37-7.32(m,4H),7.31-7.26(m,1H),5.35(t,J=4.9Hz,2H),5.10(s,1H), 5.05(s,1H),2.05-1.97(m,5H),1.50-1.43(m,2H),1.35-1.27(m,18H),0.89(dd,J=6.5Hz,3H).

[0142] Example 8: Preparation of imine derivatives using o-benzylhydroxylamine as a carrier.

[0143] Weigh 1 g (90%, 1.0 eq) of cis-9-hexadecenal and dissolve it in 5 g of DCM. Then add 0.5 g (98%, 1.0 eq) of o-benzylhydroxylamine to the solution. React at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 8.

[0144] 1 H NMR (400MHz, CDCl3) δ7.37-7.32(m,4H),7.31-7.27(m,1H),5.35(td,J=5.7,3.5Hz,2H),5.10(s,1 H),5.05(s,1H),2.05-1.97(m,5H),1.50-1.42(m,2H),1.34-1.27(m,18H),0.88(t,J=6.8Hz,3H).

[0145] Example 9: Preparation of imine derivative 9 using o-fluoroaniline as a carrier

[0146] 1 g (90%, 1.0 eq) of cis-11-hexadecenal was dissolved in 5 g of DCM, and then 0.42 g (98%, 1.0 eq) of o-fluoroaniline was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 90%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.3 g of imine derivative 9.

[0147] 1 H NMR (400MHz, CDCl3) δ7.10-7.05(m,1H),7.00-6.91(m,2H),6.83–6.73(m,1H),5.37-5. 31(m,2H),3.77-3.68(m,1H),2.07-1.96(m,4H),1.45-1.24(m,20H),0.91-0.88(m,3H).

[0148] Example 10: Preparation of imine derivative 10 using o-fluoroaniline as a carrier

[0149] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.42 g (98%, 1.0 eq) of o-fluoroaniline was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 91%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.3 g of imine derivative 10.

[0150] 1 H NMR (400MHz, CDCl3) δ7.10-7.05(m,1H),7.00-6.91(m,2H),6.83–6.73(m,1H),5.37-5.31(m,2H) ,3.77-3.68(m,1H),2.07-1.96(m,4H),1.70-1.65(m,2H),1.45-1.24(m,18H),0.91-0.86(m,3H).

[0151] Example 11: Preparation of imine derivatives using 3,4-difluoroaniline as a carrier.

[0152] 1 g (90%, 1.0 eq) of cis-11-hexadecenal was dissolved in 5 g of DCM, and then 0.49 g (98%, 1.0 eq) of 3,4-difluoroaniline was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC. The conversion rate was about 93%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 11.

[0153] 1 H NMR (400MHz, CDCl3) δ7.14-7.06(m,1H),6.96-6.88(m,1H),6.79-6.73(m,1H) ,5.38-5.30(m,2H),2.10-1.96(m,5H),1.44-1.25(m,20H),0.94-0.85(m,3H).

[0154] Example 12: Preparation of imine derivative 12 using 3,4-difluoroaniline as a carrier

[0155] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.49 g (98%, 1.0 eq) of 3,4-difluoroaniline was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC and the conversion rate was about 92%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 12.

[0156] 1 H NMR (400MHz, CDCl3) δ7.14-7.06(m,1H),7.00-6.93(m,1H),6.79-6.73(m,1H) ,5.38-5.30(m,2H),2.11-1.99(m,5H),1.44-1.25(m,20H),0.93-0.90(m,3H).

[0157] Example 13 Preparation of imine derivative 13 using 3-pyridinecarboxylhydrazide (nicotinamide hydrazide) as a support

[0158] 1 g (90%, 1.0 eq) of cis-11-hexadecenal was dissolved in 5 g of DCM, and then 0.52 g (98%, 1.0 eq) of 3-pyridinecarboxylhydrazine was added. The reaction was carried out at room temperature for 1 h. After centrifugation to remove water, the reaction was monitored by GC and the conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 13.

[0159] 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 8.73-8.64 (m, 1H), 8.19 (d, J = 7.4Hz, 1H), 7.36 (dd, J = 7.6, 5.0Hz, 1H), 5.39 -5.28(m,2H),2.40-2.19(m,2H),2.07-1.92(m,4H),1.57-1.44(m,2H),1.38-1.22(m,18H),0.90-0.85(m,3H).

[0160] Example 14: Preparation of imine derivative 14 using 3-pyridinecarboxylhydrazide (nicotinamide hydrazide) as a carrier

[0161] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.52 g (98%, 1.0 eq) of 3-pyridinecarboxylhydrazine was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC and the conversion rate was about 97%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.4 g of imine derivative 14.

[0162] 1 H NMR (400MHz, CDCl3) δ9.01(s,1H),8.69(d,J=4.2Hz,1H),8.19(d,J=6.3Hz,1H),7.36(dd,J=7.8,5.0Hz,1H),5.3 9-5.28(m,2H),2.39-2.25(m,2H),2.06-1.95(m,4H),1.55-1.46(m,2H),1.38-1.22(m,18H),0.90-0.85(m,3H).

[0163] Example 15: Preparation of imine derivative 15 using benzophenone hydrazone as a carrier

[0164] 1 g (90%, 1.0 eq) of cis-11-hexadecenal was dissolved in 5 g of DCM, and then 0.74 g (98%, 1.0 eq) of benzophenone hydrazone was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC and the conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.6 g of imine derivative 15.

[0165] 1 H NMR (400MHz, CDCl3) δ7.66-7.61(m,2H),7.40-7.32(m,6H),7.27-7.21(m,2H),5.40-5. 29(m,2H),2.05-1.98(m,4H),1.55-1.42(m,2H),1.37-1.24(m,19H),0.95-0.85(m,3H).

[0166] Example 16 Preparation of imine derivative 16 using benzophenone hydrazone as a carrier

[0167] 1 g (90%, 1.0 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.74 g (98%, 1.0 eq) of benzophenone hydrazone was added. The reaction was carried out at room temperature for 1 h. After centrifugation and water separation, the reaction was monitored by GC and the conversion rate was about 95%. The reaction solution was dehydrated with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1.6 g of imine derivative 16.

[0168] 1H NMR (400MHz, CDCl3) δ7.66-7.61(m,2H),7.39-7.31(m,6H),7.25-7.22(m,2H),5.38-5. 31(m,2H),2.05-1.98(m,4H),1.55-1.42(m,2H),1.37-1.24(m,19H),0.95-0.85(m,3H).

[0169] Example 17: Preparation of imine derivatives using polypeptide esters as carriers.

[0170] Weigh 1g of the self-made polypeptide (Ala-phe-leu-Trp-gly) (the polypeptide synthesis method is based on J.Am.Chem.Soc.2020,142,14201-14209.), 30g of methanol, and 0.3g (1.1 eq) of p-toluenesulfonic acid into a reaction vessel and react at 30°C for 2h. The reaction was monitored by GC, and the conversion rate was approximately 50%. After the reaction solution was concentrated, 13g of DCM was added, and the mixture was washed with 5% sodium bicarbonate (based on the polypeptide, 1.2 eq) aqueous solution. After standing and separating, the organic phase was washed with water and separated again. The organic phase was then evaporated under reduced pressure to obtain the crude product after methyl esterification of the polypeptide.

[0171] 0.2 g (95%, 1 eq) of cis-9-hexadecenal was dissolved in 5 g of DCM, and then 0.83 g (95%, 1.2 eq) of the crude product after methyl esterification of the polypeptide was added. The mixture was stirred at 60 °C for 6 h. The reaction was monitored by HPLC and the conversion rate was about 70%. The reaction solution was washed with HCl (based on the remaining amount of polypeptide methyl ester, 1.0-1.1 eq) in isopropanol solution (HCl concentration of 4 mol / L), filtered, and the organic phase was rotary evaporated under reduced pressure to obtain about 1 g of imine derivative 17.

[0172] Calculated Mass [M+H] + :826.54(100%); Mass Found(ESI+); 826.51[M+H] + .

[0173] Example 18: Preparation of imine derivatives using polypeptide esters as carriers.

[0174] 0.50 g (95%, 1 eq) of cis-11-hexadecenol, 0.46 g of p-toluenesulfonic acid, 1.48 g (95%, 1.2 eq) of the self-made peptide (Ala-phe-leu-Trp-gly) (peptide synthesis method referred to J.Am.Chem.Soc.2020,142,14201-14209.), and 20 g of THF were weighed and added to a reaction vessel. The reaction was carried out at 60 °C for 6 h. The conversion rate was monitored by HPLC and found to be approximately 74%. After the reaction solution was concentrated, 13 g of DCM was added, and the mixture was washed with 5% sodium bicarbonate (based on peptide, 1.2 eq) aqueous solution. After standing and separating, the organic phase was washed with water and separated again. The organic phase was then evaporated under reduced pressure to obtain 1.50 g of the peptide esterification product.

[0175] 0.25 g (95%, 1 eq) of cis-9-hexadecenal and 1.40 g (95%, 1.2 eq) of the polypeptide esterification product were weighed into 5 g of DCM and reacted at 30 °C for 3 h. The reaction was monitored by HPLC and the conversion rate was approximately 70%. The reaction solution was washed with 5% sodium bicarbonate aqueous solution (1.0-1.1 eq based on the remaining amount of esterification product), allowed to stand and separated, and the organic phase was rotary evaporated under reduced pressure to obtain 1.1 g of imine derivative 18.

[0176] Calculated Mass [M+H] + :1034.75(100%); Mass Found(ESI+); 1034.74[M+H] + .

[0177] Example 19: Preparation of imine derivatives using polypeptide esters as carriers.

[0178] The polypeptide esterification product (NH2-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-OMe) was prepared according to the method in Example 17.

[0179] 0.25 g (95%, 1 eq) of cis-9-hexadecenal and 2.5 g (95%, 1.2 eq) of the polypeptide esterification product were weighed into 10 g of DCM and reacted at 60 °C for 3 h. The reaction was monitored by HPLC and the conversion rate was approximately 63%. The reaction solution was washed with 5% sodium bicarbonate aqueous solution (1.0-1.1 eq based on the remaining amount of esterification product), allowed to stand and separated, and the organic phase was rotary evaporated under reduced pressure to obtain 1.6 g of imine derivative 19.

[0180] Calculated Mass[M+2H] 2+ 995.56 (100%); [M+3H] 3+:664.04(100%);Mass Found(ESI+);[M+2H] 2+ :995.52; [M+3H] 3+ 664.01.

[0181] Example 20: Preparation of imine derivative 20 using salicylhydrazide as a carrier

[0182] Cis-13-octadecenal (3.50 g, 13.1 mmol, 1.00 eq) was dissolved in dichloromethane (40 mL), followed by the addition of salicylhydrazine (2.00 g, 13.1 mmol, 1.00 eq). The solution was clear and transparent. The reaction mixture was stirred at room temperature (23–25 °C) for 3 h. LC-MS monitoring showed that the reaction was complete, with a conversion rate of 90.9%. The product was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 5.6 g of crude product. The crude product was dissolved in dichloromethane (5 mL) and purified by column chromatography: a silica gel column (80 g) was used, with petroleum ether and ethyl acetate as eluents. The product was obtained when the eluent volume ratio was 20% ethyl acetate. The product was combined and concentrated to obtain 4.20 g of pure product (powder-white solid, LC-MS purity: 94.8%, yield: 79.8%), i.e., imine derivative 20.

[0183] 1 H NMR (400MHz, CDCl3) δ7.55(s,1H),7.41(t,J=7.6Hz,2H),7.01(d,J=8.4Hz,1H),6.85(t,J=7.6Hz,1H),5.34(t,J=4.8Hz, 2H), 2.39 (dd, J=13.6, 7.2Hz, 2H), 2.02 (s, 4H), 1.59–1.49 (m, 2H), 1.30 (dd, J=14.0, 10.4Hz, 22H), 0.89 (t, J=7.2Hz, 3H).

[0184] Example 21: Preparation of imine derivatives using gallic acid phenylhydrazine as a carrier

[0185] Take a 100 mL round-bottom flask, add a magnetic ball of suitable size, then add cis-11-hexadecenal (647 mg, 2.72 mmol, 1.00 eq), gallic acid benzohydrazine (500 mg, 2.72 mmol, 1.00 eq), methanol (10 mL), and 2 drops of acetic acid. The reaction mixture is reacted at room temperature (23–25 °C) for 5 h. TLC monitoring shows that a new spot is generated (DCM:MeOH = 10:1, v / v, I2, Rf = 0.4). The reaction solution is filtered to remove insoluble matter. 1 g of silica gel (200–300 mesh) is added to the filtrate and the mixture is concentrated. After drying, the product is purified by column chromatography (12 g silica gel column, eluent: dichloromethane and methanol). The product is obtained when the eluent volume ratio is 5% methanol. The product is combined and concentrated to obtain 430 mg of product (brown solid, HPLC purity: 80.1%, yield: 39.1%), namely imine derivative 21.

[0186] 1 H NMR (400MHz, DMSO) δ11.05(s,1H),8.96(s,1H),7.67(s,1H),6.83(s,2H),5.39–5.26(m,2H),2.21(dd,J=12 .8,6.8Hz,2H),1.99(d,J=4.8Hz,4H),1.45(d,J=6.4Hz,2H),1.27(d,J=7.2Hz,16H),0.86(t,J=6.8Hz,3H).

[0187] Example 22: Preparation of imine derivatives using 4-hydroxybenzoylhydrazine as a support

[0188] Cis-11-hexadecenal (3.29 g, 13.8 mmol, 1.05 eq) was placed in a 100 mL single-necked flask, followed by the addition of dichloromethane (40 mL). 4-hydroxybenzoyl hydrazine (2.00 g, 13.2 mmol, 1.00 eq) was then slowly added in portions. The reaction mixture was stirred at 28–32 °C for 16 h (the mixture remained white and turbid after 1 h of stirring). LC-MS monitoring confirmed the formation of the target product. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude dichloromethane was loaded onto a column and purified by column chromatography (with a small amount of methanol added to dissolve it). Silica gel (200-300 mesh) was used as the eluent, and dichloromethane and methanol were used as the eluents. The purification was carried out with DCM:MeOH = 50:1 to DCM:MeOH = 20:1 (v / v) to obtain a colorless, transparent, oily liquid. After drying with an oil pump, 2.2 g of the product (white solid, HPLC purity: 88.6%, yield: 43.1%), namely imine derivative 22, was obtained.

[0189] 1H NMR (400MHz, DMSO) δ11.19(s,1H),7.74(d,J=8.8Hz,2H),6.84(d,J=8.4Hz,2H),5.36(dd,J=12.4,7.6Hz,2H ),2.24(t,J=11.6Hz,2H),2.01(d,J=5.2Hz,4H),1.49(s,2H),1.30(d,J=7.2Hz,18H),0.89(t,J=6.9Hz,3H).

[0190] Example 23: Preparation of imine derivatives using 2-furanoylhydrazide as a support.

[0191] Take a 40 mL glass bottle, add a magnetic ball of suitable size, then add 2-furanoyl hydrazine (1.00 g, 7.93 mmol, 1.00 eq), dichloromethane (20 mL), and cis-9-hexadecenoal (1.89 g, 7.93 mmol, 1.00 eq). Stir the reaction mixture at room temperature (24–28 °C) for 3 h. TLC (PE:EA = 5:1, v / v, UV, Rf = 0.3) showed that the starting materials had basically reacted completely, and new spots were formed. Dry the reaction solution with anhydrous Na₂SO₄, filter, and concentrate under reduced pressure to obtain 2.9 g of crude product. The crude product was dissolved in DCM:PE = 1:1 (v / v, 2 mL), purified by column chromatography using a 25 g silica gel column, with petroleum ether and ethyl acetate as eluents. When the eluent volume ratio was 5% ethyl acetate, the remaining pheromones were flushed out, and when the eluent volume ratio was 14% ethyl acetate, the product was flushed out. After combining and concentrating, 2.23 g of pure product (white waxy solid, HPLC purity: 93.0%, yield: 81.1%), namely imine derivative 23, was obtained.

[0192] 1 H NMR (400MHz, CDCl3) δ11.05(s,1H),8.96(s,1H),7.67(s,1H),6.83(s,2H),5.39–5.26(m,2H),2.21(dd,J=1 2.8, 6.8Hz, 2H), 1.99 (d, J = 4.8Hz, 4H), 1.45 (d, J = 6.4Hz, 2H), 1.27 (d, J = 7.2Hz, 16H), 0.86 (t, J = 6.8Hz, 3H).

[0193] Example 24: Preparation of imine derivatives using 2-thiophenecarbamoylhydrazine as a support.

[0194] Cis-9-hexadecenal (1.69 g, 7.04 mmol, 1.00 eq) was placed in a 50 mL single-necked flask, followed by the addition of dichloromethane (10 mL). Then, 2-thiophenecarbamoylhydrazine (1.00 g, 7.04 mmol, 1.00 eq) was slowly added in portions. The reaction mixture was stirred at 30–35 °C for 16 h (a suspension still existed after 16 h of stirring). The reaction was monitored by TLC. A new spot was generated (DCM, UV, Rf = 0.5). The reaction solution was filtered to remove insoluble matter. The filtrate was concentrated to dryness and then purified by column chromatography using silica gel (200-300 mesh, 25g silica gel column). The eluent was PE:EA = 10:1 to PE:EA = 4:1 (v / v). 2.13g of pure product (colorless transparent oily liquid, LCMS purity: 97.2%, yield: 83.8%), namely imine derivative 24, was obtained.

[0195] 1 H NMR(400MHz, CDCl3)δ9.90(d,J=103.6Hz,1H),8.11(d,J=41.2Hz,1H),7.61(s,1H),7.36(s,1H),7.16-7.04(m,1H),5.37-5.32 (m,2H),2.37(dd,J=12.6,7.4Hz,2H),2.02(d,J=3.6Hz,5H),1.62(d,J=6.8Hz,2H),1.37-1.25(m,16H),0.88(t,J=6.8Hz,3H).

[0196] Example 25: Preparation of imine derivatives using 3-indolecarbamoylhydrazide as a support.

[0197] Cis-9-hexadecenal (1.36 g, 5.71 mmol, 1.00 eq) was placed in a 50 mL single-necked flask, followed by the addition of dichloromethane (20 mL). Then, 3-indolecarbamoylhydrazine (1.00 g, 5.71 mmol, 1.00 eq) was slowly added in portions. The reaction mixture was stirred at 30–35 °C for 16 h (a suspension was still present after 16 h of stirring). TLC monitoring revealed new spots in the reaction. The reaction mixture (PE:EA = 2:1, v / v, Rf = 0.5) was generated. A small amount of silica gel was added to the reaction solution, concentrated, and dried before loading. The mixture was then purified by column chromatography using silica gel (200-300 mesh, 25g silica gel column) and eluents ranging from PE:EA = 5:1 to PE:EA = 0:1 (v / v). 1.66g of pure product (white solid, LC-MS purity: 95.0%, yield: 73.7%), i.e., imine derivative 25, was obtained.

[0198] 1H NMR (400MHz, DMSO) δ11.66(s,1H),10.92(s,1H),8.19(s,2H),7.60(s,1H),7.47(d,J=7.6Hz,1H),7.24-7.08(m,2H),5.35 (t,J=5.6Hz,2H),2.27(dd,J=12.8,7.2Hz,2H),2.01(s,4H),1.57-1.47(m,2H),1.35-1.24(m,16H),0.87(t,J=6.8Hz,3H).

[0199] Example 26: Preparation of imine derivatives using 2-methylthiazol-4-formylhydrazide as a support.

[0200] Take a 40 mL glass bottle, add a magnetic ball of suitable size, then add 2-methylthiazol-4-carboxylhydrazide (1.00 g, 6.36 mmol, 1.00 eq), dichloromethane (20 mL), and cis-9-hexadecenoal (1.52 g, 6.36 mmol, 1.00 eq). Stir the reaction mixture at room temperature (24–28 °C) for 3 h. TLC (PE:EA = 5:1, v / v, I₂, Rf = 0.2) indicates that the reactants have basically reacted completely, and new... The product was generated at a specific point. The reaction solution was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2.6 g of crude product. The crude product was dissolved in DCM (20 mL) and mixed with silica gel (4 g, 200-300 mesh). The product was purified by column chromatography using a 40 g silica gel column. The eluents were petroleum ether and ethyl acetate. When the eluent volume ratio was 15% ethyl acetate, the product was flushed out. The product was combined and concentrated to obtain 2.10 g of product (white solid, HPLC purity: 90.1%, yield: 87.5%), namely imine derivative 26.

[0201] 1 H NMR (400MHz, CDCl3) δ10.00(s,1H),8.09(s,1H),7.54(t,J=5.6Hz,1H),5.41–5.26(m,2H),2.72(d,J=8.4Hz,3H) ,2.42(dd,J=13.6,7.2Hz,2H),2.08–1.93(m,4H),1.60–1.49(m,2H),1.37–1.23(m,16H),0.88(t,J=6.8Hz,3H).

[0202] Example 27 Preparation of imine derivatives using pyrazine-2-formylhydrazide as a support 27

[0203] Take a 40 mL glass bottle, add a magnetic ball of suitable size, then add pyrazine-2-carboxylhydrazide (1.00 g, 7.24 mmol, 1.00 eq), dichloromethane (20 mL), and cis-9-hexadecenal (1.73 g, 7.24 mmol, 1.00 eq). Stir the reaction mixture at room temperature (24–28 °C) for 3 h. TLC (PE:EA = 5:1, v / v, I₂, Rf = 0.2) indicates that the reactants have basically reacted completely, and new spot formation is observed. The reaction solution was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4.1 g of crude product. The crude product was dissolved in DCM (20 mL) and mixed with silica gel (4 g, 200-300 mesh). The product was purified by column chromatography using a 40 g silica gel column and petroleum ether and ethyl acetate as eluents. When the eluent volume ratio was 35% ethyl acetate, the product was flushed out. The product was combined and concentrated to obtain 1.99 g of pure product (white solid, HPLC purity: 95.4%, yield: 76.5%), i.e., imine derivative 27.

[0204] 1 H NMR (400MHz, CDCl3) δ10.37(s,1H),9.50(d,J=1.2Hz,1H),8.79(d,J=2.4Hz,1H),8.54–8.51(m,1H),7.64(t,J=5.6Hz,1H) ,5.40–5.28(m,2H),2.51–2.41(m,2H),2.01(d,J=5.6Hz,4H),1.56(s,2H),1.30(d,J=15.6Hz,16H),0.88(t,J=6.8Hz,3H).

[0205] Example 28: Sustained release of an imine derivative prepared using dodecyl phenylalanine as a carrier

[0206] Weigh 100 mg of substrate (imine derivative product 1, prepared in Example 1) and 1 g of water into a sample tube. The substrate was allowed to stand naturally in the water at 25 °C. Under these conditions, the substrate hydrolyzed by about 76% after 15 days.

[0207] Example 29: Sustained release of imine derivatives prepared using benzoyl hydrazine as a carrier

[0208] Weigh 100 mg of substrate (imine derivative product 3, prepared in Example 3) and 1 g of water into a sample tube. Allow the substrate to stand naturally in the water at 25 °C. Under these conditions, the substrate hydrolyzes by about 50% in 15 days.

[0209] Example 30: Sustained release of imine derivatives prepared using phenylhydrazine as a carrier

[0210] Weigh 100 mg of substrate (imine derivative product 6, prepared in Example 6) and 1 g of water into a sample tube. Allow the substrate to stand naturally in water at 25 °C. Under these conditions, the substrate hydrolyzes to approximately 83% after 15 days.

[0211] Example 31: Sustained release of an imine derivative prepared using o-benzylhydroxylamine as a carrier

[0212] Weigh 100 mg of substrate (imine derivative product 8, prepared in Example 8) and 1 g of water into a sample tube. Allow the substrate to stand naturally in the water at 25 °C. Under these conditions, the substrate hydrolyzes by about 90% in 15 days.

[0213] Example 32: Preparation of sustained-release imine derivatives using o-fluoroaniline as a carrier

[0214] Weigh 100 mg of substrate (imine derivative product 10, prepared in Example 10) and 1 g of water into a sample tube. Allow the substrate to stand naturally in the water at 25 °C. Under these conditions, the substrate hydrolyzes by about 90% after 15 days.

[0215] Example 33: Sustained-release preparation of imine derivatives using 3,4-difluoroaniline as a carrier

[0216] Weigh 100 mg of substrate (imine derivative product 11, prepared in Example 11) and 1 g of water into a sample tube. Allow the substrate to stand naturally in water at 25 °C. Under these conditions, the substrate hydrolyzes by approximately 89% after 15 days.

[0217] Example 34: Sustained-release preparation of imine derivatives using benzophenone hydrazone as a carrier

[0218] Weigh 100 mg of substrate (imine derivative product 16, prepared in Example 16) and 1 g of water into a sample tube. Allow the substrate to stand naturally in the water at 25 °C. Under these conditions, the substrate hydrolyzes by approximately 78% after 15 days.

[0219] Example 35 Sustained release of imine derivatives

[0220] 125 mg of substrate (imine derivative product 18, prepared in Example 18, containing both alcohol and aldehyde pheromones) was placed in 4 mL of pure water. 2.5 mg of enzyme Y 200 (purchased from Weifang Lvdien Biotechnology Co., Ltd.) was added to the above solution and allowed to stand naturally at 25°C. Under these conditions, approximately 71% of the aldehyde pheromones and approximately 57% of the alcohol pheromones were released after 15 days.

[0221] Example 36: Preparation of sustained-release imine derivatives using nicotinamide hydrazide as a carrier

[0222] Five mg of the product prepared in Example 14 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 1, 4, 7, 11, and 14 days to monitor the hydrolysis process. The results are shown in Figure 1.

[0223] Example 37: Preparation of sustained-release imine derivatives using salicylhydrazine as a carrier

[0224] Five mg of the product prepared in Example 20 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 4, 8, 11, and 15 days to monitor the hydrolysis process. The results are shown in Figure 2.

[0225] Example 38: Preparation of sustained-release imine derivatives using 2-furanoylhydrazide as a carrier

[0226] Five mg of the product prepared in Example 23 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 1, 4, 7, 11, and 14 days to monitor the hydrolysis process. The results are shown in Figure 3.

[0227] Example 39: Sustained-release preparation of imine derivatives using 2-thiophenecarbamoylhydrazine as a carrier

[0228] Five mg of the product prepared in Example 24 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 1, 4, 7, 11, and 14 days to monitor the hydrolysis process. The results are shown in Figure 4.

[0229] Example 40: Preparation of sustained-release imine derivatives using 3-indolecarbamoylhydrazine as a carrier

[0230] Five mg of the product prepared in Example 25 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 1, 4, 7, 11, and 14 days to monitor the hydrolysis process. The results are shown in Figure 5.

[0231] Example 41: Preparation of sustained-release imine derivatives using 2-methylthiazol-4-formylhydrazide as a carrier

[0232] Five mg of the product prepared in Example 26 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 1, 4, 7, 11, and 14 days to monitor the hydrolysis process. The results are shown in Figure 6.

[0233] Example 42: Preparation of sustained-release imine derivatives using pyrazine-2-formylhydrazide as a carrier

[0234] Five mg of the product prepared in Example 27 was placed in 10 mL centrifuge tubes, resulting in three groups. Each group was placed under different temperature / relative humidity conditions (25℃ / 60%, 40℃ / 75%, and 50℃ / 90%). Samples were taken at 0, 1, 4, 7, 11, and 14 days to monitor the hydrolysis process. The results are shown in Figure 7.

[0235] As can be seen from the above embodiments, the imine derivatives provided by the present invention improve the stability of aldehyde pheromones by reacting them with carriers containing primary amine groups, such as amino acid esters, polypeptide esters, aryl amines, hydrazines, hydroxylamines, and hydrazones, through chemical methods, thus preventing their volatilization and deterioration. The resulting imine derivatives can be slowly released in air or water, and therefore have great potential as sustained-release formulations of insect pheromones. Compared with conventional physical methods, the imine derivative carriers provided by the present invention have a wide range of sources and high selectivity, thus being more economical. Some carriers are also more environmentally friendly because they are easily degraded after releasing pheromones.

[0236] Unless otherwise specified, the terms used in this invention have the meanings commonly understood by those skilled in the art.

[0237] The embodiments described in this invention are for illustrative purposes only and are not intended to limit the scope of protection of this invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of this invention. Therefore, this invention is not limited to the above embodiments, but is only defined by the claims.

Claims

1. An aldehyde insect pheromone derivative, characterized in that, with at least one primary amine group as a carrier, aldehyde insect pheromones form imine derivatives or their stereoisomers as shown in formula (I), Wherein, R represents the compound containing at least one primary amino group with x primary amino group residues removed; a represents an integer from 1 to 20; b represents an integer from 0 to 20; c represents an integer from 0 to 2; d represents an integer from 0 to 20; x represents an integer that is at least 1.

2. The aldehyde insect pheromone derivative according to claim 1, characterized in that, The carrier is an amino acid ester, and the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the carrier as shown in formula (I-1), wherein R1represents a C1-C16 alkyl group, a C0-C8 alkylene-C6-C20 aryl group or -CH2-(CH2) a1 -(CH=CH)-(CH2) b1 -(CH=CH) c1 -(CH2) d1 -CH3; R2 represents the residues of the amino acid ester after removing the ester group and amino group; a, b, c, and d are each independently defined as in claim 1; a1 represents an integer from 1 to 20; b1 represents an integer from 0 to 20; c1 represents an integer from 0 to 2; d1 represents an integer from 0 to 20.

3. The aldehyde insect pheromone derivative according to claim 1, characterized in that, The carrier is a polypeptide ester, and the aldehyde insect pheromone forms an imine derivative or its stereoisomer with the polypeptide ester, as shown in formula (I-2), wherein R1represents a C1-C16 alkyl group, a C0-C8 alkylene-C6-C20 aryl group or -CH2-(CH2) a1 -(CH=CH)-(CH2) b1 -(CH=CH) c1 -(CH2) d1 -CH3; P represents the residues of the polypeptide ester after removing the ester group and amino group; a, b, c, and d are each independently defined as in claim 1; a1 represents an integer from 1 to 20; b1 represents an integer from 0 to 20; c1 represents an integer from 0 to 2; d1 represents an integer from 0 to 20.

4. The aldehyde insect pheromone derivative according to claim 2 or 3, characterized in that, The amino acid ester or polypeptide ester is a C1-C12 alkyl ester or benzyl ester of an amino acid or polypeptide; preferably, the amino acid ester or polypeptide ester is a methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester or lauryl ester of an amino acid or polypeptide. The amino acid is a natural amino acid or a non-natural amino acid, preferably a natural amino acid, and more preferably one or more of phenylalanine, alanine, glycine, leucine, and γ-aminobutyric acid. The polypeptide is a polypeptide formed from 2 to 20 natural amino acids or non-natural amino acids, preferably a polypeptide formed from 3 to 20 natural amino acids, more preferably a polypeptide formed from 3 to 16 natural amino acids, and most preferably Ala-phe-leu-Trp-gly, Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly, Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly or Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly-Ala-Phe-Leu-Trp-Gly; Preferably, the amino acid ester is Alternatively, the amino acid ester or polypeptide ester is an ester formed by an amino acid or polypeptide and an alcoholic insect pheromone or its stereoisomer as shown in formula (II); HO-CH2-(CH2) a1 -(CH=CH)-(CH2) b1 -(CH=CH) c1 -(CH2) d1 -CH3 Formula (II) Wherein, a1, b1, c1, and d1 are each independently defined as in claim 2 or 3; Preferably, a1 represents an integer from 1 to 12, b1 represents an integer from 0 to 12, c1 represents an integer from 0 to 2, and d1 represents an integer from 0 to 10; More preferably, a1 represents an integer from 3 to 12, b1 represents an integer from 0 to 6, c1 represents an integer of 0 or 1, and d1 represents an integer from 0 to 8; More preferably, a1 represents an integer from 6 to 10, b1 represents 0, c1 represents an integer of 0 or 1, and d1 represents an integer from 0 to 6; Most preferably, the alcohol-based insect pheromone is cis-11-hexadecenol or E8E10-dodecadien-1-ol.

5. The aldehyde insect pheromone derivative according to claim 1, characterized in that, The carrier is a compound having a structure as shown in formula (I-3), and the aldehyde type insect pheromone forms an imine type derivative or its stereoisomer having a structure as shown in formula (I-4) with the carrier, R'— L— Y— NH2 Formula (I-3) Wherein, R' represents C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, C3-C20 cycloalkyl, 3-20 heterocyclic, C6-C20 aryl or 5-20 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, carboxyl, 3-8 heterocyclic, C3-C8 cycloalkyl, C6-C12 aryl or 5-12 heteroaryl; L indicates a C0-C8 alkylene group; Y represents -C(O)NH-, -NHC(O)-, -C(O)-, -NH-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NH- or not present; a, b, c, and d are each independently defined as in claim 1.

6. The aldehyde insect pheromone derivative according to claim 5, characterized in that, In formulas (I-3) and (I-4), R' represents a C6-C12 aryl or a 5-12 heteroaryl, preferably phenyl, naphthyl, biphenyl, furanyl, thiophene, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or indolyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, and carboxyl. L indicates a C0-C6 alkylene group; Y represents -C(O)NH-, -NH-, -O-, or is not present; Preferably, the compound of formula (I-3) is a compound of formula (I-3a):

7. The aldehyde insect pheromone derivative according to claim 1, characterized in that, The carrier is a compound having a structure as shown in formula (I-5), and the aldehyde type insect pheromone forms an imine type derivative having a structure as shown in formula (I-6) or a stereoisomer thereof, Wherein, R3 and R4 each independently represent C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, C3-C20 cycloalkyl, 3-20 heterocyclic, C6-C20 aryl or 5-20 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, carboxyl, 3-8 heterocyclic, C3-C8 cycloalkyl, C6-C12 aryl or 5-12 heteroaryl groups; a, b, c, and d are each independently defined as in claim 1; Preferably, in formulas (I-5) and (I-6), R3 and R4 each independently represent a C6-C12 aryl or a 5-12 heteroaryl group, and more preferably represent phenyl, naphthyl, biphenyl, furanyl, thiophene, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or indolyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, amino, nitro, hydroxyl, and carboxyl groups; More preferably, the compound is of the structure shown in formula (I-5) 8. The aldehyde insect pheromone derivative according to any one of claims 1 to 7, wherein In the formula (Ⅰ), a represents an integer from 1 to 12, b represents an integer from 0 to 12, c represents an integer from 0 to 2, and d represents an integer from 0 to 10; More preferably, a represents an integer from 3 to 12, b represents an integer from 0 to 6, c represents an integer of 0 or 1, and d represents an integer from 0 to 8; More preferably, a represents an integer from 6 to 10, b represents 0, c represents 0, and d represents an integer from 2 to 6; Most preferably, the aldehyde insect pheromone is cis-9-hexadecenal, cis-11-hexadecenal, or cis-13-octadecenal.

9. The aldehyde insect pheromone derivative according to any one of claims 1-8, characterized in that, The aldehyde insect pheromone derivative is the following compound:

10. The method for preparing the aldehyde insect pheromone derivative according to any one of claims 1-9, characterized in that, Compounds having at least one primary amine group of the structure shown in formula (III) are reacted with aldehyde insect pheromones of the structure shown in formula (IV) in an optional organic solvent to produce the imine derivative; CHO-(CH2) a -(CH=CH)-(CH2) b -(CH=CH) c -(CH2) d -CH3 formula (IV) Wherein, R, a, b, c, d, and x are each independently defined as in any one of claims 1-9.

11. The method of claim 10, wherein, The compound containing at least one primary amine group is reacted with an aldehyde insect pheromone in an optional organic solvent at 10–150 °C to prepare the imine derivative. Preferably, the organic solvent is one or more of the following: aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, heterocyclic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, alcohols, ketones, esters, ethers, nitriles, alkyl sulfoxides, and alkyl amides.

12. Use of any of the aldehyde insect pheromone derivatives according to claims 1-9 in the preparation of sustained-release and / or controlled-release formulations of insect pheromones.

13. The method of releasing an aldehyde insect pheromone derivative according to any one of claims 1 to 9, characterized in that, In the presence of an optional enzyme, the aldehyde insect pheromone derivative is hydrolyzed in water or in air to release the aldehyde insect pheromone. Preferably, the aldehyde insect pheromone derivative is hydrolyzed in air at a temperature of 10–60°C and a relative humidity of 10–100% to release the aldehyde insect pheromone.

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