Alpha, beta-unsaturated ketone compounds, processes for their preparation and use, and algicides and algicidal materials

Abstract

The application relates to the field of pesticides and environment, and discloses an alpha, beta-unsaturated ketone compound, a preparation method and application of the alpha, beta-unsaturated ketone compound, and an algicide and an algicidal material, wherein the compound has a structure shown in formula (I). The compound provided by the application has a good inhibiting effect on blue-green algae, is high in crop safety, and has good social value and economic value.

Description

Technical Field

[0001] This invention relates to the fields of pesticides and the environment, specifically to α,β-unsaturated ketone compounds, their preparation methods and applications, as well as algaecides and algaecidal materials. Background Technology

[0002] Cyanobacteria are large, single-celled prokaryotes that lack chloroplasts but can perform oxygen-producing photosynthesis. Their survival and development have played a crucial role in transforming the Earth's atmosphere from an oxygen-free to an oxygen-rich environment. However, with global warming and eutrophication, harmful algal blooms (Cyano-HABs) have become a global concern. During blooms, the accumulation of large amounts of algae in surface water severely impairs the photosynthesis of aquatic plants and hinders gas exchange at the air / water interface, causing aquatic animals to suffocate. Simultaneously, some cyanobacteria (such as Microcystis aeruginosa, Anabaena globulus, and Oscillatoria) also produce cyanotoxins that are toxic to aquatic organisms and humans.

[0003] Currently, methods for controlling algal blooms are divided into three main categories: chemical, physical, and biological. Each of these methods has its advantages and disadvantages. Among them, chemical methods are characterized by their speed and high efficiency, making them a highly effective and widely used approach. Commonly used chemical algaecides mainly include inorganic copper bactericides (such as copper sulfate, copper oxychloride, and copper citrate), herbicides (such as promethazine, dichlorvos, and paraquat), and chemical oxidants (such as chlorine dioxide, potassium permanganate, and calcium peroxide).

[0004] However, most algaecides currently available on the market have some toxicity and potential side effects on humans and non-cyanobacteria species. Therefore, developing a new generation of highly efficient, low-toxicity, and environmentally friendly algaecides is an urgent problem to be solved. Summary of the Invention

[0005] The purpose of this invention is to provide a novel α,β-unsaturated ketone compound that exhibits excellent anti-cyanobacterial activity and is green and safe.

[0006] To achieve the above objectives, a first aspect of the present invention provides an α,β-unsaturated ketone compound having the structure shown in formula (I).

[0007]

[0008] In equation (I),

[0009] L is either O or NH;

[0010] R1 is selected from C 1-4 Alkyl groups, unsubstituted or A-substituted phenyl groups, -(CH2) x -Si(OR 1 Any one of the following 3; x is an integer from 2 to 5, R1 C 1-4 Alkyl group; A group is selected from halogen, C 1-4 At least one of the alkoxy and hydroxyl groups;

[0011] R2 is selected from ethynyl, phenyl groups substituted with B, or C groups substituted with at least one phenyl group. 1-4 Any one of the alkyl groups; the B group is selected from ethynyl, sulfonamide, trifluoromethyl, morpholinyl, -O-CH2-R 2 -CH2-Ph, -R 2 -(CH2) z -R 3 At least one of them; R 2 R is a linking group provided by the removal of any two leaving H atoms from a triazole; 3 For not replaced or by R 4 Substituted phenyl; R 4 Selected from at least one of halogens and carboxyl groups; z is an integer between 0 and 2;

[0012] n is an integer between 0 and 4;

[0013] m is an integer between 0 and 2.

[0014] A second aspect of the present invention provides a method for preparing the α,β-unsaturated ketone compounds described in the first aspect above, the method comprising:

[0015] In the presence of catalyst I, the compound shown in formula (1) and the compound shown in formula (2) are subjected to a first contact reaction to obtain the α,β-unsaturated ketone compound shown in formula (I);

[0016]

[0017] Wherein, R2 is selected from ethynyl, B-substituted phenyl, or C-substituted phenyl. 1-4 Any one of the alkyl groups; and the B group is selected from at least one of ethynyl, sulfonamide, trifluoromethyl, and morpholinyl;

[0018] The definitions of L, R1, m, and n are the same as those in the first aspect mentioned above.

[0019] A third aspect of the present invention provides a method for preparing the α,β-unsaturated ketone compounds described in the first aspect above, the method comprising:

[0020] In the presence of solvent II and catalyst II, the compound shown in formula (3) is subjected to a second contact reaction with the compound shown in formula (4) to obtain the α,β-unsaturated ketone compound shown in formula (I);

[0021]

[0022] Wherein, R2 is a phenyl group substituted with B; and the B group is selected from -O-CH2-R. 2 -CH2-Ph, -R 2 -(CH2) z -R 3 At least one of them;

[0023] R 5 It can be hydrogen, halogen, or carboxyl; y is 0 or 1;

[0024] L, R1, R 2 R 3 The definitions of m, n, and z are the same as those in the first aspect mentioned above.

[0025] The fourth aspect of the present invention provides the application of the α,β-unsaturated ketone compounds described in the first aspect above in the inhibition of cyanobacteria.

[0026] A fifth aspect of the present invention provides an algaecide composed of an active ingredient I and excipients, wherein the active ingredient I contains at least one of the α,β-unsaturated ketone compounds described in the first aspect above.

[0027] A sixth aspect of the present invention provides an algicidal material comprising an active ingredient II and a base material, wherein the active ingredient II contains at least one of the α,β-unsaturated ketone compounds represented by formula (I);

[0028]

[0029] Wherein, R1 is -(CH2). x -Si(OCH2CH3)3, where x is an integer between 2 and 5;

[0030] R2 is selected from ethynyl, phenyl groups substituted with B, or C groups substituted with at least one phenyl group. 1-4 Any one of the alkyl groups; and the B group is selected from at least one of ethynyl, sulfonamide, trifluoromethyl, and morpholinyl;

[0031] L is 0 or NH; n is an integer from 0 to 4; m is an integer from 0 to 2.

[0032] A seventh aspect of the present invention provides a method for preparing the algicidal material described in the sixth aspect above, the method comprising:

[0033] In the presence of solvent III and catalyst III, the compound shown in formula (I) is subjected to a third contact reaction with the substrate material to obtain the algaecide material;

[0034]

[0035] The definitions of R1, R2, L, m, and n are the same as those in the sixth aspect mentioned above.

[0036] The compounds and algaecides provided by this invention have a good inhibitory effect on cyanobacteria and are highly safe for crops. The inhibitory effect of some compounds is better than that of existing algaecides such as copper sulfate or pyrazinamide on the market. Attached Figure Description

[0037] Figure 1 These are the time-dependent curves of the algicidal activity of each substance. Detailed Implementation

[0038] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0039] HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, CAS number 148893-10-1;

[0040] EDCI·HCl: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0041] In this invention, C 1-4 The alkyl group indicates an alkyl group with a total number of 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl.

[0042] In this invention, C 1-4 The alkoxy group indicates an alkoxy group with a total number of carbon atoms of 1, 2, 3 or 4, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy.

[0043] In this invention, This indicates that the ethynyl group can be substituted at any position on the phenyl group that can be substituted; similarly, R represents 4 It can be substituted at any position where the phenyl group can be substituted. Other similar representations in this invention have similar definitions, which will not be repeated here.

[0044] In this invention, "-----" in the structural formula or group indicates the bonding position.

[0045] In this invention, "R" 2"A linking group provided by the removal of any two departing H atoms from the triazole" refers to R 2 The linking group is provided by triazole, and the two groups being linked can be connected to any two positions of the linking group.

[0046] As previously described, a first aspect of the present invention provides an α,β-unsaturated ketone compound having the structure shown in formula (I).

[0047]

[0048] In equation (I), L is O or NH;

[0049] R1 is selected from C 1-4 Alkyl groups, unsubstituted or A-substituted phenyl groups, -(CH2) x -Si(OR 1 Any one of the following 3; x is an integer from 2 to 5, R 1 C 1-4 Alkyl group; A group is selected from halogen, C 1-4 At least one of the alkoxy and hydroxyl groups;

[0050] R2 is selected from ethynyl, phenyl groups substituted with B, or C groups substituted with at least one phenyl group. 1-4 Any one of the alkyl groups; the B group is selected from ethynyl, sulfonamide, trifluoromethyl, morpholinyl, -O-CH2-R 2 -CH2-Ph, -R 2 -(CH2) z -R 3 At least one of them; R 2 R is a linking group provided by the removal of any two leaving H atoms from a triazole; 3 For not replaced or by R 4 Substituted phenyl; R 4 Selected from at least one of halogens and carboxyl groups; z is an integer between 0 and 2;

[0051] n is an integer between 0 and 4;

[0052] m is an integer between 0 and 2.

[0053] Preferably, in formula (I), L is O or NH;

[0054] R1 is selected from methyl, ethyl, n-propyl, isopropyl, unsubstituted or substituted phenyl groups, and -(CH2). x -Si(OR 1 Any one of the following 3; x is 3 or 4, R 1It is methyl or ethyl; the A group is selected from at least one of fluorine, chlorine, bromine, methoxy, ethoxy, and hydroxyl;

[0055] R2 is selected from ethynyl, B-substituted phenyl, or C-substituted phenyl with two phenyl groups. 1-3 Any one of the alkyl groups; the B group is selected from ethynyl, sulfonamide, trifluoromethyl, morpholinyl, -O-CH2-R 2 -CH2-Ph, -R 2 -(CH2) z -R 3 At least one of them; R 2 R is a linking group provided by the removal of any two leaving H atoms from a triazole; 3 For not replaced or by R 4 Substituted phenyl; R 4 Selected from at least one of fluorine, chlorine, and bromine; z is 0, 1, or 2;

[0056] n is 0, 1, or 2;

[0057] m can be 0, 1, or 2.

[0058] In a preferred embodiment, L in formula (I) is O or NH;

[0059] R1 is selected from methyl, ethyl, unsubstituted or substituted phenyl, -(CH2)3-Si(OCH2CH3)3, -(CH2)4-Si(OCH2CH3)3; A group is selected from at least one of fluorine, chlorine, bromine, methoxy, ethoxy, and hydroxyl.

[0060] R2 is selected from any one of ethynyl, B-substituted phenyl, and -CH(Ph)2; B group is selected from ethynyl, sulfonamide, trifluoromethyl, Any one of them; R 4 Selected from at least one of fluorine, chlorine, and bromine; z is 0, 1, or 2;

[0061] n is 0, 1, or 2;

[0062] m can be 0, 1, or 2.

[0063] More preferably, the compound represented by formula (I) is selected from any one of the following:

[0064]

[0065]

[0066]

[0067] Particularly preferably, the compound represented by formula (I) is selected from any one of compound 7, compound 15, and compound 19.

[0068] The present invention does not impose any particular limitation on the method for preparing the α,β-unsaturated ketone compounds. A suitable preparation method can be determined by combining the structural formula of the present invention with conventional methods in the art. However, in order to improve the yield and purity of the compounds described in the first aspect above, the present invention provides the following preferred embodiments of the method for preparing the α,β-unsaturated ketone compounds of the present invention.

[0069] As previously described, a second aspect of the present invention provides a method for preparing the α,β-unsaturated ketone compounds described in the first aspect, the method comprising:

[0070] In the presence of catalyst I, the compound shown in formula (1) and the compound shown in formula (2) are subjected to a first contact reaction to obtain the α,β-unsaturated ketone compound shown in formula (I);

[0071]

[0072] Wherein, R2 is selected from ethynyl, B-substituted phenyl, or C-substituted phenyl. 1-4 Any one of the alkyl groups; and the B group is selected from at least one of ethynyl, sulfonamide, trifluoromethyl, and morpholinyl;

[0073] The definitions of L, R1, m, and n are the same as those in the first aspect mentioned above.

[0074] Preferably, the conditions for the first contact reaction include: a temperature of 25-90°C and a time of 0.5-4h.

[0075] In a preferred embodiment, the catalyst I is selected from at least one of 70-98 wt% sulfuric acid, HATU, and EDCI·HCl.

[0076] Preferably, L in formula (2) is NH, and the first contact reaction is carried out in the presence of solvent I.

[0077] Preferably, solvent I is selected from at least one of dichloromethane, methanol, and ethanol.

[0078] As previously stated, a third aspect of the present invention provides a method for preparing the α,β-unsaturated ketone compounds described in the first aspect, the method comprising:

[0079] In the presence of solvent II and catalyst II, the compound shown in formula (3) is subjected to a second contact reaction with the compound shown in formula (4) to obtain the α,β-unsaturated ketone compound shown in formula (I);

[0080]

[0081]

[0082] Wherein, R2 is a phenyl group substituted with B; and the B group is selected from -O-CH2-R. 2 -CH2-Ph, -R 2 -(CH2) z -R 3 At least one of them;

[0083] R 5 It can be hydrogen, halogen, or carboxyl; y is 0 or 1;

[0084] L, R1, R 2 R 3 The definitions of m, n, and z are the same as those in the first aspect mentioned above.

[0085] Preferably, the conditions for the second contact reaction include: a temperature of 25-30°C and a time of 2-6 hours.

[0086] In a preferred embodiment, the catalyst II is selected from at least two of copper sulfate pentahydrate, sodium ascorbate, and cuprous iodide.

[0087] Preferably, solvent II is selected from at least one of ethanol and tert-butanol.

[0088] According to a preferred embodiment 1, when R2 is selected from ethynyl, B-group substituted phenyl, or at least one phenyl-substituted C 1-4 When the B group is selected from any one of the alkyl groups; and the B group is selected from at least one of ethynyl, sulfonamide, trifluoromethyl, and morpholinyl, the compound of the present invention is preferably prepared by the following synthetic route.

[0089]

[0090] S1-1: Intermediate II is reacted with the corresponding primary amine compound to obtain intermediate III-1;

[0091] S1-2: In the presence of catalyst I, intermediate III-1 is reacted with the corresponding alcohol to obtain the compound shown in formula (I); catalyst I is 70-98 wt% sulfuric acid;

[0092] Alternatively, in the presence of solvent I and catalyst I, the intermediate III-1 is reacted with the corresponding primary amine compound in a third reaction to obtain the compound shown in formula (I); wherein solvent I is dichloromethane; and catalyst I is HATU or EDCI·HCl.

[0093] Preferably, in step S1-1, the conditions for the first reaction include: a temperature of 15-30°C and a time of 4-6 hours.

[0094] In a preferred embodiment, in steps S1-2, the sulfuric acid is introduced into the reaction system by dropwise addition, and the conditions for the second reaction include: a temperature of 70-90°C and a time of 0.4-1.5 h.

[0095] The timing of the second reaction begins after the sulfuric acid has been introduced into the reaction system, excluding the time of dropwise addition.

[0096] Preferably, in steps S1-2, the conditions for the third reaction include: a temperature of 15-30°C and a time of 0.5-4 hours.

[0097] According to a preferred embodiment 2, R2 is a phenyl group substituted with a B group; and the B group is -R 2 -(CH2) z -R 3 The compounds described in this invention are preferably prepared using the following synthetic route.

[0098]

[0099] S2-1: Intermediate II is first contacted with the corresponding ethynylaniline compound to obtain intermediate III-2;

[0100] S2-2: Intermediate III-2 is subjected to a second contact with the corresponding alcohol compound under the catalysis of 70-98 wt% sulfuric acid to obtain intermediate IV;

[0101] Alternatively, intermediate III-2 can be subjected to a third contact with the corresponding primary amine compound under HATU or EDCI·HCl catalysis to obtain intermediate IV;

[0102] S2-3: In the presence of solvent II and catalyst II, intermediate IV is brought into a fourth contact with intermediate VI to obtain the compound shown in formula (I) of the present invention; wherein solvent II is anhydrous ethanol and catalyst II is a combination of copper sulfate pentahydrate and sodium ascorbate;

[0103] Preferably, the method of the present invention further includes reacting intermediate V with sodium azide at 15-30°C in the presence of dimethyl sulfoxide (DMSO) to obtain intermediate VI.

[0104] Preferably, in step S2-1, the conditions for the first contact include: a temperature of 15-30°C and a time of 5-7 hours.

[0105] In a preferred embodiment, in step S2-2, the sulfuric acid is introduced into the reaction system by dropwise addition, and the conditions for the second contact include: a temperature of 70-90°C and a time of 0.4-1.5 h.

[0106] The second contact time begins from the end of the sulfuric acid introduction into the reaction system, excluding the time of dropwise addition.

[0107] Preferably, in step S2-2, the conditions for the third contact include: a temperature of 15-30°C and a time of 0.5-4 hours.

[0108] Preferably, in steps S2-3, the conditions for the fourth contact include: a temperature of 25-30°C and a time of 1.5-2 hours.

[0109] According to a preferred embodiment 3, R2 is a phenyl group substituted with a B group; and the B group is -O-CH2-R. 2 When -CH2-Ph, the following synthetic route is preferred for preparing the compounds of the present invention.

[0110]

[0111] S3-1: Intermediate II is first mixed with the corresponding propargyloxyaniline compound to obtain intermediate III-3;

[0112] S3-2: Under the catalysis of 70-98 wt% sulfuric acid, the intermediate III-3 is mixed with the corresponding alcohol compound in a second manner to obtain intermediate VII;

[0113] Alternatively, intermediate III-3 can be mixed with the corresponding primary amine compound in the presence of HATU or EDCI·HCl catalysis to obtain intermediate VII;

[0114] S3-3: In the presence of solvent II and catalyst II, intermediate VII and intermediate IX are mixed for the fourth time to obtain the compound shown in formula (I) of the present invention; solvent II is anhydrous ethanol, and catalyst II is a combination of copper sulfate pentahydrate and sodium ascorbate;

[0115] Preferably, the method of the present invention further includes reacting intermediate VIII with sodium azide in the presence of DMSO at 15-30°C to obtain intermediate IX.

[0116] Preferably, in step S3-1, the conditions for the first mixing include: a temperature of 15-30°C and a time of 5-7 hours.

[0117] In a preferred embodiment, in step S3-2, the sulfuric acid is introduced into the reaction system by dropwise addition, and the conditions for the second mixing include: a temperature of 70-90°C and a time of 0.4-1.5 h.

[0118] The second mixing time begins from the end of the reaction after the sulfuric acid is introduced into the reaction system, excluding the time of dropwise addition.

[0119] Preferably, in step S3-2, the conditions for the third mixing include: a temperature of 15-30°C and a time of 0.5-4 hours.

[0120] Preferably, in step S3-3, the conditions for the fourth mixing include: a temperature of 25-30°C and a time of 1.5-2 hours.

[0121] As previously stated, the fourth aspect of the present invention provides the application of the α,β-unsaturated ketone compounds described in the first aspect in the inhibition of cyanobacteria.

[0122] In a preferred embodiment, the cyanobacteria are selected from at least one of Microcystis aeruginosa, Anabaena aquatica, Oscillatoria, and Synechocystis.

[0123] As previously described, the fifth aspect of the present invention provides an algaecide composed of an active ingredient I and excipients, wherein the active ingredient I contains at least one of the α,β-unsaturated ketone compounds described in the first aspect.

[0124] Preferably, the content of active ingredient I is 0.01-99.99% by weight, more preferably 0.1-99.9% by weight. Exemplarily, the content of active ingredient I is 1% by weight, 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, 95% by weight, or 99% by weight.

[0125] When the α,β-unsaturated ketone compounds described in the first aspect of this invention are used as the active ingredients of algaecides, the compounds can be mixed with a permissible carrier or diluent in water to formulate various commonly used dosage forms, such as mixtures, powders, emulsions, water-soluble agents, flowable agents, etc., and used as the algaecides described in this invention.

[0126] Preferably, the algaecide is formulated as at least one of hydration agents, powders, emulsions, suspensions, and granules.

[0127] The present invention does not have any particular requirements on the specific types of excipients. Those skilled in the art can select appropriate types of excipients known in the art according to the dosage form requirements.

[0128] As previously mentioned, a sixth aspect of the present invention provides an algaecide material composed of an active ingredient II and a base material, wherein the active ingredient II contains at least one of the α,β-unsaturated ketone compounds represented by formula (I);

[0129]

[0130] Wherein, R1 is -(CH2). x -Si(OCH2CH3)3, where x is an integer between 2 and 5;

[0131] R2 is selected from ethynyl, phenyl groups substituted with B, or C groups substituted with at least one phenyl group. 1-4 Any one of the alkyl groups; and the B group is selected from at least one of ethynyl, sulfonamide, trifluoromethyl, and morpholinyl;

[0132] L is 0 or NH; n is an integer from 0 to 4; m is an integer from 0 to 2.

[0133] Preferably, the content of active ingredient II is 0.01-99.99% by weight, more preferably 0.1-99.9% by weight. Exemplarily, the content of active ingredient II is 1% by weight, 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, 95% by weight, or 99% by weight.

[0134] As previously stated, a seventh aspect of the present invention provides a method for preparing the algicidal material described in the sixth aspect, the method comprising:

[0135] In the presence of solvent III and catalyst III, the compound shown in formula (I) is subjected to a third contact reaction with the substrate material to obtain the algaecide material;

[0136]

[0137] The definitions of R1, R2, L, m, and n are the same as those in the sixth aspect mentioned above.

[0138] Preferably, the conditions for the third contact reaction include: a temperature of 50-70°C and a time of 0.5-2 hours.

[0139] Preferably, solvent III is selected from at least one of methanol, ethanol, and isopropanol.

[0140] Preferably, catalyst III is sodium hydroxide and / or potassium hydroxide.

[0141] When using the α,β-unsaturated ketone compounds described in this invention as active ingredients in algicidal materials, the compounds are immobilized on a permissible substrate material in the water body. The substrate material described in this invention can be at least one of polymer materials, metallic materials, inorganic materials, and nanomaterials. However, in order to obtain algicidal materials with superior algicidal activity and better safety, this invention preferably selects at least one of polyurethane, copper mesh, nylon cloth, carbon fiber, and glass fiber as the algicidal material described in this invention.

[0142] The algaecide and algaecide material provided by this invention have excellent biocompatibility with aquatic organisms including zebrafish, medaka, and guppies, especially with zebrafish.

[0143] The inventors of this invention discovered in their research that when the compound provided by this invention is prepared together with a base material to form the algicidal material described in this invention, the toxicity of the compound can be significantly reduced, and the algicidal activity can be more efficient.

[0144] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, all raw materials are commercially available. In the following examples, "room temperature" and "room temperature" refer to 25±2℃.

[0145] Concentrated sulfuric acid is 98 wt% sulfuric acid.

[0146] The following test examples demonstrate that the α,β-unsaturated ketone compounds provided by this invention have good inhibitory and algicidal effects on cyanobacteria.

[0147] Preparation Example 1: Compound 1

[0148]

[0149] 5 mmol of intermediate II was dissolved in 20 mL of ethyl acetate, and 5 mmol of 4-(4-morpholino)aniline was added. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC monitoring, the insoluble matter was filtered to obtain intermediate III-1 (4 mmol).

[0150] The obtained intermediate III-1 (4 mmol) was dissolved in 20 mL of methanol and heated under reflux. After intermediate III-1 dissolved, 0.125 mL of concentrated sulfuric acid was added dropwise, and the reaction was continued for 0.5 h after the addition was complete. After the reaction was completed, the mixture was cooled to room temperature and 100 mL of water was added. The mixture was filtered to obtain the crude product of compound 1. The crude product was subjected to column chromatography to obtain the final product, which was a brown solid powder with a yield of 68%.

[0151] Molecular formula: C 15 H 18 N2O4

[0152] 1H NMR(600MHz,DMSO-d6)δ10.08(s,1H),7.47(d,J=8.9Hz,2H),6.90(d,J=8.8Hz,2H),6 .45(d,J=11.6Hz,1H),6.38(d,J=11.6Hz,1H),3.73(s,4H),3.66(s,3H),3.05(s,4H).

[0153] 13C NMR (151MHz, DMSO-d6) δ169.44,164.34,150.10,134.53,133.44,131.25,123.00,117.99,68.68,54.15,51.38.

[0154] HRMS(ESI):m / z calculated for C 15 H 18 N₂O₄[M+Na] + :313.1164,found 313.1158

[0155] Preparation Example 2: Compound 2

[0156]

[0157] 5 mmol of intermediate II was dissolved in 20 mL of ethyl acetate, and 5 mmol of p-ethynylaniline was added. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC monitoring, the insoluble matter was filtered to obtain intermediate III-1 (4 mmol).

[0158] The obtained intermediate III-1 (4 mmol) was dissolved in 20 mL of methanol and heated under reflux. After intermediate III-1 dissolved, 0.125 mL of concentrated sulfuric acid was added dropwise, and the reaction was continued for 0.5 h after the addition was complete. After the reaction was completed, the mixture was cooled to room temperature and 100 mL of water was added. The mixture was filtered to obtain the crude product of compound 2. The crude product was subjected to column chromatography to obtain the final product, which was a white solid powder with a yield of 73%.

[0159] Molecular formula: C 13H 11 NO3

[0160] 1 H NMR (600MHz, DMSO-d6): δ10.45(s,1H),7.63(d,J=8.3Hz,2H),7.44(d,J=8.3Hz ,2H),6.52(d,J=11.7Hz,1H),6.43(d,J=11.7Hz,1H),4.11(s,1H),3.67(s,3H).

[0161] 13 C NMR (151MHz, DMSO-d6): δ166.91,163.19,139.60,132.86,132.66,129.39,119.64,117.01,83.91,80.58,52.09.

[0162] HRMS(ESI):m / z calculated for C 13 H 11 NO3[M+Na] + :252.0637,found 252.0640

[0163] Preparation Example 3: Compound 3

[0164]

[0165] 5 mmol of intermediate II was dissolved in 20 mL of ethyl acetate, and 5 mmol of diphenylmethylamine was added. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC monitoring, the insoluble matter was filtered to obtain intermediate III-1 (4 mmol).

[0166] The obtained intermediate III-1 (4 mmol) was dissolved in 20 mL of methanol and heated under reflux. After intermediate III-1 dissolved, 0.125 mL of concentrated sulfuric acid was added dropwise, and the reaction was continued for 2 h after the addition was complete. After the reaction was completed, the temperature was lowered to room temperature, 100 mL of water was added, and the insoluble matter was filtered to obtain the final product, which was a white solid powder with a yield of 64%.

[0167] Molecular formula: C 18 H 17 NO3

[0168] 1H NMR (600MHz, DMSO-d6): δ9.19(d,J=8.4Hz,1H),7.34(t,J=7.5Hz,4H),7.29(d,J=7.2Hz,4H),7.26( t,J=7.2Hz,2H),6.44(d,J=11.8Hz,1H),6.33(d,J=11.8Hz,1H),6.15(d,J=8.5Hz,1H),3.57(s,3H).

[0169] 13 C NMR (151MHz, DMSO-d6): δ167.34,163.36,142.54,131.48,129.24,128.84,127.77,127.49,56.34,51.87.

[0170] HRMS(ESI):m / z calculated for C 18 H 17 NO3[2M+Na] + :613.2314,found 613.2320

[0171] Preparation Example 4: Compound 4

[0172]

[0173] The preparation was carried out using a method similar to that used in Preparation Example 2, except that 5 mmol of 3-aminophenylacetylene was used instead of 5 mmol of p-acetylenylaniline in Preparation Example 2. The final product was a white solid powder with a yield of 71%.

[0174] Molecular formula: C 13 H 11 NO3

[0175] 1 H NMR (600MHz, DMSO-d6): δ10.39(s,1H),7.82(s,1H),7.57(d,J=7.7Hz,1H),7.35(t,J=7.7Hz,1H) ,7.20(d,J=7.1Hz,1H),6.53(d,J=11.7Hz,1H),6.43(d,J=11.7Hz,1H),4.19(s,1H),3.68(s,3H).

[0176] 13C NMR (151MHz, DMSO-d6): δ166.86,163.29,139.28,132.78,129.73,129.26,127.34,122.59,122.50,120.40,83.70,81.15,52.09.

[0177] HRMS(ESI):m / z calculated for C 13 H 11 NO3[M+Na] + :252.0637,found 252.0640

[0178] Preparation Example 5: Compound 5

[0179]

[0180] The preparation was carried out using a method similar to that of Preparation Example 2, except that 20 mL of anhydrous ethanol was used instead of the 20 mL of methanol in Preparation Example 2. The final product was a white solid powder with a yield of 59%.

[0181] Molecular formula: C 14 H 13 NO3

[0182] 1 H NMR (600MHz, DMSO-d6): δ10.44(s,1H),7.64(d,J=7.8Hz,2H),7.44(d,J=7.7Hz,2H),6. 54(d,J=11.7Hz,1H),6.38(d,J=11.7Hz,1H),4.22–4.04(m,3H),1.17(t,J=6.6Hz,3H).

[0183] 13 C NMR (151MHz, DMSO-d6): δ166.20,163.38,139.66,133.03,132.84,129.09,119.59,116.95,83.92,80.46,60.73,14.31.

[0184] HRMS(ESI):m / z calculated for C 14 H 13 NO3[M+Na] + :266.0793,found 266.0796

[0185] Preparation Example 6: Compound 6

[0186]

[0187] 5 mmol of intermediate II was dissolved in 20 mL of ethyl acetate, and 5 mmol of p-ethynylaniline was added. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC monitoring, the insoluble matter was filtered to obtain intermediate III-1 (4 mmol).

[0188] The obtained intermediate III-1 (4 mmol) was dissolved in dichloromethane, and 4 mmol of HATU was added sequentially. After reacting for about 15 minutes, 4.8 mmol of ethylamine (provided as an aqueous solution of ethylamine at a concentration of 70 mmol / L) was added, and the reaction was continued for 1 hour. After the reaction was completed, 100 mL of saturated brine was added, and the product was extracted with ethyl acetate (3 × 50 mL). The combined organic compounds were washed first with 2N hydrochloric acid, water, and 5 wt% sodium bicarbonate, and then washed with water. The organic compounds were dried on magnesium sulfate, filtered, and concentrated under vacuum to obtain a crude product. The crude product was subjected to column chromatography to obtain the final product, which was a pale yellow solid powder with a yield of 75%.

[0189] Molecular formula: C 14 H 14 N2O2

[0190] 1 H NMR (600MHz, DMSO-d6): δ11.49(s,1H),8.63(s,1H),7.64(s,2H),7.44(s,2 H), 6.28 (d, J = 12.5Hz, 2H), 4.11 (s, 1H), 3.16 (s, 2H), 1.07 (d, J = 4.3Hz, 3H).

[0191] 13 C NMR (151MHz, DMSO-d6): δ164.93,163.89,139.80,133.12,132.86,131.37,119.48,116.72,83.96,80.46,34.02,14.71.

[0192] HRMS(ESI):m / z calculated for C 14 H 14 N₂O₂[M+Na] + :265.0953,found 265.0949

[0193] Preparation Example 7: Compound 7

[0194]

[0195] 5 mmol of intermediate II was dissolved in 20 mL of ethyl acetate, and 5 mmol of p-ethynylaniline was added. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC monitoring, the insoluble matter was filtered to obtain intermediate III-1 (4 mmol).

[0196] The obtained intermediate III-1 (4 mmol) was dissolved in dry dichloromethane, and 4.8 mmol of EDCI·HCl and 4.8 mmol of 3-aminopropyltriethoxysilane were added sequentially, and the reaction was carried out for 2.5 h. After the reaction was completed, the solution was concentrated under vacuum to obtain a crude product. The crude product was subjected to column chromatography to obtain the final product, which was a yellow oil with a yield of 45%.

[0197] Molecular formula: C 21 H 30 N2O5Si

[0198] 1 H NMR (600MHz, DMSO-d6): δ11.43(s,1H),8.61(s,1H),7.62(s,2H),7.43(d,J=6.8Hz,2H),6 .27(s,2H),4.11(s,1H),3.74(s,6H),3.11(s,2H),1.50(s,2H),1.14(s,9H),0.58(s,2H).

[0199] 13 C NMR (151MHz, DMSO-d6): δ165.11,163.87,139.82,132.83,131.65,119.48,116.75,83.96,80.46,58.14,41.91,22.84,18.66,7.81.

[0200] HRMS(ESI):m / z calculated for C 21 H 30 N₂O₅Si[M+Na] + :441.1822,found441.1821

[0201] Preparation Example 8: Compound 8

[0202]

[0203] The preparation was carried out using a method similar to that used in Preparation Example 2, except that 5 mmol of 4-trifluoromethylaniline was used instead of 5 mmol of p-ethynylaniline in Preparation Example 2. The final product was a white solid powder with a yield of 70%.

[0204] Molecular formula: C 12 H10 F3NO3

[0205] 1 H NMR (600MHz, DMSO-d6): δ10.66(s,1H),7.83(d,J=6.4Hz,2H),7.70(d,J=8.3Hz,2H),6.58(d,J=11.7Hz,1H),6.47(d,J=11.8Hz,1H),3.68(s,3H).

[0206] 13 C NMR (151MHz, DMSO-d6): δ166.76,163.63,142.62,132.75,129.46,127.43,126.54 ,125.63,124.38,124.17,123.96,123.83,123.75,122.03,119.69,117.44,52.08.

[0207] HRMS(ESI):m / z calculated for C 12 H 10 NO3F3[M+Na] + :296.0510,found 296.0516

[0208] Preparation Example 9: Compound 9

[0209]

[0210] Compound 2 was prepared according to the method described in Preparation Example 2. The reaction was continued. 5 mmol of benzyl bromide was dissolved in 15 mL of DMSO, and 15 mmol of NaN3 was added. The reaction was carried out at room temperature for 12 h, quenched with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate VI. 3.3 mmol of compound 2 and 3 mmol of intermediate VI were dissolved in 25 mL of anhydrous ethanol, and 0.3 mmol of copper sulfate pentahydrate and 0.3 mmol of sodium ascorbate were added. The reaction was carried out for 2 h. After the reaction was complete, the crude product was filtered to obtain the crude product. The crude product was dissolved in a mixed solvent of methanol and dichloromethane and recrystallized to obtain the final product, a white solid, with a yield of 40%.

[0211] Molecular formula: C 20 H 18 N4O3

[0212] 1H NMR (600MHz, DMSO-d6): δ10.36(s,1H),8.55(s,1H),7.77(s,2H),7.66(s,2H ),7.34(d,J=19.0Hz,5H),6.45(d,J=43.4Hz,2H),5.61(s,2H),3.65(s,3H).

[0213] 13 C NMR (151MHz, DMSO-d6): δ167.09,163.00,146.94,138.81,136.51,132.62,12 9.39,129.29,128.64,128.38,126.60,126.17,121.55,120.14,53.50,52.10.

[0214] HRMS(ESI):m / z calculated for C20H18N4O3[M+Na]+:385.1277,found385.1274

[0215] Preparation Example 10: Compound 10

[0216]

[0217] The preparation was carried out using a method similar to that of Preparation Example 6, except that 4.8 mmol of phenylethylamine was used instead of the 4.8 mmol of ethylamine used in Preparation Example 6. The final product was a pale yellow solid powder with a yield of 76%.

[0218] Molecular formula: C 20 H 18 N2O2

[0219] 1 H NMR (600MHz, DMSO-d6): δ11.35(s,1H),8.73(s,1H),7.64(d,J=8.6Hz,2H),7.44(d,J=8.6Hz,2H),7.34–7 .26(m,2H),7.25–7.15(m,3H),6.34–6.22(m,2H),4.11(s,1H),3.41–3.35(m,2H),2.77(t,J=7.4Hz,2H).

[0220] 13C NMR (151MHz, DMSO-d6): δ164.82,163.62,139.47,139.35,132.78,132.52,1 31.01,128.73,128.43,126.24,119.20,116.44,83.64,80.12,40.49,34.86.

[0221] HRMS(ESI):m / z calculated for C 20 H 18 N₂O₂[M+Na] + :341.1266,found 341.1269

[0222] Preparation Example 11: Compound 11

[0223]

[0224] The preparation was carried out using a method similar to that of Preparation Example 6, except that 4.8 mmol of 4-aminomethylphenol was used instead of 4.8 mmol of ethylamine in Preparation Example 6. The final product was a white solid powder with a yield of 70%.

[0225] Molecular formula: C 19 H 16 N2O3

[0226] 1 H NMR (600MHz, DMSO-d6): δ11.33(s,1H),9.32(s,1H),8.96(t,J=5.6Hz,1H),7.64(d,J=8.6Hz,2H),7.44(d,J=8.6 Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 6.71 (d, J = 8.5Hz, 2H), 6.31 (d, J = 1.2Hz, 2H), 4.24 (d, J = 5.7Hz, 2H), 4.11 (s, 1H).

[0227] 13 C NMR (151MHz, DMSO-d6): δ164.54,163.77,156.50,139.50,133.08,132.53,130.63,129.01,128.82,119.20,116.41,115.14,83.66,80.10,42.02.

[0228] HRMS(ESI):m / z calculated for C 19 H 16 N₂O₃[M+Na]+ :343.1059,found 343.1064

[0229] Preparation Example 12: Compound 12

[0230]

[0231] Compound 4 was prepared according to the method described in Preparation Example 4. The reaction was continued. 5 mol of 4-bromobenzyl bromide was dissolved in 15 mL of DMSO, and 15 mmol of NaN3 was added. The reaction was carried out at room temperature for 12 h, quenched with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate VI. 3.3 mmol of compound 4 and 3 mmol of intermediate VI were dissolved in 25 mL of anhydrous ethanol, and 0.3 mmol of copper sulfate pentahydrate and 0.3 mmol of sodium ascorbate were added. The reaction was carried out for 2 h. After the reaction was complete, the crude product was filtered to obtain the crude product. The crude product was dissolved in a mixed solvent of methanol and dichloromethane and recrystallized to obtain the final product, a white solid with a yield of 38%.

[0232] Molecular formula: C 20 H 17 BrN4O3

[0233] 1 H NMR (600MHz, DMSO-d6): δ10.40(s,1H),8.62(s,1H),8.18(s,1H),7.60(d,J=7.1Hz,2H),7.56(d,J=7.4Hz,1H),7.51(d,J=6.6H z,1H),7.39(d,J=7.3Hz,1H),7.32(d,J=7.2Hz,2H),6.52(d,J=11.4Hz,1H),6.43(d,J=11.5Hz,1H),5.64(s,2H),3.68(s,3H).

[0234] 13 C NMR (151MHz, DMSO-d6): δ167.03,163.02,146.90,139.63,135.82,132.52,132.14,13 1.54,130.62,129.85,129.39,122.14,121.86,121.17,119.32,116.32,52.69,52.07.

[0235] HRMS(ESI):m / z calculated for C 20 H 17 N4O3Br[M+Na] +:463.0382,found463.0382

[0236] Preparation Example 13: Compound 13

[0237]

[0238] The preparation was carried out using a method similar to that of Preparation Example 6, except that 4.8 mmol of 4-methoxybenzylamine was used instead of 4.8 mmol of ethylamine in Preparation Example 6. The final product was a white solid powder with a yield of 71%.

[0239] Molecular formula: C 20 H 18 N2O3

[0240] 1 H NMR (600MHz, DMSO-d6): δ11.30(s,1H),9.02(t,J=5.2Hz,1H),7.66(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,2H),7. 24(d,J=8.0Hz,2H),6.89(d,J=8.0Hz,2H),6.47–6.18(m,2H),4.30(d,J=5.6Hz,2H),4.11(s,1H),3.73(s,3H).

[0241] 13 C NMR (151MHz, DMSO-d6): δ164.96,164.08,158.74,139.82,133.26,132.85,131.02,129.27,119.52,116.74,114.12,83.97,80.43,55.46,42.19.

[0242] HRMS(ESI):m / z calculated for C 20 H 18 N₂O₃[M+Na] + :357.1215,found 357.1219

[0243] Preparation Example 14: Compound 14

[0244]

[0245] The preparation was carried out using a method similar to that of Preparation Example 6, except that 4.8 mmol of 4-fluoroaniline was used instead of 4.8 mmol of ethylamine in Preparation Example 6. The final product was a white solid powder with a yield of 71%.

[0246] Molecular formula: C 18H 13 FN2O2

[0247] 1 H NMR (600MHz, DMSO-d6): δ10.63(s,1H),10.47(s,1H),7.65(d,J=8.0Hz,4H),7.43(d,J=8.2Hz,2H),7.16(t,J=8.1Hz,2H),6.46(s,2H),4.10(s,1H).

[0248] 13 C NMR (151MHz, DMSO-d6): δ164.01,163.65,159.23,157.64,139.66,135.45,13 2.67,131.89,121.46,121.41,119.44,116.65,115.70,115.55,83.81,80.30.

[0249] HRMS(ESI):m / z calculated for C 18 H 13 N₂O₂F[M+Na] + :331.0859,found 331.0862

[0250] Preparation Example 15: Compound 15

[0251]

[0252] The preparation was carried out using a method similar to that used in Preparation Example 2, except that 5 mmol of propargylamine was used instead of 5 mmol of p-ethynylaniline in Preparation Example 2. The final product was a white solid powder with a yield of 78%.

[0253] Molecular formula: C8H9NO3

[0254] 1 H NMR (600MHz, DMSO-d6): δ8.68(s,1H),6.42-6.17(m,2H),3.91(s,2H),3.64(s,3H),3.35(s,1H).

[0255] 13 C NMR (151MHz, DMSO-d6): δ167.07,163.89,131.40,129.14,81.03,73.72,51.92,28.22.

[0256] HRMS(ESI):m / z calculated for C8H9NO3[M+Na]+ :190.0480,found 190.0477

[0257] Preparation Example 16: Compound 16

[0258]

[0259] (2Z)-4-{[4-(propynyloxy)phenyl]amino}-4-oxonyl-2-butenoic acid methyl ester was prepared according to the method described in Preparation Example 2.

[0260] 5 mmol of intermediate II was dissolved in 20 mL of ethyl acetate, and 5 mmol of 4-(2-propynyloxy)aniline was added. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC monitoring, the insoluble matter was filtered to obtain intermediate III-1 (4 mmol).

[0261] The obtained intermediate III-1 (4 mmol) was dissolved in 20 mL of methanol and heated under reflux. After intermediate III-1 dissolved, 0.125 mL of concentrated sulfuric acid was added dropwise, and the reaction was continued for 0.5 h after the addition was complete. After the reaction was completed, the mixture was cooled to room temperature and 100 mL of water was added. The mixture was filtered to obtain the crude product of the compound. The crude product was subjected to column chromatography to obtain methyl (2Z)-4-{[4-(propynyloxy)phenyl]amino}-4-oxonyl-2-butenoate.

[0262] Based on this, the reaction continued. 5 mol of benzyl bromide was dissolved in 15 mL of DMSO, and 15 mmol of NaN3 was added. The reaction was carried out at room temperature for 12 h, quenched with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate IX. 3.3 mmol of (2Z)-4-{[4-(propynyloxy)phenyl]amino}-4-oxonyl-2-butenoic acid methyl ester and 3 mmol of intermediate IX were dissolved in 25 mL of anhydrous ethanol, and 0.3 mmol of copper sulfate pentahydrate and 0.3 mmol of sodium ascorbate were added. The reaction was carried out for 2 h. After the reaction was complete, the crude product was filtered to obtain the crude product. The crude product was dissolved in a mixed solvent of methanol and dichloromethane and recrystallized to obtain the final product, a white solid with a yield of 35%.

[0263] Molecular formula: C 21 H 20 N4O4

[0264] 1H NMR (600MHz, DMSO-d6): δ10.17(s,1H),8.28(s,1H),7.53(d,J=8.4Hz,2H),7.38(t,J=6.7Hz,2H),7.32(t,J=10.1Hz ,3H),6.99(d,J=8.4Hz,2H),6.48(d,J=11.7Hz,1H),6.39(d,J=11.7Hz,1H),5.61(s,2H),5.11(s,2H),3.66(s,3H).

[0265] 13 C NMR (151MHz, DMSO-d6): δ167.13,162.43,154.63,143.48,136.43,132.54,12 9.18,129.02,128.57,128.35,125.10,121.23,115.26,61.62,53.24,51.99.

[0266] HRMS(ESI):m / z calculated for C21H20N4O4[M+Na]+:415.1382,found415.1385

[0267] Preparation Example 17: Compound 17

[0268]

[0269] The preparation was carried out using a method similar to that of Preparation Example 2, except that 20 mL of phenylethanol was used instead of 20 mL of methanol in Preparation Example 2. The final product was a white solid powder with a yield of 55%.

[0270] Molecular formula: C 20 H 17 NO3

[0271] 1 H NMR (600MHz, DMSO-d6): δ10.46(s,1H),7.64(d,J=7.9Hz,2H),7.44(d,J=8.2Hz,2H),7.30–7.23(m,3H),7.23–7.13(m,2 H), 6.53 (d, J = 11.8Hz, 1H), 6.38 (d, J = 11.7Hz, 1H), 4.30 (t, J = 6.2Hz, 2H), 4.11 (d, J = 8.1Hz, 1H), 2.88 (d, J = 6.6Hz, 2H).

[0272] 13C NMR (151MHz, DMSO-d6): δ167.04,163.13,163.02,161.51,146.87,139.62,132.67,132.51,13 1.57,130.71,129.85,129.40,122.05,121.16,119.30,116.31,116.14,116.00,52.64,52.08.

[0273] HRMS(ESI):m / z calculated for C 20 H 17 NO3[M+Na] + :342.1106,found 342.1105

[0274] Preparation Example 18: Compound 18

[0275]

[0276] The preparation was carried out using a method similar to that of Preparation Example 9, except that 5 mmol of benzyl bromide was replaced with 5 mmol of 4-fluorophenylethylamine in Preparation Example 9. The final product was a white solid powder with a yield of 42%.

[0277] Molecular formula: C 21 H 18 FN4O3

[0278] 1 H NMR (600MHz, DMSO-d6): δ10.39(s,1H),8.46(s,1H),7.76(s,2H),7.69(s,2H),7.25(s,2H),7.1 1(s,2H),6.53(d,J=10.5Hz,1H),6.44(d,J=10.1Hz,1H),4.63(s,2H),3.68(s,3H),3.21(s,2H).

[0279] 13 C NMR (151MHz, DMSO-d6): δ167.06,162.92,162.27,160.66,146.35,138.66,134.21,132.4 9,130.99,129.38,126.65,126.00,121.27,120.09,115.63,115.50,52.05,51.03,35.09.

[0280] HRMS(ESI):m / z calculated for C 21 H 19N4O3F[M+Na] + :417.1339,found 417.1335

[0281] Preparation Example 19: Compound 19

[0282]

[0283] The preparation was carried out using a method similar to that of Preparation Example 7, except that 4.8 mmol of 3-aminopropyltriethoxysilane was replaced with 4.8 mmol of 4-aminobutyltriethoxysilane in Preparation Example 7. The final product was a white solid powder with a yield of 44%.

[0284] Molecular formula: C 22 H 32 N2O5Si

[0285] 1 H NMR (600MHz, DMSO-d6): δ11.58(s,1H),8.67(t,J=5.5Hz,1H),7.63(d,J=8.6Hz,2H),7.43(d,J=8.6Hz,2H),6.27(s,2H),4.11(s, 1H),3.72(q,J=7.0Hz,6H),3.14(q,J=6.6Hz,2H),1.54-1.43(m,2H),1.41-1.29(m,2H),1.13(t,J=7.0Hz,9H),0.64-0.50(m,2H).

[0286] 13 C NMR (151MHz, DMSO-d6): δ165.14,163.85,139.84,133.41,132.90,131.49 ,119.57,116.86,84.00,80.43,58.12,38.88,32.40,20.40,18.67,10.09.

[0287] HRMS(ESI):m / z calculated for C 22 H 32 N₂O₅Si[M+Na] + :455.1978,found455.1978

[0288] Preparation Example 20: Compound 20

[0289]

[0290] Molecular formula: C 19 H 15 ClN2O2

[0291] The preparation was carried out using a method similar to that of Preparation Example 7, except that 4-chlorobenzylamine was used instead of the aqueous ethylamine solution in Preparation Example 6. The final product was a white solid powder with a yield of 72%.

[0292] 1 H NMR (600MHz, DMSO-d6) δ11.10(s,1H),9.06(s,1H),7.66(d,J=8.4Hz,2H),7.45(d,J=8.4Hz,2H) ,7.39(d,J=8.3Hz,2H),7.35(d,J=8.1Hz,2H),6.36(s,2H),4.36(d,J=5.6Hz,2H),4.11(s,1H).

[0293] 13 C NMR (151MHz, DMSO-d6) δ165.30,164.02,139.81,138.34,132.84,132.73,131.88,131.34,129.71,128.64,119.53,116.77,83.97,80.43,41.97.

[0294] HRMS(ESI):m / z calculated for C 19 H 15 N2O2Cl[M+Na]+:361.0720,found361.0718

[0295] Preparation Example 21: Algicidal Material

[0296] Compound 7 - Polyurethane Fixation Material

[0297] Compound 7 was prepared according to the method described in Preparation Example 7. 10 mg of compound 7 was dissolved in 20 mL of anhydrous ethanol, and the pH was adjusted to 10 by adding saturated NaOH aqueous solution. A sample with dimensions of 2 × 2 × 1 cm was then prepared. 3 The polyurethane sponge was immersed in the above solution and heated at 60°C for 1 hour. After the reaction was completed, the material was removed, washed with 20 mL of acetone, and dried to obtain compound 7-polyurethane immobilized material.

[0298] Preparation Example 22: Algicide Material

[0299] Compound 19 - Polyurethane Fixation Material

[0300] Compound 19 was prepared according to the method described in Preparation Example 19, and then a polyurethane immobilized material of compound 19 was prepared using a method similar to that in Preparation Example 21, except that an equal mass of compound 19 was used to replace compound 7 in Preparation Example 21.

[0301] Test Example 1

[0302] Non-toxic algae *Synthia spp.* PCC6803 and toxic algae *Microcystis aeruginosa* FACHB905 are the most important model algae among cyanobacteria. This invention selected *Synthia spp.* PCC6803 and *Microcystis aeruginosa* FACHB905 as in vivo experimental subjects to test the inhibitory effect of the α,β-unsaturated ketone compounds described in this invention on algal growth.

[0303] The specific steps are as follows: Prepare fresh Synechocystis PCC6803 stock solution (OD... 680 =1.0±0.1) or Microcystis aeruginosa FACHB905 stock solution (OD 680 =1.0±0.1) Inoculate 1% of the sample into 150mL Erlenmeyer flasks, seal with sealing film, and incubate in an artificial climate incubator at 28℃, light intensity 6000lx, humidity 50%–55%, with a 12h light: 12h dark cycle. Cyanobacterial cell density was determined by absorbance at 680nm wavelength; 200μL was injected into 96-well plates for testing, subtracting 200μL of BG11 medium for background. The cyanobacterial cell density in the logarithmic growth phase (OD) was measured. 680 =0.31±0.0155(905) or 0.33±0.0165(6803)), diluted with BG11 culture medium at an inoculum of 5% (905) or 2% (6803). Add 2 μL of DMSO solution of the test compound to a 96-well plate, and then add 198 μL of diluted algal solution using a pipette. Perform three parallel experiments for each group. After sealing the 96-well plate, place it in an artificial climate incubator. DMSO is used as a blank control. Incubate for 14 days, and adjust the direction regularly every day to ensure uniform light. OD is read on day 7 and day 14. 680 Corrected OD after removing the compound's own color background. 680 =Octopus content in algae-containing culture medium 680 - Algae-free culture medium OD 680 .

[0304] The inhibition rate of the compound is calculated using the following formula:

[0305]

[0306] Set up a concentration gradient for the compound (0.5, 1, 2, 4, 6, 8, 10 μM or 1, 2, 4, 8, 12, 16, 20 μM). Based on the compound concentration and the corresponding inhibition rate, use the logistic regression formula in Origin to obtain a curve formula. Substitute a 50% inhibition rate into the formula to calculate the EC50 of the compound. 50 Values ​​were determined. Copper sulfate and pyrazosulfate were used as positive controls. The results are shown in Tables 1, 2, 3, and 4.

[0307] Table 1

[0308]

[0309]

[0310] Note: a~b:a <EC 50 <b。

[0311] Table 2

[0312]

[0313] Note: a~b:a <EC 50 <b。

[0314] As can be seen from the data in Tables 1 and 2, the compounds provided by this invention have good inhibitory effects on Synechocystis PCC6803, and the inhibitory effects of some compounds are better than those of commercially available copper sulfate or pyrimethanil. In particular, compound 15 has better activity against Synechocystis PCC6803 than copper sulfate.

[0315] Furthermore, copper sulfate and chlorpyrifos can only kill algae in a short period of time, and the algae will resume growth in the later stage, with the algae-killing activity continuously decreasing in the later stage. Compared with algaecides on the market, including copper sulfate and chlorpyrifos, the compound provided by this invention can continuously inhibit the growth of algae for a longer period of time, and the algae-killing activity increases with the extension of time, showing long-lasting effect.

[0316] Table 3

[0317]

[0318]

[0319] Note: a~b:a <EC 50 <b。

[0320] Table 4

[0321]

[0322] Note: a~b:a <EC 50 <b。

[0323] As can be seen from the data in Tables 3 and 4, the compounds provided by this invention have good inhibitory effects on Microcystis aeruginosa 905, and the inhibitory effects of most of the compounds are better than those of commercially available copper sulfate, and are comparable to those of chlorpyrifos. In particular, compounds 7 and 6 showed significantly better activity against Microcystis aeruginosa 905 than copper sulfate on day 14.

[0324] Test Example 2

[0325] Microcystis aeruginosa FACHB905 is an important toxin-producing algae causing cyanobacterial blooms. This invention selects this algae as a live experimental subject to test the algicidal effects of the α,β-unsaturated ketone compounds and the immobilized materials described in this invention in conical flasks; and provides exemplary algicidal activity data of compound 7 and compound 7-polyurethane immobilized materials.

[0326] The specific procedure is as follows: Take Microcystis aeruginosa FACHB905 cells in the logarithmic growth phase, dilute them 5-fold with BG11 culture medium, and dispense them into 250mL Erlenmeyer flasks; add DMSO solution of compound 7, polyurethane material, and compound 7-polyurethane immobilization material (2×2×1cm in size) respectively. 3 ) and Compound 19 - Polyurethane fixing material (2×2×1cm) 3 After sealing, the samples were placed in an artificial climate incubator and cultured under the same conditions as in Test Example 1. DMSO was used as a blank control, and copper sulfate was used as a positive control. Samples were taken at different culture times to test the concentration of cyanobacteria and calculate the inhibition rate, using the same method as in Test Example 1. The results are as follows: Figure 1 As shown.

[0327] from Figure 1 As can be seen, the compounds and immobilized materials of this invention exhibit excellent long-lasting inhibitory activity against Microcystis aeruginosa FACHB905. At the same concentration, copper sulfate initially showed some algicidal activity, but the activity continuously decreased after day 3 until it became inactive; the unloaded polyurethane material did not show a significant algicidal effect; the activity of compounds 7, 19, compound 7-polyurethane immobilized material, and compound 19-polyurethane immobilized material continuously increased from day 3, and the algicidal effect remained unchanged even after 35 days, demonstrating long-lasting efficacy, significantly superior to copper sulfate. Furthermore, immobilizing compound 7 or compound 19 onto the polyurethane material resulted in a faster onset of algicidal activity.

[0328] Test Example 3

[0329] Algaecides need to be added to the water body during use. This invention selects the zebrafish, a model organism, as the experimental subject to test the toxicity of the α,β-unsaturated ketone compounds and the immobilization material described in this invention to aquatic organisms. Compounds 7 and 19, as well as compound 7-polyurethane immobilization material (2×2×1cm in size), are provided exemplary. 3 Biosafety data.

[0330] The specific procedures are as follows: Collect tap water and expose it to sunlight for 3 days to remove residual chlorine. Prepare 1 mL each of DMSO solutions with concentrations of 10000, 1000, and 100 μg / mL of the compound, and set aside. Feed the zebrafish under experimental conditions (20-25℃) to allow them to adapt to the experimental environment. A mortality rate of no more than 5% within 48 hours indicates a suitable experimental environment. Stop feeding two days before the start of the experiment. The prepared compound solutions and compound 7-polyurethane immobilizing material were added to 1L of dechlorinated water to prepare experimental water solutions or immobilizing material immersion water solutions of 10, 1, and 0.1 μg / mL. Ten zebrafish with a body length of 1.5-2 cm were added to each experimental water solution. The survival of the zebrafish was observed at 24, 48, 72, and 96 hours (zebrafish death was confirmed by no swimming, no gill opening or closing, and no reaction upon touch). Dead zebrafish were promptly removed to prevent contamination of the experimental water. Experimental water with only 1 mL of DMSO was used as a negative control (to confirm the effect of the solvent on zebrafish survival), while copper sulfate and pyrimethanil were used as positive controls, treated in the same way as the compounds. The zebrafish mortality rate at 96 hours was used as the LC-weighted average. 50 The criteria for determining the value are based on LC. 50 The values ​​confirmed the acute toxicity of the compound in zebrafish. The results are shown in Table 5.

[0331] Table 5

[0332]

[0333] The results above indicate that compound 19 of this invention has a low toxicity level to zebrafish, and no zebrafish mortality was observed in the 10 μg / mL concentration treatment group, which is superior to the highly toxic copper sulfate and the moderately toxic atrazine positive control. When compound 7, which has a moderate toxicity level, was immobilized onto a polyurethane material, the immobilized material did not exhibit toxicity, thus reducing the toxicity of compound 7.

[0334] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. An α,β-unsaturated ketone compound, characterized in that, The compound has the structure shown in formula (I). Equation (I), The compound represented by formula (I) is selected from any one of the following: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26; In formula (I), the definitions of L, R1, R2, m, and n correspond to the corresponding positions of compounds 1 to 26.

2. A method for preparing the α,β-unsaturated ketone compound of claim 1, characterized in that, The method includes: In the presence of catalyst I, the compound shown in formula (1) and the compound shown in formula (2) are subjected to a first contact reaction to obtain the α,β-unsaturated ketone compound shown in formula (I); Equation (I), Equation (1), Equation (2), The definitions of L, R1, R2, m, and n are the same as those of compounds 1 to 26 in claim 1.

3. A method for preparing the α,β-unsaturated ketone compound of claim 1, characterized in that, The method includes: In the presence of solvent II and catalyst II, the compound shown in formula (3) is subjected to a second contact reaction with the compound shown in formula (4) to obtain the α,β-unsaturated ketone compound shown in formula (I); Equation (I), Equation (3), Equation (4), Where y is 0 or 1; L, R1, R2, R 5 The definitions of m, n, and z correspond to the corresponding positions of compounds 9, 12, 16, 18, 22, 24, and 25 as shown in claim 1.

4. The application of the α,β-unsaturated ketone compounds of claim 1 in inhibiting cyanobacteria.

5. The application according to claim 4, characterized in that, The cyanobacteria are selected from at least one of Microcystis aeruginosa, Anabaena aquatica, Oscillatoria, and Synechocystis.

6. An algaecide, characterized in that, The algaecide is composed of active ingredient I and excipients, wherein active ingredient I contains at least one of the α,β-unsaturated ketone compounds as described in claim 1.

7. The algaecide according to claim 6, characterized in that, The content of active ingredient I is 0.01-99.99% by weight.

8. An algaecide, characterized in that, The algaecide material is composed of active ingredient II and a base material, wherein active ingredient II contains at least one of the α,β-unsaturated ketone compounds represented by formula (I); Equation (I), In formula (I), the definitions of L, R1, R2, m, and n correspond to the corresponding positions of compounds 1 to 26 as shown in claim 1.

9. The algaecide material according to claim 8, characterized in that, The content of active ingredient II is 0.01-99.99% by weight. And / or, the base material of the algaecide is selected from at least one of polyurethane, copper mesh, nylon cloth, carbon fiber, and glass fiber.

10. A method for preparing the algicidal material according to claim 8 or 9, characterized in that, The method includes: In the presence of solvent III and catalyst III, the compound shown in formula (I) is subjected to a third contact reaction with the substrate material to obtain the algaecide material; Equation (I), The definitions of R1, R2, L, m, and n are the same as those in claim 8.

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