Bis (N-acylamino-3, 1-benzoxazinyl) methane compound as well as preparation method and application thereof

Abstract

The invention discloses a bis (N-acylamino-3, 1-benzoxazinyl) methane compound and a preparation method and application thereof.The compound takes an arylamine compound and bromoacetyl bromide as raw materials, triethylamine as an acid-binding agent and dichloromethane as a solvent to react in an ice-water bath to obtain an N-aryl-2-bromoacetyl arylamine compound, then the N-aryl-2-bromoacetyl arylamine compound is subjected to multi-step reaction, and the bis (N-acylamino-3, 1-benzoxazinyl) methane compound is obtained. Finally, the bis (N-acylamino-3, 1-benzoxazinyl) methane compound with bactericidal activity is obtained. The raw materials for synthesis of the compound are cheap and easy to obtain, and the synthesis method is simple. Meanwhile, the compound has a good inhibition effect on the activity of crop germs, especially has remarkable inhibition activity on sclerotinia sclerotiorum, phytophthora, gibberellic disease bacteria, magnaporthe oryzae, botrytis cinerea and rhizoctonia solani, and has remarkable application value in the aspects of crop disease control and drug resistance challenge.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical drugs, and specifically relates to a bis(N-acylamino-3,1-benzoxazinyl)methane compound, a preparation method thereof, and uses thereof. Background Art

[0002] In the field of research on bioactive molecules, nitrogen-oxygen heterocyclic compounds have become an important direction for new drug development due to their unique molecular configurations and multi-target action characteristics. Among them, benzoxazine compounds, as typical representatives, exhibit significant advantages in terms of biological activities. In particular, the 3,1-benzoxazine structural unit has attracted much attention in the development of anti-infective drugs due to its wide range of biological activities, such as antibacterial, anti-inflammatory, anti-tumor, antiviral, anti-allergic, anti-malarial, anti-fungal, anti-convulsant, herbicidal, etc., and shows good effects especially in antibacterial and anti-tumor aspects. Bis-benzoxazine compounds can enhance the interaction between molecules and biological targets by integrating two active units, further improving the activity intensity and selectivity.

[0003] In the pharmaceutical field, breakthrough research on bis-benzoxazine compounds has continued to emerge: The bis-benzoxazine derivative developed by the Heinisch team (in 2002) showed extremely strong inhibitory effects on pathogenic bacteria such as Pseudomonas aeruginosa, with an in vitro minimum inhibitory concentration (MIC) value of 0.005 mg / L - 5 mg / L, and more importantly, it achieved efficient killing of drug-resistant bacteria by simulating the bacterial iron uptake mechanism. The bis-benzoxazine compounds systematically screened by Lalcheta et al. (in 2015) had an MIC value of 62.5 - 200 μg / mL when tested for biological activity using Salmonella typhi, confirming their potential as antibacterial lead compounds. The nitrogen-rich bis-benzoxazine compound containing a C=N double bond designed by the Mohamed Mydeen K team (in 2024) showed good antibacterial activity against Staphylococcus aureus and Escherichia coli by disrupting the integrity of the microbial membrane.

[0004] Despite significant progress, there are still key bottlenecks in this field: At the level of synthetic chemistry, existing bis-benzoxazine systems mostly focus on 1,3-benzoxazine dimers, and the research on compounds containing 3,1-benzoxazine double units is severely lacking. Their synthesis methods generally have problems such as narrow raw material adaptability and difficult regioselectivity control. The synthesis of reported bis-benzoxazine compounds strictly depends on the salicylaldehyde-hexamethylenediamine-formaldehyde system, which greatly limits the development of structural diversity and also has a high cost. In view of this, we have innovatively developed the synthesis of bis(N-acylamino-3,1-benzoxazinyl)methane compounds to solve the problems of specific raw materials and high costs in the existing technology. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a bis(N-acylamino-3,1-benzoxazinyl)methane compound, a preparation method and a use thereof. This type of compound uses an aromatic amine compound and bromoacetyl bromide as raw materials, triethylamine as an acid-binding agent, and dichloromethane as a solvent to react in an ice-water bath to obtain an N-aryl-2-bromoacetylaniline compound; then, the N-aryl-2-bromoacetylaniline compound and 2-aminobenzyl alcohol are reacted in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran under the action of potassium carbonate to obtain an N-aryl-2-(2-hydroxymethylphenyl)acetamide compound. Further, the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound and formaldehyde solution are reacted in dichloromethane under the action of trifluoroacetic acid to obtain a bis(N-acylamino-3,1-benzoxazinyl)methane compound with bactericidal activity. The raw materials used in the synthesis of this type of compound are cheap and easily available, the synthesis method is simple, and the bis(N-acylamino-3,1-benzoxazinyl)methane compound has a good inhibitory effect on the activity of crop pathogens, especially on the inhibitory activities against Sclerotinia sclerotiorum, Phytophthora infestans, Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea, and Rhizoctonia solani are significant.

[0006] To solve the above technical problems, the basic concept of the technical solution adopted by the present invention is:

[0007] On the one hand, the present invention provides a bis(N-acylamino-3,1-benzoxazinyl)methane compound, which is a compound having the structural formula (IV),

[0008]

[0009] In formula (IV), R1 is one of an alkyl group having 1 to 6 carbon atoms, a halogen atom, a methoxy group, H, or a naphthyl group; n is 0 or 1;

[0010] Preferably, R1 is methyl, methoxy group, fluorine atom, bromine atom, chlorine atom, H, or naphthyl group.

[0011] Preferably, the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural formula (IV) is specifically selected from one or more of the following compounds:

[0012] Bis(N-(4-methylphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane:

[0013]

[0014] Bis(N-((3-methoxyphenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0015]

[0016] Bis(N-((2-methoxyphenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0017]

[0018] Bis(N-((4-fluorophenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0019]

[0020] Bis(N-((4-bromophenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0021]

[0022] Bis(N-(1-naphthylaminocarbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0023]

[0024] BisN-(benzylaminocarbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0025]

[0026] Bis(N-((4-chlorobenzylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane:

[0027]

[0028] Another aspect of the present invention provides a method for preparing bis(N-acylamino-3,1-benzoxazinyl)methane compounds having the structural formula (IV), which specifically includes the following steps:

[0029] S1) Using an aromatic amine compound having the structural formula (I) and bromoacetyl bromide as raw materials, triethylamine as an acid-binding agent, and dichloromethane as a solvent, synthesize an N-aryl-2-bromoacetylarylamine compound having the structural formula (II) in an ice-water bath;

[0030]

[0031] S2) Reacting the N-aryl-2-bromoacetylarylamine compound having the general formula (II) with o-aminobenzyl alcohol under the action of potassium carbonate in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran to obtain an N-aryl-2-(2-hydroxymethylphenyl)acetamide compound having the structural formula (III);

[0032]

[0033] S3) React the N-aryl-2-(2-hydroxymethylphenyl)acetamide compounds with the structural general formula (Ⅲ) and formaldehyde solution in dichloromethane under the action of trifluoroacetic acid to obtain bis(N-acylamino-3,1-benzoxazinyl)methane compounds with the structural general formula (Ⅳ);

[0034]

[0035] In formula (Ⅳ), R1 is one of an alkyl group with 1 to 6 carbon atoms, a halogen atom, a methoxy group, H, or a naphthyl group; n is 0 or 1;

[0036] Preferably, R 1 is methyl, methoxy group, fluorine atom, bromine atom, chlorine atom, H, naphthyl group; n is 0 or 1;

[0037] Preferably, step S1) is specifically as follows: Weigh the aromatic amine compound with the structural formula (I) and triethylamine, place them in a 500 mL round-bottom flask, and add 250 mL of dichloromethane as a solvent. Dissolve bromoacetyl bromide in 30 mL of dichloromethane and transfer it to a constant-pressure dropping funnel, and slowly add it dropwise to the reaction system under the temperature control of an ice-water bath (0 °C). After the dropping is completed, continuously stir for 30 min and monitor the reaction process by TLC. After the reaction is completed, obtain a solid crude product by vacuum distillation under reduced pressure, and successively carry out suction filtration, recrystallization, and vacuum drying treatments to obtain the purified N-aryl-2-bromoacetylarylamine compounds with the structural general formula (Ⅱ).

[0038] In the present invention, in step S1), the preferred molar ratio of the aromatic amine compound, bromoacetyl bromide, and triethylamine is 1:0.6:1.2, the preferred reaction temperature is controlled at 0 °C, and the preferred stirring time is 30 min.

[0039] Preferably, step S2) is specifically as follows: Take the N-aryl-2-bromoacetylarylamine compounds with the structural general formula (Ⅱ) obtained in step S1), o-aminobenzyl alcohol, and potassium carbonate and add them to a 250 mL round-bottom flask, inject a mixed solvent of THF and DMF (V:V = 2:1, total amount 60 mL), and heat to reflux at 65 °C for 3 h with stirring (TLC tracking). After the reaction is completed, filter off potassium carbonate by suction filtration, wash the filter cake with ethyl acetate, combine the filtrates, carry out vacuum distillation under reduced pressure, add 30 mL of saturated NaCl solution, and extract with ethyl acetate (30 mL × 3 times). The organic phase is successively washed with water (30 mL × 2 times) and saturated NaCl solution (30 mL × 2 times), dried over anhydrous Na2SO4, concentrated, and subjected to column chromatography separation to obtain the N-aryl-2-(2-hydroxymethylphenyl)acetamide compounds with the structural general formula (Ⅲ).

[0040] In the present invention, in step S2), the molar ratio of the N-aryl-2-bromoacetanilide compound having the structural general formula (II), o-aminobenzyl alcohol and potassium carbonate is 1.2:1:1.4. The preferred reaction temperature is 65 °C, and the preferred reflux time is 3 h.

[0041] Preferably, step S3) is specifically as follows: The N-aryl-2-(2-hydroxymethylphenyl)acetamide compound having the structural general formula (III), trifluoroacetic acid and 37% formaldehyde solution are added to a 100 mL round-bottom flask containing 20 mL of dichloromethane, and stirred and reacted in a constant temperature water bath at 25 °C for 18 h (monitored by TLC). After the reaction is terminated, saturated K2CO3 solution is added for neutralization. After liquid separation, the organic phase is washed with saturated NaHSO3 solution (30 mL × 3 times) to remove residual formaldehyde, and then washed with distilled water (30 mL × 3 times) and saturated NaCl solution (30 mL × 2 times), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. After purification by column chromatography, the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV) is finally obtained.

[0042] In the present invention, in step S3), the preferred molar ratio of the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound having the structural general formula (III), trifluoroacetic acid and formaldehyde is 1:1:1.8. The preferred reaction temperature is 25 °C, and the preferred reaction time is 18 h.

[0043] In the chemical reaction system of the present invention, introducing triethylamine has a dual key role. First, it can effectively remove acidic impurities that may exist in the reactant system, such as hydrochloric acid, etc., to purify the reaction environment; second, it can neutralize the hydrobromic acid generated during the reaction of bromoacetyl bromide and the reactants, which will strongly promote the reaction and significantly improve the reaction conversion rate and product yield.

[0044] Preferably, in the reaction stage of S1), the selected solvent system is an inert organic solvent, and dichloromethane (CH2Cl2) becomes the core solvent due to its low boiling point and high solubility. In the reaction system, the feeding molar ratio of bromoacetyl bromide and arylamine compounds is set to 0.5 - 0.7:1. Optimization experiments show that a ratio of 0.55 - 0.65:1 can significantly improve the yield of intermediate II. The addition amount of triethylamine as an acid absorbent and the molar ratio of arylamine compounds are controlled at 1.1 - 1.3:1, and further optimized to 1.15 - 1.25:1 can effectively inhibit the formation of by-products.

[0045] Preferably, in the reaction stage of S2), the molar ratio of intermediate II to o-aminobenzyl alcohol is set to 1.15 - 1.25:1, and the reaction efficiency reaches the peak value when the preferred range is 1.18 - 1.22:1. The molar ratio of potassium carbonate as the base catalyst to intermediate II is maintained at 1.3 - 1.5:1, and the ratio of 1.35 - 1.45:1 can not only ensure the full progress of the reaction but also reduce the residue of excessive reagents.

[0046] Preferably, for the optimized design of the solvent system, the present invention makes differential selections according to the physicochemical characteristics of different reaction stages: single solvent CH2Cl2 is used in both S1 and S3 reactions to ensure homogeneous reaction; for the S2 reaction, a composite solvent system of THF and DMF (V:V = 2:1) is used, and the significant change in its polarity gradient significantly improves the reaction activity of amide bond formation. The mixed solvent exhibits the best dissolution performance and reaction activity, so it is used as the main reaction solvent.

[0047] Preferably, in the dropping process of the S1) reaction, a dual regulation mechanism is formed by the dropping rate and temperature control of the bromoacetyl bromide solution: a low-temperature environment of 0 - 5°C (preferably 0 - 2°C) is maintained throughout the dropping process, and the reaction duration at this stage is controlled within 0.5 - 1.5 h. Among them, the reaction time of 0.5 - 1 h can not only ensure the full progress of the reaction but also improve production efficiency.

[0048] Preferably, in the S2) reaction, the reaction temperature of heating under reflux is maintained at 60 - 70°C. After optimization, the temperature range of 63 - 67°C can achieve a better balance between the reaction rate and the product yield. The time for this reaction stage is set to 2.5 - 3.5 h. Experiments have found that the reaction duration of 2.8 - 3.3 h can effectively ensure the integrity of the reaction and the product quality.

[0049] Preferably, in the S3) reaction, a trifluoroacetic acid / formaldehyde bifunctional catalytic system is innovatively introduced. The molar ratio of compound III to formaldehyde is optimized to 1:1.7 - 1.9, and the preferred range is 1:1.75 - 1.85. The reaction temperature is maintained under a constant temperature condition of 20 - 40°C. After optimization, the product yield is relatively high when the reaction temperature is maintained at 23 - 28°C, lasting for 10 - 25 h. The preferred reaction time is 15 - 20 h to ensure the full completion of the reaction and improve the product formation rate.

[0050] Preferably, in step S3), dichloromethane is selected as the reaction solvent based on its excellent dissolution ability for trifluoroacetic acid and formaldehyde solutions, and at the same time, it can maintain the homogeneous state of the reaction system and promote the directional progress of intermolecular condensation reactions.

[0051] Preferably, the molar ratio of trifluoroacetic acid to the compound of structural general formula (Ⅲ) is 1:1, and its function is to activate the amide group through a strong acidic environment, while the molar ratio of formaldehyde is set to 1.8:1, which not only ensures an adequate amount of formylation reagent required for the condensation reaction but also avoids the generation of by-products caused by excessive reagents.

[0052] Preferably, the reaction temperature is controlled at the equilibrium point of 25 °C, which can not only meet the energy requirements of the ring contraction reaction but also inhibit the self-polymerization side reaction caused by high temperature. The continuous reaction time of 18 h provides sufficient kinetic guarantee for the condensation-cyclization two-step process, ensuring the complete conversion of the intermediate into the target benzoxazine structure.

[0053] Preferably, a staged washing strategy is adopted in the post-treatment process: the saturated NaHSO3 solution specifically removes the residual unreacted formaldehyde, distilled water removes water-soluble impurities, and washing with saturated NaCl solution helps to further remove the residual moisture and some possible salt impurities, while reducing the dissolution loss of the product in the aqueous phase.

[0054] Preferably, the present invention also includes drying the washed organic phase, and anhydrous Na2SO4 is used for drying treatment.

[0055] Preferably, the present invention also includes a desolvation process for the dried product, and the method of rotary evaporation under reduced pressure is used for desolvation.

[0056] On the other hand, the present invention provides a use of a bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (Ⅳ) or a bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (Ⅳ) prepared by the above method, and the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (Ⅳ) is used for antibacterial of crops; specifically, it is used to inhibit one or more of Gibberella zeae, Magnaporthe oryzae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani.

[0057] Preferably, the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (Ⅳ) is used to inhibit Phytophthora infestans, Sclerotinia sclerotiorum, Magnaporthe oryzae, Gibberella zeae.

[0058] On the other hand, the present invention provides a bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV), or the use of a bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV) prepared by the above method. The bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV) is used for preparing a drug for inhibiting bacteria in crops, specifically for preparing a drug for inhibiting one or more of Gibberella zeae, Magnaporthe oryzae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani.

[0059] Preferably, the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV) is used for preparing a drug for inhibiting Phytophthora infestans, Sclerotinia sclerotiorum, Magnaporthe oryzae and Gibberella zeae.

[0060] The preparation method of the compound of the present invention is simple. Using common and low-cost aromatic amine compounds and bromoacetyl bromide as starting materials, triethylamine as an acid-binding agent, and dichloromethane as a solvent, reacting under an ice-water bath condition to generate N-aryl-2-bromoacetylaniline compounds. Subsequently, the 2-bromoacetylaniline compounds and 2-aminobenzyl alcohol are reacted in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran under the catalysis of potassium carbonate to successfully prepare N-aryl-2-(2-hydroxymethylphenyl)acetamide compounds. Further, the N-aryl-2-(2-hydroxymethylphenyl)acetamide compounds and formaldehyde solution are reacted in dichloromethane under the action of trifluoroacetic acid to obtain a bis(N-acylamino-3,1-benzoxazinyl)methane compound.

[0061] Particularly importantly, the bis(N-acylamino-3,1-benzoxazinyl)methane compound of the present invention has excellent antibacterial activity against crop pathogens. After a large number of experimental verifications, this compound can show extremely significant inhibitory effects on common and severely harmful pathogens such as Gibberella zeae, Phytophthora infestans, Magnaporthe oryzae, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani. By effectively inhibiting the growth and reproduction of these pathogens, the occurrence of crop diseases can be greatly reduced, the healthy growth of crops can be effectively guaranteed, and thus the crop yield can be effectively improved, providing a solid and reliable technical support for the stability and development of agricultural production.

[0062] After adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art.

[0063] The present invention innovatively develops a synthetic strategy for bis(N-acylamino-3,1-benzoxazinyl)methane compounds. By applying the principle of pharmacodynamic superposition, the synthetic route is designed, key reaction conditions are optimized, an efficient and green synthetic methodology is established, breaking the dependence on specific raw materials in traditional methods and achieving the directional modification of aromatic ring substituents. The quantitative relationship between substituent electronic effects, steric hindrance and antibacterial activity is systematically studied to clarify the action mode of key pharmacophores. At the same time, the new mechanism of the antibacterial activity of such compounds is explored, laying a foundation for the development of novel antibacterial drugs with independent intellectual property rights. It has significant application value in addressing crop disease control and drug resistance challenges.

[0064] 1. The preparation of bis(N-acylamino-3,1-benzoxazinyl)methane compounds with the general structural formula (IV) in the present invention is a completely new compound, and this compound has good antibacterial activity against crops; especially good antibacterial activity against Gibberella zeae, Magnaporthe oryzae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani.

[0065] 2. In the preparation method of bis(N-acylamino-3,1-benzoxazinyl)methane compounds with the general structural formula (IV) provided by the present invention, the synthetic raw materials are cheap and easily available, the synthetic method is simple, the yield is relatively high, and the product is easy to separate and purify.

[0066] The following further describes the specific embodiments of the present invention in detail with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] The accompanying drawings, as part of this application, are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention, but do not constitute an improper limitation of the present invention. Obviously, the accompanying drawings in the following description are only some embodiments, and those of ordinary skill in the art can obtain other drawings based on these drawings without creative efforts. In the drawings:

[0068] Figure 1 is the structural diagram of bis(N-acylamino-3,1-benzoxazinyl)methane compounds with the general structural formula (IV) described in the present invention.

[0069] Figure 2 is the synthetic route diagram of bis(N-acylamino-3,1-benzoxazinyl)methane compounds with the general structural formula (IV) described in the present invention.

[0070] It should be noted that these drawings and textual descriptions are not intended to limit the scope of the concept of the present invention in any way, but to illustrate the concept of the present invention to those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0071] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the following will clearly and completely describe the technical solutions in the embodiments in conjunction with the accompanying drawings in the embodiments of the present invention. The following embodiments are used to illustrate the present invention but are not used to limit the scope of the present invention.

[0072] The structural formula of the intermediate product of the present invention is shown in Table 1 below

[0073] Table 1 Structural formula of the intermediate product

[0074]

[0075]

[0076] The sources of the chemical reagents used in the embodiments of the present invention are as follows:

[0077] Shanghai Merck Chemical Technology Co., Ltd.: 4-methylaniline (CAS: 106-49-0), 4-fluoroaniline (CAS: 371-40-4), 2-methoxyaniline (CAS: 90-04-0), 3-methoxyaniline (CAS: 536-90-3), 4-bromoaniline (CAS: 106-40-1), 1-naphthylamine (CAS: 134-32-7), benzylamine (CAS: 100-46-9), 4-chlorobenzylamine (CAS: 104-86-9), 2-aminobenzyl alcohol (CAS: 5344-90-1), bromoacetyl bromide (CAS: 598-21-0), potassium carbonate (CAS: 584-08-7), formaldehyde solution (37%) (CAS: 50-00-0), trifluoroacetic acid (CAS: 76-05-1), anhydrous sodium sulfate (CAS: 7757-82-6), deuterated dimethyl sulfoxide (CAS: 2206-27-1), deuterated chloroform (CAS: 865-49-6).

[0078] Xilong Scientific Co., Ltd.: tetrahydrofuran (CAS: 109-99-9), N,N-dimethylformamide (CAS: 68-12-2), triethylamine (CAS: 121-44-8).

[0079] Changsha Xinghao Chemical Co., Ltd.: dichloromethane (CAS: 75-09-2).

[0080] Example A1

[0081] Synthesis of bis(N-(4-methylphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane

[0082]

[0083] In a 100 mL round-bottom flask, N-(4-methylbenzyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.08 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) were added, and 20 mL of dichloromethane was added. The mixture was stirred in a 25 °C water bath and reacted for 18 h (TLC tracking monitoring). After the reaction was completed, saturated potassium carbonate solution was added and stirred to quench the reaction. Then 50 mL of dichloromethane was added, and the organic phase was first extracted with saturated sodium bisulfite solution (30 ml x 3) to remove excess formaldehyde, and then washed with distilled water (30 ml x 3) and saturated brine (30 ml x 2) in sequence. Finally, the organic phase was dried over anhydrous sodium sulfate. After desolventizing under reduced pressure, the residue was purified by column chromatography to obtain a white solid product with a yield of 92%; melting point (mp): 196.8-197.3 °C.

[0084] 1 H NMR (400MHz, CDCl3) δ8.82(s,2H),7.42(d,J=8.3Hz,4H),7.12(d,J=8.2Hz,4H),6.97(d,J=8.2H z,2H),6.75(d,J=8.5Hz,4H),4.91(s,4H),4.74(s,4H),3.92(s,4H),3.79(s,2H),2.31(s,6H).

[0085] 13 C NMR(101MHz, CDCl3)δ168.18(2C),141.84(2C),134.89(2C),134.33(2C),129.62(4C),128.54(2C),125 .38(2C),124.08(2C),119.91(4C),116.90(2C),82.13(2C),68.02(2C),57.58(2C),40.52,20.99(2C).

[0086] Example A2

[0087] Synthesis of Bis(N-((3-methoxyphenylamino)formylmethyl)-3H-3,1-benzoxazinyl)methane

[0088]

[0089] Add N-(3-methoxybenzyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.15 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask. Add 20 mL of dichloromethane, stir under the condition of a 25 °C water bath, and react for 18 h (monitored by TLC). After the reaction is completed, add saturated potassium carbonate solution and stir to quench the reaction. Then add 50 mL of dichloromethane. First, extract the organic phase with saturated sodium bisulfite solution (30 ml x 3) to remove the excess formaldehyde, then wash it successively with distilled water (30 mL x 3) and saturated brine (30 ml x 2). Finally, dry the organic phase with anhydrous sodium sulfate. After solvent removal under reduced pressure, the residue is purified by column chromatography to obtain a white solid product with a yield of 80%; melting point (mp): 119.5 - 120.9 °C.

[0090] 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 2H), 7.30 (t, J = 2.0 Hz, 2H), 7.20 (t, J = 8.1 Hz, 2H), 7.03 - 6.95 (m, 4H), 6.74 (d, J = 8.6 Hz, 4H), 6.69 - 6.65 (m, 2H), 4.91 (s, 4H), 4.73 (s, 4H), 3.93 (s, 4H), 3.79 (s, 8H).

[0091] 13 C NMR (101 MHz, CDCl3) δ 168.32 (2C), 160.20 (2C), 141.69 (2C), 138.57 (2C), 134.30 (2C), 129.73 (2C), 128.46 (2C), 125.31 (2C), 124.03 (2C), 116.85 (2C), 111.90 (2C), 110.39 (2C), 105.50 (2C), 82.04 (2C), 67.92 (2C), 57.59 (2C), 55.35 (2C), 40.42 (1C).

[0092] Example A3

[0093] Synthesis of bis(N-((2-methoxyphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane

[0094]

[0095] Add N-(2-methoxybenzyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.15 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask. Add 20 mL of dichloromethane, stir under the condition of a 25 °C water bath, and react for 18 h (monitored by TLC). After the reaction is completed, add saturated potassium carbonate solution and stir to quench the reaction. Then add 50 mL of dichloromethane. First, extract the organic phase with saturated sodium bisulfite solution (30 ml × 3) to remove the excess formaldehyde, and then wash it successively with distilled water (30 mL × 3) and saturated brine (30 ml × 2). Finally, dry the organic phase with anhydrous sodium sulfate. After solvent removal under reduced pressure, the residue is purified by column chromatography to obtain a white solid product with a yield of 83%; melting point (mp): 159.6 - 161.4 °C.

[0096] 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 2H), 8.39 (dd, J = 8.0, 1.6 Hz, 2H), 7.07 (td, J = 7.8, 1.7 Hz, 2H), 7.01 - 6.95 (m, 4H), 6.86 (dd, J = 8.1, 1.2 Hz, 2H), 6.80 (d, J = 8.5 Hz, 4H), 4.90 (s, 4H), 4.74 (s, 4H), 3.98 (s, 4H), 3.81 (s, 2H), 3.77 (s, 6H).

[0097] 13 C NMR (101 MHz, CDCl3) δ 168.35 (2C), 148.53 (2C), 142.23 (2C), 134.47 (2C), 128.35 (2C), 127.12 (2C), 125.22 (2C), 124.64 (2C), 124.36 (2C), 121.15 (2C), 120.17 (2C), 117.91 (2C), 110.30 (2C), 81.93 (2C), 67.84 (2C), 58.60 (2C), 55.88 (2C), 40.65 (1C).

[0098] Example A4

[0099] Synthesis of bis(N-((4-fluorophenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane

[0100]

[0101] Add N-(4-fluorobenzyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.10 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask, add 20 mL of dichloromethane, stir under the condition of 25 °C water bath, react for 18 h (monitored by TLC), after the reaction is completed, add saturated potassium carbonate solution to stir and quench the reaction, then add 50 mL of dichloromethane, first extract the organic phase with saturated sodium bisulfite solution (30 ml x 3) to remove the excessive formaldehyde, then wash with distilled water (30 mL x 3) and saturated brine (30 ml x 2) in turn, finally dry the organic phase with anhydrous sodium sulfate, after concentration under reduced pressure, the residue is purified by column chromatography to obtain a white solid product, with a yield of 89%; melting point (mp): 159.9 - 161.3 °C.

[0102] 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 2H), 7.53 - 7.47 (m, 4H), 6.99 (t, J = 8.7 Hz, 6H), 6.78 - 6.72 (m, 4H), 4.91 (s, 4H), 4.74 (s, 4H), 3.93 (s, 4H), 3.79 (s, 2H).

[0103] 13 C NMR (101 MHz, CDCl3) δ 168.31 (2C), [160.78, 158.36] (2C-F), 141.72 (2C), 134.37 (2C), [133.50, 133.48] (2C-F), 128.53 (2C), 125.42 (2C), 124.07 (2C), 121.65 (2C), 121.57 (2C), 116.79 (2C), 115.87 (2C), 115.64 (2C), 82.11 (2C), 68.01 (2C), 57.39 (2C), 40.50 (1C).

[0104] Example A5

[0105] Synthesis of bis(N-((4-bromophenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane

[0106]

[0107] Add N-(4-bromobenzyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.34 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask, add 20 mL of dichloromethane, stir under the condition of 25 °C water bath, react for 18 h (monitored by TLC), after the reaction is completed, add saturated potassium carbonate solution to stir and quench the reaction, then add 50 mL of dichloromethane, first extract the organic phase with saturated sodium bisulfite solution (30 ml x 3) to remove the excessive formaldehyde, then wash successively with distilled water (30 mL x 3) and saturated brine (30 ml x 2), finally dry the organic phase with anhydrous sodium sulfate, after solvent removal under reduced pressure, the residue is purified by column chromatography to obtain a white solid product, with a yield of 88%; melting point (mp): 192.9 - 201.7 °C.

[0108] 1 H NMR(400MHz,CDCl3)δ8.93(s,2H),7.47-7.39(m,8H),6.97(d,J=8.3Hz,2H),6.79-6.70(m,4H),4.91(s,4H),4.74(s,4H),3.93(s,4H),3.79(s,2H).

[0109] 13 C NMR(101MHz,CDCl3)δ168.44,141.68(2C),136.55(2C),134.49(2C),132.12(4C),128.59(2C),125.47(2C),124.15(2C),121.39(4C),117.29(2C),116.90(2C),82.18(2C),68.06(2C),57.58(2C),40.53(1C).

[0110] Example A6

[0111] Synthesis of bis(N-(1-naphthylcarbamoylmethyl)-3H-3,1-benzoxazinyl)methane

[0112]

[0113] Add N-(1-naphthyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.23 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask. Add 20 mL of dichloromethane, stir under the condition of a 25 °C water bath, and react for 18 h (monitored by TLC). After the reaction is completed, add saturated potassium carbonate solution and stir to quench the reaction. Then add 50 mL of dichloromethane. First, extract the organic phase with saturated sodium bisulfite solution (30 ml × 3) to remove the excess formaldehyde, and then wash it successively with distilled water (30 mL × 3) and saturated brine (30 ml × 2). Finally, dry the organic phase with anhydrous sodium sulfate. After concentration under reduced pressure, the residue is purified by column chromatography to obtain a white solid product with a yield of 84%; melting point (mp): 254.4 - 256.8 °C.

[0114] 1 H NMR (400 MHz, DMSO) δ 10.01 (s, 2H), 7.97 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 7.5 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 7.3 Hz, 2H), 7.55 - 7.45 (m, 6H), 6.98 (d, J = 8.1 Hz, 2H), 6.82 - 6.74 (m, 4H), 4.89 (s, 4H), 4.80 (s, 4H), 4.23 (s, 4H), 3.70 (s, 2H).

[0115] 13C NMR (101 MHz, DMSO) δ 169.90 (2C), 142.14 (2C), 134.14 (2C), 133.60 (2C), 132.35 (2C), 128.61 (2C), 128.04 (2C), 128.14 (2C), 126.51 (2C), 126.34 (2C), 126.00 (2C), 125.84 (2C), 125.29 (2C), 122.93 (2C), 122.65 (2C), 121.98 (2C), 113.91 (2C), 81.43 (2C), 67.83 (2C), 54.17 (2C), 40.53 (1C).

[0116] Example A7

[0117] Synthesis of bis-N-((benzamidomethyl)-3H-3,1-benzoxazinyl)methane

[0118]

[0119] Add N-phenethyl-2-[(2-hydroxymethylphenyl)amino]acetamide (1.08 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask, add 20 mL of dichloromethane, stir under the condition of 25 °C water bath, react for 18 h (monitored by TLC), after the reaction is completed, add saturated potassium carbonate solution to stir and quench the reaction, then add 50 mL of dichloromethane, first extract the organic phase with saturated sodium bisulfite solution (30 ml x 3) to remove the excessive formaldehyde, then wash with distilled water (30 mL x 3) and saturated brine (30 ml x 2) in turn, finally dry the organic phase with anhydrous sodium sulfate, after decompression evaporation, the residue is purified by column chromatography to obtain a white solid product, with a yield of 76%; melting point (mp): 213.8 - 215.8 °C.

[0120] 1 H NMR(400MHz,CDCl3)δ7.39(t,J=5.8Hz,2H),7.28 - 7.20(m,6H),7.18 - 7.12(m,4H),6.95(dd,J=8.3,1.6Hz,2H),6.68(d,J=4.6Hz,3H),6.66(s,1H),4.77(s,4H),4.64(s,4H),4.45(d,J=5.9Hz,4H),3.87(s,4H),3.77(s,2H).

[0121] 13 C NMR(101MHz,CDCl3)δ170.03(2C),141.68(2C),138.05(2C),133.89(2C),128.69(4C),128.31(2C),127.51(4C),127.47(2C),125.25(2C),123.75(2C),116.47(2C),81.97(2C),67.89(2C),56.77(2C),43.25(2C),40.44(C).

[0122] Example A8

[0123] Synthesis of bis(N-((4-chlorobenzylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane

[0124]

[0125] Add N-(4-chlorophenethyl)-2-[(2-hydroxymethylphenyl)amino]acetamide (1.22 g, 4 mmol), trifluoroacetic acid 0.456 (4 mmol), formaldehyde solution (37%) (0.584 g, 7.2 mmol) into a 100 mL round-bottom flask. Add 20 mL of dichloromethane, stir under the condition of 25 °C water bath, and react for 18 h (monitored by TLC). After the reaction is completed, add saturated potassium carbonate solution and stir to quench the reaction. Then add 50 mL of dichloromethane. First, extract the organic phase with saturated sodium bisulfite solution (30 ml x 3) to remove the excess formaldehyde, and then wash it successively with distilled water (30 mL x 3) and saturated brine (30 ml x 2). Finally, dry the organic phase with anhydrous sodium sulfate. After concentration under reduced pressure, the residue is purified by column chromatography to obtain a white solid product with a yield of 73%; melting point (mp): 196.6 - 199.5 °C.

[0126] 1 H NMR(400MHz,CDCl3)δ7.44(s,2H),7.17(d,J=7.2Hz,4H),7.00(dd,J=29.3,7.2Hz,6H),6.73-6.64(m,4H),4.79(s,4H),4.66(s,4H),4.40(d,J=4.3Hz,4H),3.89(s,4H),3.78(s,2H).

[0127] 13 C NMR(101MHz,CDCl3)δ170.11(2C),141.52(2C),136.72(2C),133.97(2C),133.20(2C),128.79(2C),128.90(2C),128.36(2C),125.33(2C),123.72(2C),116.34(2C)82.12(2C),67.99(2C),56.65(2C),42.57(2C),40.50(C).

[0128] Antibacterial activity test:

[0129] Using the in vitro method, antibacterial activity tests were carried out on bis(N-((4-methylphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane, bis(N-((3-methoxyphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane, bis(N-((2-methoxyphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane, bis(N-((4-fluorophenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane, bis(N-((4-bromophenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane, bis(N-(1-naphthylaminocarbonylmethyl)-3H-3,1-benzoxazinyl)methane, bisN-((benzylaminocarbonylmethyl)-3H-3,1-benzoxazinyl)methane, bis(N-((4-chlorobenzylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane.

[0130] Taking Gibberella zeae, Phytophthora capsici, Magnaporthe oryzae, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani as test materials for bactericidal activity tests, the test agents were dissolved in acetone and then diluted into a 500 g / mL liquid medicine with 200 g / mL sorpol-144 emulsifier. Under sterile operating conditions, 1 mL of the compound solution was pipetted into a sterilized petri dish, and then 9 mL of sterilized PDA culture medium was added to the petri dish with a pipette and mixed well to prepare a drug-containing plate with the corresponding concentration. The cultured pathogenic bacteria were cut into disks with a diameter of 4 mm from the edge of the colony with a sterilized punch under sterile conditions. After the culture medium solidified, the disks were inoculated in the center of the drug-containing plate with an inoculator and cultured in an incubator at an appropriate temperature. Using no agent as a blank control. Each treatment was cultured in an incubator at 24 ± 1 °C. After 72 hours, the colony diameter was observed and measured. The diameter of each colony was measured vertically once by the cross method, and the average value was taken.

[0131] Growth inhibition rate (%) = (control colony diameter - treatment colony diameter) × 100 / (control colony diameter - 4 mm).

[0132] The drug concentration was 50 μg / mL. The results of the antibacterial activity test are shown in Table 2.

[0133] Table 2 Results of antibacterial activity

[0134]

[0135] According to the data in Table 2, the target compounds showed broad-spectrum antibacterial activities against Gibberella zeae, Magnaporthe oryzae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani, and some compounds showed significant inhibitory effects on specific pathogens. Among them, the inhibition rate of bis(N-((4-fluorophenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane against Phytophthora infestans was up to 73.6%; the inhibition rate of bis(N-((4-bromoanilino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane against Sclerotinia sclerotiorum further increased to 66.3%; the inhibition rate of bis(N-(1-naphthylaminocarbonylmethyl))-3H-3,1-benzoxazinyl)methane against Phytophthora infestans reached 64.8%.

[0136] The above are only the preferred embodiments of the present invention, and do not impose any formal restrictions on the present invention. Although the present invention has been disclosed above with the preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art of this patent can make some changes or modifications to equivalent embodiments by using the technical content prompted above within the scope of the technical solution of the present invention. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention still fall within the scope of the present invention's solution.

Claims

1. A bis(N-acylamino-3,1-benzoxazinyl)methane compound, characterized in that, The compound has the general structural formula (IV), In formula (IV), R 1 is one of C1-C6 alkyl, halogen atom, methoxy, H or naphthyl; n is 0 or 1.

2. The bis(N-acylamino-3,1-benzoxazinyl)methane compound according to claim 1, wherein, R 1 is methyl, methoxy, fluorine atom, bromine atom, chlorine atom, H or naphthyl.

3. A bis(N-acylamino-3,1-benzoxazinyl)methane compound, characterized in that, The compound is selected from one or more of the following compounds: Bis(N-(4-methylphenylamino)carbonylmethyl)-3H-3,1-benzoxazinyl)methane Bis(N-((3-methoxyphenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane Bis(N-((2-methoxyphenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane Bis(N-((4-fluorophenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane Bis(N-((4-bromophenylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane Bis(N-(1-naphthylaminocarbonylmethyl))-3H-3,1-benzoxazinyl)methane BisN-(benzylaminocarbonylmethyl))-3H-3,1-benzoxazinyl)methane Bis(N-((4-chlorobenzylamino)carbonylmethyl))-3H-3,1-benzoxazinyl)methane 4. A method for preparing a bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV), characterized in that, The general structural formula (IV) is: The preparation method specifically includes the following steps: S1) Using the aromatic amine compound with the structural formula (I) and bromoacetyl bromide as raw materials, triethylamine as an acid-binding agent, and dichloromethane as a solvent, synthesize the N-aryl-2-bromoacetylaniline compound with the general structural formula (II) in an ice-water bath. S2) React the N-aryl-2-bromoacetylaniline compound with the general formula (II) and o-aminobenzyl alcohol under the action of potassium carbonate in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran to obtain the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound with the general structural formula (III). S3) React the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound with the general structural formula (III) and formaldehyde solution under the action of trifluoroacetic acid in dichloromethane to obtain the bis(N-acylamino-3,1-benzoxazinyl)methane compound with the general structural formula (IV). In formula (IV), R1 is one of C1-C6 alkyl, halogen atom, methoxy, H or naphthyl; n is 0 or 1.

5. The preparation method according to claim 4, characterized in that, R1 is methyl, methoxy, fluorine atom, bromine atom, chlorine atom, H or naphthyl; the aromatic amine compound is one of aniline, 4-methylaniline, 3-methoxyaniline, 2-methoxyaniline, 4-fluoroaniline, 4-bromoaniline, 1-naphthylaniline, 4-chloroaniline.

6. According to the preparation method described in claim 4, characterized in that Step S1) is specifically: Weigh the aromatic amine compound with the structural formula (I) and triethylamine, place them in a 500 mL round-bottom flask, add 250 mL of dichloromethane as a solvent, dissolve bromoacetyl bromide in 30 mL of dichloromethane and transfer it to a constant-pressure dropping funnel, slowly add it dropwise to the reaction system under the temperature control of an ice-water bath. After dropping, continuously stir for 30 min and monitor the reaction process by TLC. After the reaction is completed, obtain the solid crude product by reduced-pressure desolvation, and successively carry out suction filtration, recrystallization and vacuum drying treatment to obtain the purified N-aryl-2-bromoacetylaniline compound with the general structural formula (II). Step S2) Specifically: The N-aryl-2-bromoacetylaniline compound of structural formula (Ⅱ) obtained in Step S1, o-aminobenzyl alcohol, and potassium carbonate are jointly added to a 250 mL round-bottom flask, and a mixed solvent of THF and DMF is injected. The temperature is raised to 65 °C under stirring and refluxed for 3 h. After the reaction is completed, potassium carbonate is removed by suction filtration. The filter cake is washed with ethyl acetate. The combined filtrate is concentrated under reduced pressure, 30 mL of saturated NaCl solution is added, and extraction is carried out with ethyl acetate three times. The organic phase is washed with water twice and saturated NaCl solution twice in sequence, dried over anhydrous Na2SO4, concentrated, and subjected to column chromatography separation to obtain the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound of structural formula (Ⅲ); Step S3) Specifically: The N-aryl-2-(2-hydroxymethylphenyl)acetamide compound of structural formula (Ⅲ), trifluoroacetic acid, and 37% formaldehyde solution are added to a 100 mL round-bottom flask containing 20 mL of dichloromethane, and the reaction is stirred at a constant temperature of 25 °C for 18 h. After the reaction is terminated, saturated K2CO3 solution is added for neutralization. After liquid separation, the organic phase is washed three times with saturated NaHSO3 solution to remove residual formaldehyde, and then washed three times with distilled water and twice with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography to finally obtain the bis(N-acylamino-3,1-benzoxazinyl)methane compound of structural formula (Ⅳ).

7. The preparation method according to claim 6, wherein in Step S1), the preferred molar ratio of the arylamine compound of structural formula (Ⅰ), bromoacetyl bromide, and triethylamine is 1:0.5 - 0.7:1.1 - 1.3; in Step S2), the molar ratio of the N-aryl-2-bromoacetylaniline compound of structural formula (Ⅱ), o-aminobenzyl alcohol, and potassium carbonate is 1.15 - 1.25:1:1.5 - 1.9; in Step S3), the preferred molar ratio of the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound of structural formula (Ⅲ), trifluoroacetic acid, and formaldehyde is 1:1:1.7 - 1.

9.

8. The preparation method according to claim 6, wherein in Step S1), the preferred molar ratio of the arylamine compound of structural formula (Ⅰ), bromoacetyl bromide, and triethylamine is 1:0.6:1.2; in Step S2), the molar ratio of the N-aryl-2-bromoacetylaniline compound of structural formula (Ⅱ), o-aminobenzyl alcohol, and potassium carbonate is 1.2:1:1.7; in Step S3), the preferred molar ratio of the N-aryl-2-(2-hydroxymethylphenyl)acetamide compound of structural formula (Ⅲ), trifluoroacetic acid, and formaldehyde is 1:1:1.

8.

9. Use of the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV) as described in any one of claims 1-3 or the bis(N-acylamino-3,1-benzoxazinyl)methane compound having the structural general formula (IV) prepared by the method as described in any one of claims 4-8, characterized in that, For antibacterial of crops, or for preparing drugs for antibacterial of crops.

10. The use according to claim 9, characterized in that, For antibacterial of crops includes for inhibiting one or more of Sclerotinia sclerotiorum, Phytophthora infestans, Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea, Rhizoctonia solani; For preparing drugs for antibacterial of crops includes for preparing drugs for inhibiting one or more of Sclerotinia sclerotiorum, Phytophthora infestans, Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea, Rhizoctonia solani.

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