A 4-aryl (methyl)-1,4-benzoxazine imidazoline compound and its preparation method and use

Abstract

The invention discloses a 4-aryl (first) group-1,4-benzoxazine and imidazoline compounds and their preparation method and use. Such compounds are reacted with 3,4-dihydro-2H-1,4-benzoxazine and 1,2-dibromoethane as raw materials to generate N-(2-bromoethyl)-1,4-benzoxazine, and then reacted with aromatic amine compounds to generate corresponding N-(2-arylaminoethyl)-1,4-benzoxazine, and then further reacted under the action of a catalyst to obtain 4-aryl (first) group-1,4-benzoxazine and imidazoline compounds. The raw materials used for the synthesis of the compound are cheap and easy to obtain, and the synthesis method is simple. At the same time, the compound has a good inhibitory effect on the activity of crop pathogens, especially the inhibitory activity of fusarium head blight, rice blast, phytophthora, sclerotinia, gray mold and sheath blight is remarkable.

Description

Technical Field

[0001] The invention relates to a benzoxazine imidazoline compound, in particular to a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound with antibacterial activity and a preparation method and use thereof, belonging to the technical field of agricultural drugs. Background Art

[0002] Both benzoxazine compounds and imidazoline compounds have good biological activity and have become one of the hot spots in pesticide and drug research. For example, benzoxazine compounds have antibacterial, antitumor, antioxidant activities, etc., and can be used as anticancer drugs, protease inhibitors, etc. Imidazoline compounds have antifungal, antihypertensive, anti-inflammatory and other biological activities, and can also be used as depression, anticancer, antihypertensive and analgesic drugs. Therefore, the research on benzoxazine compounds and imidazoline compounds is very important and has received increasing attention. In 2014, Wasilewska et al. reported a series of substituted imidazoline derivatives and found that some of them had good antihypertensive effects and could be used as potential antihypertensive agents. In 2017, Rajitha Bollu et al. synthesized a series of substituted triazole 1,4-benzoxazinones, and tested the antibacterial activity against Gram-positive and Gram-negative strains using miconazole and ciprofloxacin as controls. It was found that most compounds had moderate to good activity against the detected pathogens. In 2019, Dai Ningning et al. synthesized a series of imidazoline compounds and found that some of them had good antibacterial activity. In 2021, Farooq et al. synthesized a series of 1-arylaminomethyl-2-phenylimidazoline derivatives and found that some of them had antioxidant activity. In 2019, Yan et al. studied and synthesized a series of 1,4-benzoxazinone compounds. Activity tests showed that some compounds were effective PI3K / mTOR dual inhibitors and could be used as anticancer drug candidates. In 2023, Zhang Peng et al. reported a series of 4H-3,1-benzoxazin-4-one derivatives. Experiments found that some compounds had a strong affinity with α-glucosidase and were significantly more active than the positive control acarbose.

[0003] However, these compounds as a whole still have deficiencies in the antibacterial effect on crops (the antibacterial effect is relatively low), and there is still great room for improvement. In addition, through research, it was found that there is no relevant literature in the prior art reporting the study of compounds combining benzoxazine rings with imidazoline rings and their antibacterial activity. Therefore, we designed and synthesized 4-aryl (methyl)-1,4-benzoxazin-imidazoline compounds containing both benzoxazine rings and imidazoline ring structures. And studied the inhibitory activity of these compounds against Fusarium head blight, Phytophthora, Rice blast, Sclerotinia, Botrytis cinerea or Sheath blight. Summary of the invention

[0004] In view of the disadvantage that the antibacterial effects of existing benzoxazine compounds and imidazoline compounds in the prior art are generally low, the present invention provides a 4-aryl (methyl)-1,4-benzoxazin-imidazoline compound, the synthetic material of which is cheap and easy to obtain, the synthetic method is simple, and the compound has good antibacterial activity against crop pathogens, especially against fusarium head blight, phytophthora, rice blast, sclerotinia, gray mold or sheath blight. At the same time, the present invention also provides a preparation method of the above-mentioned 4-aryl (methyl)-1,4-benzoxazin-imidazoline compound and its application of antibacterial activity.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is specifically described as follows:

[0006] According to a first embodiment of the present invention, a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound is provided:

[0007] A 4-aryl(methyl)-1,4-benzoxazine imidazoline compound, which is a compound having the following general structural formula (IV):

[0008]

[0009] In formula (IV), n is an integer of 0-12, and R is selected from one or more of H, alkyl, alkoxy, and halogen atoms.

[0010] Preferably, n is an integer of 0-6, and R is one or more of H, C1-C8 alkyl, C1-C8 alkoxy, and halogen atom.

[0011] Preferably, n is 0 or 1, wherein:

[0012] When n=0, R is one of H, C1-C4 alkyl, C1-C4 alkoxy, and chlorine atom, and preferably R is one of H, 2-CH3, 3-Cl, 4-CH3, 2-OCH3, 3-OCH3, 2-Cl, 3,4-(CH3)2, and 3-CH2CH3.

[0013] When n=1, the R is one of H, a C1-C2 alkyl group, and a chlorine atom, and preferably the R is one of H, 3-CH3, and 3-Cl.

[0014] Preferably, the 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is selected from one or more of the following compounds:

[0015] 4-Phenyl-1,4-benzoxazinimidazoline:

[0016]

[0017] 4-(2-Methylphenyl)-1,4-benzoxazinimidoline:

[0018]

[0019] 4-(3-Chlorophenyl)-1,4-benzoxazinimidoline:

[0020]

[0021] 4-(4-Methylphenyl)-1,4-benzoxazinimidoline:

[0022]

[0023] 4-(2-Methoxyphenyl)-1,4-benzoxazinimidazoline:

[0024]

[0025] 4-(3-Methoxyphenyl)-1,4-benzoxazinimidazoline:

[0026]

[0027] 4-(2-Chlorophenyl)-1,4-benzoxazinimidoline:

[0028]

[0029] 4-(3,4-Dimethylphenyl)-1,4-benzoxazinimidoline:

[0030]

[0031] 4-(3-Ethylphenyl)-1,4-benzoxazinimidoline:

[0032]

[0033] 4-Benzyl-1,4-benzoxazinimidazoline:

[0034]

[0035] 4-(3-Methylbenzyl)-1,4-benzoxazinimidazoline:

[0036]

[0037] 4-(3-Chlorobenzyl)-1,4-benzoxazinimidazoline:

[0038]

[0039] According to a second embodiment of the present invention, a method for preparing 4-aryl(methyl)-1,4-benzoxazine imidazoline compounds is provided:

[0040] A method for preparing a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound or a method for preparing the 4-aryl(methyl)-1,4-benzoxazine imidazoline compound described in the first embodiment, the method specifically comprising the following steps:

[0041] S1) reacting 3,4-dihydro-2H-1,4-benzoxazine having the structural formula (I) with 1,2-dibromoethane in the presence of a base in a first solvent to obtain N-(2-bromoethyl)-1,4-benzoxazine having the structural formula (II):

[0042]

[0043] S2) reacting N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II) with an aromatic amine compound having structural formula (V) in a second solvent in the presence of a base and a first catalyst to obtain an N-(2-arylaminoethyl)-1,4-benzoxazine compound having structural formula (III):

[0044]

[0045] S3) reacting an N-(2-arylaminoethyl)-1,4-benzoxazine compound having a general structural formula (III) in the presence of a second catalyst in a third solvent to obtain a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having a general structural formula (IV):

[0046]

[0047] Wherein: n is an integer of 0-12, and R is selected from one or more of H, alkyl, alkoxy, and halogen atoms. Preferably, n is an integer of 0-6, and R is one or more of H, C1-C8 alkyl, C1-C8 alkoxy, and halogen atoms.

[0048] Preferably, n is 0 or 1, wherein:

[0049] When n=0, R is one of H, C1-C4 alkyl, C1-C4 alkoxy, and chlorine atom, and preferably R is one of H, 2-CH3, 3-Cl, 4-CH3, 2-OCH3, 3-OCH3, 2-Cl, 3,4-(CH3)2, and 3-CH2CH3.

[0050] When n=1, the R is one of H, a C1-C2 alkyl group, and a chlorine atom, and preferably the R is one of H, 3-CH3, and 3-Cl.

[0051] Preferably, in step S1), the first solvent is an organic solvent, preferably N,N-dimethylformamide (DMF). The base is NaH.

[0052] Preferably, in step S2), the second solvent is an organic solvent, preferably acetonitrile. The base is one or two of Na2CO3, K2CO3 and, preferably K2CO3. The first catalyst is one or two of KI and NaI, preferably NaI.

[0053] Preferably, in step S3), the third solvent is an organic solvent, preferably N,N-dimethylformamide (DMF). The second catalyst is one or both of Cu(OAc)2 and Ag2CO3, preferably a mixture of Cu(OAc)2 and Ag2CO3.

[0054] Preferably, in step S1), the molar ratio of the 3,4-dihydro-2H-1,4-benzoxazine having the structural formula (I), 1,2-dibromoethane and the added base is 1:8-20:4-12, preferably 1:10-15:6-10.

[0055] Preferably, in step S2), the molar ratio of the N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II), the aromatic amine compound having structural formula (V), the base, and the first catalyst added is 1:1-3:1.5-4:0.8-2.5, preferably 1:1.1-2:1.8-3:1-2.

[0056] Preferably, in step S3), the molar ratio of the N-(2-arylaminoethyl)-1,4-benzoxazine compound having the general structural formula (III) to the second catalyst is 1:2.5-6, preferably 1:3-5.

[0057] Preferably, step S1) is specifically as follows: 3,4-dihydro-2H-1,4-benzoxazine having structural formula (I) and 1,2-dibromoethane are added to a reaction container in proportion, and then a base is slowly added under stirring in an ice-water bath, and then the first solvent is added, and after stirring evenly, the mixture is reacted in an oil bath (preferably the oil bath temperature is 90-110° C.) (preferably the reaction time is 8-24 h). After the reaction is completed, the mixture is cooled and a saturated sodium chloride solution is added, and then extracted with ethyl acetate (preferably the number of extractions is 1-5 times), and the obtained organic phase is washed with distilled water and a saturated sodium chloride solution (preferably the number of washings with distilled water and saturated sodium chloride is 1-4 times respectively), and after drying (preferably drying with anhydrous sodium sulfate), desolventizing and column chromatography separation and purification, N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II) is obtained.

[0058] Preferably, step S2) is specifically as follows: N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II) and the first catalyst are added to a reaction container in proportion, and then the second solvent is added to react (preferably a reflux reaction, the reaction temperature is 80-85°C, and the reaction time is 10-60min). After the reaction is completed, the reaction is cooled to room temperature, and then an aromatic amine compound having structural formula (V) and a base are added in proportion to react (preferably a stirring reaction, the reaction temperature is 85-110°C, and the reaction time is 10-36h). After the reaction is completed, the reaction is cooled to room temperature, filtered, and the filtrate is successively subjected to reduced pressure desolventizing and column chromatography separation and purification to obtain N-(2-arylaminoethyl)-1,4-benzoxazine compounds having structural formula (III).

[0059] Preferably, step S3) is specifically as follows: adding an N-(2-arylaminoethyl)-1,4-benzoxazine compound having a general structural formula (III) and a second catalyst to a reaction container in proportion, and then adding a third solvent to react (preferably a reflux reaction, a reaction temperature of 100-150° C., and a reaction time of 8-20 h). After the reaction is completed, filtering, extracting the filtrate with dichloromethane (preferably 1-3 times of extraction), washing the obtained organic phase with a saturated sodium chloride solution in turn (preferably 1-3 times of washing), drying (preferably using anhydrous sodium sulfate for drying), desolventizing under reduced pressure and separating and purifying by column chromatography to obtain a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having a general structural formula (IV).

[0060] According to a third embodiment of the present invention, there is provided a use of a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound:

[0061] A use of a 4-aryl (methyl)-1,4-benzoxazine imidazoline compound or a use of a 4-aryl (methyl)-1,4-benzoxazine imidazoline compound described in the first embodiment or a use of a 4-aryl (methyl)-1,4-benzoxazine imidazoline compound prepared by the method described in the second embodiment, wherein the 4-aryl (methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is used for inhibiting fungi in crops. Specifically, it is used to inhibit one or more of Fusarium head blight, Phytophthora, Rice blast, Sclerotinia, Botrytis cinerea and Sheath blight. Preferably, the 4-aryl (methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is used to inhibit Rice blast and / or Phytophthora.

[0062] Preferably, the 4-aryl (methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is used to prepare a drug for inhibiting fungi of crops, specifically for preparing a drug for inhibiting one or more pathogens selected from Gibberella, Phytophthora, Rice Blast, Sclerotinia, Botrytis and Sheath Blight. Preferably, the 4-aryl (methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is used to prepare a drug for inhibiting Rice Blast and / or Phytophthora.

[0063] In the present invention, in the prior art, many scholars have studied and reported the biological activities of benzoxazine compounds and imidazoline compounds, but the authors have found that the direct use of these compounds for crop antibacterial (for example, inhibition of the activity of pathogens such as fusarium head blight, phytophthora, rice blast, sclerotinia, gray mold, and sheath blight) is still insufficient, and the overall antibacterial effect is relatively low, which is not enough to achieve the ideal antibacterial and bactericidal effect. Therefore, the authors of the present invention, through targeted research and exploration, intend to design and synthesize 4-aryl (methyl)-1,4-benzoxazine imidazoline compounds containing benzoxazine rings and imidazoline ring structures according to the principle of active substructure splicing and the principle of drug efficacy superposition. The preparation method of the compound is simple, the raw materials are easily available, and the compound has good antibacterial activity against the activity of crop pathogens, especially against fusarium head blight, phytophthora, rice blast, sclerotinia, gray mold, or sheath blight. The activity inhibition effect is significant.

[0064] In the present invention, the 4-aryl (methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is prepared by the following method: first, 3,4-dihydro-2H-1,4-benzoxazine having the structural formula (I) and 1,2-dibromoethane are added to a reaction container (such as a reaction kettle or a reaction bottle), and a first solvent (such as anhydrous DMF) and a base (such as NaH) are added, and then reacted in an oil bath at 90-110° C. (such as 100° C.) for 8-24 h (such as 12 h) to generate N-(2-bromoethyl)-1,4-benzoxazine having the structural formula (II). The reaction process is as follows:

[0065]

[0066] Secondly, N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II), aromatic amine compounds having structural formula (V), a first catalyst (e.g., NaH) and a base (e.g., anhydrous potassium carbonate), and a second solvent (e.g., acetonitrile) are added to a reaction vessel (e.g., a reaction kettle or a reaction bottle) and reacted at a temperature of 85-110° C. (e.g., 90° C.) for 10-36 h (e.g., 24 h) to generate N-(2-arylaminoethyl)-1,4-benzoxazine compounds having structural formula (III). The reaction process is as follows:

[0067]

[0068] (wherein: n is an integer of 0-12, and R is selected from one or more of H, alkyl, alkoxy, and halogen atoms).

[0069] Finally, the N-(2-arylaminoethyl)-1,4-benzoxazine compound having the general structural formula (III), the second catalyst (e.g., Cu(OAc)2, Ag2CO3), and the third solvent (e.g., DMF) are added to a reaction vessel (e.g., a reaction kettle or a reaction bottle) and reacted at a temperature of 100-150° C. (e.g., 120° C.) for 8-20 h (e.g., 12 h) to generate a 4-aryl(methyl)-1,4-benzoxazin-imidazoline compound having the general structural formula (IV). The reaction process is as follows:

[0070]

[0071] In the present invention, as a preferred embodiment, the N-(2-arylaminoethyl)-1,4-benzoxazine compound having the general structural formula (III) is selected from N-(2-(anilino)ethyl)-1,4-benzoxazine, N-(2-(2-methylanilino)ethyl)-1,4-benzoxazine, N-(2-(3-chloroanilino)ethyl)-1,4-benzoxazine, N-(2-(4-methylanilino)ethyl)-1,4-benzoxazine, N-(2-(2-methoxyanilino)ethyl)-1,4-benzoxazine, N-( One or more of the group consisting of 2-(3-methoxyanilino)ethyl)-1,4-benzoxazine, N-(2-(2-chloroanilino)ethyl)-1,4-benzoxazine, N-(2-(3,4-dimethylanilino)ethyl)-1,4-benzoxazine, N-(2-(3-ethylanilino)ethyl)-1,4-benzoxazine, N-(2-(benzylamino)ethyl)-1,4-benzoxazine, N-(2-(3-methylbenzylamino)ethyl)-1,4-benzoxazine, and N-(2-(3-chlorobenzylamino)ethyl)-1,4-benzoxazine. These compounds are prepared by the following method: first, 3,4-dihydro-2H-1,4-benzoxazine is reacted with 1,2-dibromoethane to obtain N-(2-bromoethyl)-1,4-benzoxazine; then, N-(2-bromoethyl)-1,4-benzoxazine is reacted with different aromatic amine compounds (for example, one of aniline, 2-methylaniline, 3-chloroaniline, 4-methylaniline, 2-methoxyaniline, 3-methoxyaniline, 2-chloroaniline, 3,4-dimethylaniline, 3-ethylaniline, benzylamine, 3-methylbenzylamine, and 3-chlorobenzylamine) in an organic solvent to obtain the corresponding N-(2-arylaminoethyl)-1,4-benzoxazine compounds. Specifically, 3,4-dihydro-2H-1,4-benzoxazine and anhydrous DMF were stirred in an ice-water bath and NaH was slowly added. After a period of reaction, 1,2-dibromoethane was added, stirred evenly, and then transferred to an oil bath pot to continue the reaction. After the reaction was complete, the mixture was cooled and a saturated sodium chloride solution was added, and then extracted with ethyl acetate. The organic phase was washed with distilled water and a saturated sodium chloride solution for multiple times, and then dried with anhydrous sodium sulfate. After desolventizing under reduced pressure, it was separated and purified by rapid column chromatography to obtain N-(2-bromoethyl)-1,4-benzoxazine; N-(2-bromoethyl)-1,4-benzoxazine and NaI were placed in a three-necked round-bottom flask, acetonitrile was added as a solvent, refluxed and cooled to room temperature, and aromatic amine and anhydrous K2CO3 were added. The system was reacted under stirring conditions, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, and the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain the corresponding N-(2-arylaminoethyl)-1,4-benzoxazine compounds.

[0072] In the present invention, N-(2-arylaminoethyl)-1,4-benzoxazine compounds having a general structural formula (III) are reacted with catalysts Cu(OAc)2 and Ag2CO3 in the presence of an organic solvent (such as anhydrous DMF) to obtain a mixed product containing 4-aryl(methyl)-1,4-benzoxazine imidazoline compounds having a general structural formula (IV). The preparation method provided by the present invention has a simple process, a high yield, and the product is easy to separate and purify.

[0073] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0074] 1: The 4-aryl(methyl)-1,4-benzoxazinimidazoline compound having the general structural formula (IV) prepared by the present invention is a brand-new compound, and the compound has very good antibacterial activity on crops; in particular, it has a significant inhibitory effect on the activity of pathogens such as fusarium head blight, phytophthora, rice blast, sclerotinia, gray mold or sheath blight.

[0075] 2: In the preparation method of 4-aryl(methyl)-1,4-benzoxazine imidazoline compounds having the general structural formula (IV) provided by the present invention, the synthetic raw materials are cheap and readily available, the synthesis method is simple, the yield is high, and the product is easy to separate and purify. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 The diagram is a structural diagram of the 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) of the present invention.

[0077] Figure 2 The synthetic route diagram of the 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) of the present invention is shown. DETAILED DESCRIPTION

[0078] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0079] Preparation of N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II):

[0080]

[0081] Preparation Example 1

[0082] 3,4-dihydro-2H-1,4-benzoxazine (1.35 g, 0.01 mol) and 20 mL of anhydrous DMF were stirred in an ice-water bath and NaH (1.6 g, 0.06 mol) was slowly added. After 30 minutes, 10 mL of 1,2-dibromoethane was added. After stirring for 5 minutes, the mixture was transferred to an oil bath at 100°C for reaction for 12 hours. After the reaction was complete, a saturated sodium chloride solution was added after cooling, and then extracted with ethyl acetate three times. The organic phase was washed twice with distilled water (20 mL) and a saturated sodium chloride solution (20 mL), respectively, and then dried with anhydrous sodium sulfate. After desolventizing under reduced pressure, it was separated by rapid column chromatography to obtain N-(2-bromoethyl)-1,4-benzoxazine with the general structural formula (II).

[0083] Preparation of N-(2-arylaminoethyl)-1,4-benzoxazine compounds having the general structural formula (III):

[0084] Preparation Example 2

[0085] Preparation of N-(2-(anilino)ethyl)-1,4-benzoxazine:

[0086] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, and then aniline (0.307 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, and the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, and the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(anilino)ethyl)-1,4-benzoxazine.

[0087] Preparation Example 3

[0088] Preparation of N-(2-(2-methylanilino)ethyl)-1,4-benzoxazine:

[0089] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 2-methylaniline (0.353 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(2-methylanilino)ethyl)-1,4-benzoxazine.

[0090] Preparation Example 4

[0091] Preparation of N-(2-(3-chloroanilino)ethyl)-1,4-benzoxazine:

[0092] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 3-chloroaniline (0.419 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(3-chloroanilino)ethyl)-1,4-benzoxazine.

[0093] Preparation Example 5

[0094] Preparation of N-(2-(4-methylanilino)ethyl)-1,4-benzoxazine:

[0095] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 4-methylaniline (0.353 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(4-methylanilino)ethyl)-1,4-benzoxazine.

[0096] Preparation Example 6

[0097] Preparation of N-(2-(2-methoxyanilino)ethyl)-1,4-benzoxazine:

[0098] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 2-methoxyaniline (0.406 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(2-methoxyanilino)ethyl)-1,4-benzoxazine.

[0099] Preparation Example 7

[0100] Preparation of N-(2-(3-methoxyanilino)ethyl)-1,4-benzoxazine:

[0101] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 3-methoxyaniline (0.406 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(3-methoxyanilino)ethyl)-1,4-benzoxazine.

[0102] Preparation Example 8

[0103] Preparation of N-(2-(2-chloroanilino)ethyl)-1,4-benzoxazine:

[0104] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 2-chloroaniline (0.419 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(2-chloroanilino)ethyl)-1,4-benzoxazine.

[0105] Preparation Example 9

[0106] Preparation of N-(2-(3,4-dimethylanilino)ethyl)-1,4-benzoxazine:

[0107] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, 3,4-dimethylaniline (0.400 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90 ° C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(3,4-dimethylanilino)ethyl)-1,4-benzoxazine.

[0108] Preparation Example 10

[0109] Preparation of N-(2-(3-ethylanilino)ethyl)-1,4-benzoxazine:

[0110] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then 3-ethylaniline (0.400 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(3-ethylanilino)ethyl)-1,4-benzoxazine.

[0111] Preparation Example 11

[0112] Preparation of N-(2-(Benzylamino)ethyl)-1,4-benzoxazine:

[0113] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, then benzylamine (0.353 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(benzylamino)ethyl)-1,4-benzoxazine.

[0114] Preparation Example 12

[0115] Preparation of N-(2-(3-methylbenzylamino)ethyl)-1,4-benzoxazine:

[0116] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, 3-methylbenzylamine (0.400 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90°C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(3-methylbenzylamino)ethyl)-1,4-benzoxazine.

[0117] Preparation Example 13

[0118] Preparation of N-(2-(3-chlorobenzylamino)ethyl)-1,4-benzoxazine:

[0119] N-(2-bromoethyl)-1,4-benzoxazine (0.726 g, 3 mmol) and NaI (0.495 g, 3.3 mmol) were placed in a 100 mL three-necked round-bottom flask, 30 mL of acetonitrile was added as solvent, refluxed for 20 min and cooled to room temperature, 3-chlorobenzylamine (0.465 g, 3.3 mmol) and anhydrous K2CO3 (0.828 g, 6 mmol) were added, the system was stirred at 90 ° C for 24 h, and cooled to room temperature after the reaction was complete. The precipitate was filtered out, the filtrate was concentrated under reduced pressure and separated by column chromatography to finally obtain N-(2-(3-chlorobenzylamino)ethyl)-1,4-benzoxazine.

[0120] Synthesis of 4-aryl(methyl)-1,4-benzoxazine imidazoline compounds having the general structural formula (IV):

[0121] Example 1

[0122] Synthesis of 4-phenyl-1,4-benzoxazinimidazole:

[0123]

[0124] Weigh N-(2-(anilino)ethyl)-1,4-benzoxazine (1.2707 g, 5.0 mmol), Cu(OAc)2 (0.5989 g, 3 mmol), Ag2CO3 (4.1363 g, 15 mmol) into a 250 mL round-bottom flask, then add 20 mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12 h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain an organic phase, and wash the organic phase with a saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a yellow-brown solid, melting point (mp): yellow-brown solid melting point: 83.5-85.6, yield: 65.0%.

[0125] 1H NMR(500MHz, CDCl3)δ7.32(dd,J=8.8,7.3Hz,2H),7.01–6.94(m,3H),6.85(ttd, J=6.1,3.6,2.9,1.7Hz,2H),6.81–6.75(m,2H),4.72(dd,J=9.0,2.7Hz,1H),4.6 6(dd,J=10.5,2.7Hz,1H),4.02(ddd,J=8.5,6.1,2.0Hz,1H),3.73(ddd,J=7.6,6 .3,2.0Hz,1H),3.46(tdd,J=17.7,9.1,6.7Hz,2H),3.26(dd,J=10.5,8.9Hz,1H).

[0126] 13 C NMR(101MHz,Chloroform-d)δ146.77,145.09,134.08,129.60(2C),122.03,120.63,118.91,118.53,117.07,113.17(2C),70.56,64.07,50.17,47.08.

[0127] Example 2

[0128] Synthesis of 4-(2-methylphenyl)-1,4-benzoxazinimidazole:

[0129]

[0130] Weigh N-(2-(2-methylanilino)ethyl)-1,4-benzoxazine (1.3407g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a brown solid; melting point: 90.8-92.4; yield: 58.0%.

[0131] 1H NMR (500MHz, CDCl3) δ7.33–7.22(m,3H),7.12(td,J=7.4,1.4Hz,1H),7.02–6.93(m,2 H),6.82–6.71(m,2H),4.84(dd,J=8.6,3.4Hz,1H),4.31(dd,J=10.2,3.4Hz,1H),3.85 (ddd,J=8.3,6.5,3.0Hz,1H),3.64(ddd,J=9.3,6.6,3.0Hz,1H),3.53(td,J=8.1,6.6 Hz, 1H), 3.34 (dd, J=10.2, 8.6Hz, 1H), 3.20 (ddd, J=9.1, 8.1, 6.6Hz, 1H), 2.37 (s, 3H).

[0132] 13 C NMR (125MHz, CDCl3) δ146.26,143.68,134.87,134.75,131.47,127.07,124.79 ,122.37,120.88,118.07,116.48,114.33,72.13,66.55,51.81,48.62,18.43.

[0133] Example 3

[0134] Synthesis of 4-(3-chlorophenyl)-1,4-benzoxazinimidazole:

[0135]

[0136] Weigh N-(2-(3-chloroanilino)ethyl)-1,4-benzoxazine (1.4405 g, 5.0 mmol), Cu(OAc)2 (0.5989 g, 3 mmol), Ag2CO3 (4.1363 g, 15 mmol) into a 250 mL round-bottom flask, then add 20 mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12 h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain an organic phase, and wash the organic phase with a saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography to obtain a light yellow solid with a melting point of 114.3-115.7 and a yield of 57.8%.

[0137] 1H NMR(500MHz, CDCl3)δ7.20(t,J=8.1Hz,1H),7.01–6.93(m,3H),6.89–6.79(m,2H),6.73(s,1H),6.62(dd,J=8.4,2.4Hz,1H),4.69 (dd,J=9.0,2.7Hz,1H),4.58(dd,J=10.6,2.7Hz,1H),4.06–3.99(m,1H),3.71–3.65(m,1H),3.52–3.38(m,2H),3.30–3.22(m,1H).

[0138] 13 C NMR (125MHz, CDCl3) δ147.72,145.13,135.46,133.82,130.54,122.10,120 .97,119.19,118.39,117.15,113.13,111.21,70.44,63.56,50.23,46.92.

[0139] Example 4

[0140] Synthesis of 4-(4-methylphenyl)-1,4-benzoxazinimidazole:

[0141]

[0142] Weigh N-(2-(4-methylanilino)ethyl)-1,4-benzoxazine (1.3407g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a yellow-brown solid with a melting point of 112.8-114.9 and a yield of 68.0%.

[0143] 1H NMR(500MHz, CDCl3) δ7.09(d,J=8.1Hz,2H),6.97–6.91(m,3H),6.83–6.78(m,1H),6.67(d,J=8.5Hz,2H),4.63(dd,J =16.3,9.6Hz,2H),3.97(t,J=6.9Hz,1H),3.69(t,J=6.9Hz,1H),3.46–3.34(m,2H),3.26–3.18(m,1H),2.28(s,3H).

[0144] 13 C NMR(125MHz, CDCl3)δ144.95,144.69,134.13,130.05(2C),127.86,122.00 ,120.36,118.55,116.98,113.36(2C),70.75,64.40,49.98,47.45,20.44.

[0145] Example 5

[0146] Synthesis of 4-(2-methoxyphenyl)-1,4-benzoxazinimidazole:

[0147]

[0148] Weigh N-(2-(2-methoxyanilino)ethyl)-1,4-benzoxazine (1.4207g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, desolventize under reduced pressure, separate by column chromatography, and finally obtain a yellow-brown oil; yield: 53.2%.

[0149] 1 H NMR (500MHz, CDCl3) δ7.07–7.00(m,2H),6.98–6.85(m,4H),6.79–6.68(m,2H),4.93(dd,J=8.6,3.2Hz,1H),4.44(dd,J=1 0.1,3.1Hz,1H),4.05–3.92(m,1H),3.89(s,3H),3.80(dtd,J=8.6,4.1,2.5Hz,1H),3.59–3.48(m,1H),3.36–3.23(m,2H).

[0150] 13 C NMR (125MHz, CDCl3) δ152.25,143.75,136.27,134.44,123.07,122.23,121.32,11 8.44,118.20,116.37,114.77,112.05,77.44,70.32,65.86,55.61,49.19,48.30.

[0151] Example 6

[0152] Synthesis of 4-(3-methoxyphenyl)-1,4-benzoxazinimidazole:

[0153]

[0154] Weigh N-(2-(3-methoxyanilino)ethyl)-1,4-benzoxazine (1.4207g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a yellow-brown solid; melting point: 80.6-84.3; yield: 52.4%.

[0155] 1 H NMR (500MHz, CDCl3) δ7.05–7.01(m,2H),6.98–6.90(m,4H),6.78–6.70(m,2H),4.93(dd,J=8.6,3.2Hz,1H),4.46(dd,J=10.2, 3.2Hz, 1H), 3.98 (ddd, J=9.1, 6.9, 4.1Hz, 1H), 3.89 (s, 3H), 3.83–3.76 (m, 2H), 3.55 (dt, J=8.5, 7.1Hz, 1H), 3.36–3.26 (m, 2H).

[0156] 13 C NMR (125MHz, CDCl3) δ152.24,143.74,136.26,134.43,123.07,122.24,121.31 ,118.43,118.19,116.37,114.77,112.04,70.31,65.86,55.62,49.19,48.30.

[0157] Example 7

[0158] Synthesis of 4-(2-chlorophenyl)-1,4-benzoxazinimidazole:

[0159]

[0160] Weigh N-(2-(2-chloroanilino)ethyl)-1,4-benzoxazine (1.4405g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, desolventize under reduced pressure, and separate by column chromatography to finally obtain a brown oily substance; yield: 44.0%.

[0161] 1 H NMR (500MHz, CDCl3) δ7.32(dd,J=8.7,7.3Hz,2H),6.99–6.96(m,2H),6.87(tdd,J=5.9,4.4,2.4Hz,2H),6.80–6.76(m,2H),4.72(dd,J=8.9,2.7Hz,1H ),4.65(dd,J=10.5,2.7Hz,1H),4.02(ddd,J=8.5,6.1,2.0Hz,1H),3.75(dd d,J=7.7,6.3,2.1Hz,1H),3.54–3.39(m,2H),3.28(dd,J=10.5,9.0Hz,1H).

[0162] 13 C NMR (125MHz, CDCl3) δ146.77,145.09,134.08,129.60(2C),122.03,120.64,118.92,118.53,117.07,113.17(2C),70.56,64.07,50.17,47.08.

[0163] Example 8

[0164] Synthesis of 4-(3,4-dimethylphenyl)-1,4-benzoxazinimidazole:

[0165]

[0166] Weigh N-(2-(3,4-dimethylanilino)ethyl)-1,4-benzoxazine (1.4108 g, 5.0 mmol), Cu(OAc)2 (0.5989 g, 3 mmol), Ag2CO3 (4.1363 g, 15 mmol) into a 250 mL round-bottom flask, then add 20 mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12 h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with a saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography to obtain a yellow-brown solid with a melting point of 121.4-122.8 and a yield of 66.4%.

[0167] 1 H NMR(500MHz, CDCl3)δ7.08(d,J=8.2Hz,1H),7.02–6.93(m,3H),6.88–6.80(m,1H),6.64–6.52(m,2H),4.72–4.63( m,2H),4.05–3.96(m,1H),3.73(d,J=6.0Hz,1H),3.50–3.38(m,2H),3.31–3.21(m,1H),2.29(s,3H),2.22(s,3H).

[0168] 13 C NMR (125MHz, CDCl3) δ145.16,144.98,137.71,134.23,130.61,126.78,122.04,12 0.29,118.44,116.98,115.03,110.95,70.72,64.58,49.94,47.53,20.37,18.79.

[0169] Example 9

[0170] Synthesis of 4-(3-ethylphenyl)-1,4-benzoxazinimidazole:

[0171]

[0172] Weigh N-(2-(3-ethylanilino)ethyl)-1,4-benzoxazine (1.4108 g, 5.0 mmol), Cu(OAc)2 (0.5989 g, 3 mmol), Ag2CO3 (4.1363 g, 15 mmol) into a 250 mL round-bottom flask, then add 20 mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12 h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with a saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a yellow-brown solid; melting point: 105.3-108.8; melting point: 66.7%.

[0173] 1 H NMR (500MHz, CDCl3) δ7.21 (dd, J=9.0, 7.2Hz, 1H), 6.98–6.92 (m, 3H), 6.84 (ddd, J=8.3, 5.7, 3.3 Hz,1H),6.70(d,J=7.5Hz,1H),6.59(d,J=6.8Hz,2H),4.70(dd,J=9.0,2.7Hz,1H),4.64(dd,J=10 .5,2.7Hz,1H),4.01(ddd,J=8.5,6.5,2.0Hz,1H),3.72(td,J=6.4,3.1Hz,1H),3.50–3.44(m,1H ),3.43–3.37(m,1H),3.25(dd,J=10.5,9.0Hz,1H),2.63(q,J=7.6Hz,2H),1.26(d,J=7.5Hz,3H).

[0174] 13 C NMR (125MHz, CDCl3) δ146.87,145.88,145.05,134.15,129.54,122.04,120.53,11 8.81,118.24,117.03,112.83,110.66,70.54,64.22,50.10,47.15,29.40,15.87.

[0175] Example 10

[0176] Synthesis of 4-benzyl-1,4-benzoxazinimidazole:

[0177]

[0178] Weigh N-(2-(Benzylamino)ethyl)-1,4-benzoxazine (1.3407g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a brown solid; melting point: 73.3-75.1; yield: 40.0%.

[0179] 1 H NMR (500MHz, CDCl3) δ7.40–7.27(m,5H),6.94–6.85(m,2H),6.66(t,J=7.5Hz,2H),4.01(dd,J=10.0,3.5Hz,1H),3.94(dd,J=8.6 ,3.5Hz,1H),3.80(q,J=12.9Hz,2H),3.69(t,J=6.9Hz,1H),3.31–3.23(m,2H),3.18(dd,J=10.0,8.6Hz,1H),2.82–2.72(m,1H).

[0180] 13 C NMR (125MHz, CDCl3) δ143.37,138.35,134.49,128.95(2C),128.63(2C),12 7.71,122.37,117.51,116.24,113.37,74.74,67.42,58.66,52.26,47.47.

[0181] Embodiment 11

[0182] Synthesis of 4-(3-methylbenzyl)-1,4-benzoxazinimidazole:

[0183]

[0184] Weigh N-(2-(3-methylbenzylamino)ethyl)-1,4-benzoxazine (1.4108g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a brown solid; melting point: 69.6-71.8; yield: 47.1%.

[0185] 1 H NMR (500MHz, CDCl3) δ7.29–7.22(m,1H),7.18(dd,J=23.7,6.7Hz,3H),6.97–6.87(m,2H),6.68(t,J=7.6Hz,2H),4.03(dd,J=10.1,3.4 Hz,1H),3.95(dd,J=8.7,3.5Hz,1H),3.85–3.66(m,3H),3.35–3.26(m,2H),3.22–3.15(m,1H),2.79(h,J=6.6,5.9Hz,1H),2.39(s,3H).

[0186] 13 C NMR (125MHz, CDCl3) δ143.37,138.29,138.25,134.52,129.68,128.51,128.45,12 6.03,122.37,117.48,116.23,113.32,74.77,67.47,58.68,52.31,47.44,21.53.

[0187] Example 12

[0188] Synthesis of 4-(3-chlorobenzyl)-1,4-benzoxazinimidazole:

[0189]

[0190] Weigh N-(2-(3-chlorobenzylamino)ethyl)-1,4-benzoxazine (1.5106g, 5.0mmol), Cu(OAc)2 (0.5989g, 3mmol), Ag2CO3 (4.1363g, 15mmol) into a 250mL round-bottom flask, then add 20mL of DMF as solvent, and heat to reflux in an oil bath at 120°C for 12h (TLC plate tracking monitoring). After the reaction is complete, filter, extract (extract with dichloromethane to obtain the organic phase, and wash the organic phase with saturated sodium chloride solution), dry with sodium sulfate, desolventize under reduced pressure, and separate by column chromatography after desolventizing under reduced pressure to obtain a white solid; melting point: 61.4-63.5; yield: 54.6%.

[0191] 1 H NMR (500MHz, CDCl3) δ7.40(s,1H),7.34–7.24(m,3H),6.93(ddd,J=16.1,8.0,1.4Hz,2H),6.69(tt,J=7.9,1.5Hz,2H),4.08(dd,J=10. 1,3.5Hz,1H),3.96(dd,J=8.7,3.5Hz,1H),3.86(d,J=13.2Hz,1H),3.73(dd,J=13.6,5.5Hz,2H),3.34–3.17(m,3H),2.82–2.71(m,1H).

[0192] 13 C NMR (125MHz, CDCl3) δ143.35,140.57,134.53,134.40,129.89,128.87,127.87 ,126.91,122.45,117.68,116.31,113.49,74.72,67.34,57.96,52.16,47.55.

[0193] The sources or structural formulas of the chemical reagents used in various embodiments of the present invention are as follows:

[0194]

[0195]

[0196]

[0197]

[0198] Active effect test

[0199] The in vitro method was used to characterize 4-phenyl-1,4-benzoxazine imidazoline, 4-(2-methylphenyl)-1,4-benzoxazine imidazoline, 4-(3-chlorophenyl)-1,4-benzoxazine imidazoline, 4-(4-methylphenyl)-1,4-benzoxazine imidazoline, 4-(2-methoxyphenyl)-1,4-benzoxazine imidazoline, 4-(3-methoxyphenyl)-1,4-benzoxazine imidazoline, 4 -(2-chlorophenyl)-1,4-benzoxazine imidazoline, 4-(3,4-dimethylphenyl)-1,4-benzoxazine imidazoline, 4-(3-ethylphenyl)-1,4-benzoxazine imidazoline, 4-benzyl-1,4-benzoxazine imidazoline, 4-(3-methylbenzyl)-1,4-benzoxazine imidazoline, and 4-(3-chlorobenzyl)-1,4-benzoxazine imidazoline were tested for fungicidal activity.

[0200] Fusarium head blight, Phytophthora, Magnaporthe oryzae, Sclerotinia sclerotiorum, Botrytis cinerea or Sheath blight were used as the test materials for the fungicidal activity test. The test agent was dissolved in acetone and then diluted to 500 g / mL with 200 g / mL sorporl-144 emulsifier. Under aseptic operating conditions, 1 mL of the compound solution was pipetted into a sterilized plate with a pipette, and then 9 mL of sterilized PDA culture medium was added to the plate with a pipette, mixed, and a drug-containing plate of the corresponding concentration was prepared. The cultured pathogens were cut from the edge of the colony with a sterile puncher with a diameter of 4 mm under aseptic conditions. After the culture medium solidified, the bacterial cake was inoculated in the center of the drug-containing plate with an inoculator and placed in an incubator at a suitable temperature for culture. A blank control was used without adding the agent. 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 using the cross method and the average value was taken.

[0201] Growth inhibition rate (%) = (control colony diameter - treated colony diameter) × 100 / (control colony diameter - 4 mm).

[0202] The drug concentration is 50 μg / mL. The bactericidal activity test results are shown in Table 1 below.

[0203] Table 1 Antibacterial activity results of 4-aryl (methyl)-1,4-benzoxazine imidazoline compounds (inhibition rate / %)

[0204]

[0205] As shown in Table 1, the target compounds have moderate to good inhibitory activity against the tested pathogens. Among them, the inhibition rate of 4-(4-methylphenyl)-1,4-benzoxazinimidazoline against rice blast fungus is as high as 93.9%, and the inhibition rate of 4-benzyl-1,4-benzoxazinimidazoline is as high as 91.8%; the inhibition rate of 4-(2-methylphenyl)-1,4-benzoxazinimidazoline against Phytophthora is as high as 90.3%, and the inhibition rate of 4-(3,4-dimethylphenyl)-1,4-benzoxazinimidazoline is as high as 83. .8%, the inhibition rate of 4-(3-chlorophenyl)-1,4-benzoxazine imidazoline was 78.9%, the inhibition rate of 4-(4-methylphenyl)-1,4-benzoxazine imidazoline was 77.4%, the inhibition rate of 4-(3-methoxyphenyl)-1,4-benzoxazine imidazoline was 76.7%, the inhibition rate of 4-(3-ethylphenyl)-1,4-benzoxazine imidazoline was 70.0%; 4-phenyl-1, The inhibition rate of 4-benzoxazine imidazoline against Sclerotinia sclerotiorum was as high as 81.4%, and the inhibition rate of 4-(2-methoxyphenyl)-1,4-benzoxazine imidazoline was 77.9%; the inhibition rate of 4-phenyl-1,4-benzoxazine imidazoline against Botrytis cinerea was as high as 82.4%, and the inhibition rate of 4-(2-methoxyphenyl)-1,4-benzoxazine imidazoline was 71.8%, and the inhibition rate of 4-(2-chlorophenyl)-1,4-phenyl The inhibition rate of benzoxazine imidazoline was 75.8%, the inhibition rate of 4-(3-ethylphenyl)-1,4-benzoxazine imidazoline was 78.4%, the inhibition rate of 4-benzyl-1,4-benzoxazine imidazoline was 74.5%, the inhibition rate of 4-(3-methylbenzyl)-1,4-benzoxazine imidazoline was 70.5%, and the inhibition rate of 4-(3-chlorobenzyl)-1,4-benzoxazine imidazoline was 75.8%.

Claims

1. A 4-aryl(methyl)-1,4-benzoxazine imidazoline compound, characterized in that: The compound is a compound having the general structural formula (IV) shown below: In formula (IV), n is an integer of 0-6, and R is selected from one of H, C1-C8 alkyl, C1-C8 alkoxy, and halogen atom.

2. The compound according to claim 1, characterized in that: n is 0 or 1, where: When n=0, R is one of H, C1-C4 alkyl, C1-C4 alkoxy, and chlorine atom; When n=1, R is one of H, a C1-C2 alkyl group and a chlorine atom.

3. The compound according to claim 1 or 2, characterized in that: When n=0, R is one of H, 2-CH3, 3-Cl, 4-CH3, 2-OCH3, 3-OCH3, 2-Cl, and 3-CH2CH3; When n=1, the R is one of H, 3-CH3, and 3-Cl.

4. A 4-aryl(methyl)-1,4-benzoxazine imidazoline compound, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compound is selected from the following compounds: 4-Phenyl-1,4-benzoxazinimidazoline: 4-(2-Methylphenyl)-1,4-benzoxazinimidoline: 4-(3-Chlorophenyl)-1,4-benzoxazinimidoline: 4-(4-Methylphenyl)-1,4-benzoxazinimidoline: 4-(2-Methoxyphenyl)-1,4-benzoxazinimidazoline: 4-(3-Methoxyphenyl)-1,4-benzoxazinimidazoline: 4-(2-Chlorophenyl)-1,4-benzoxazinimidoline: 4-(3,4-Dimethylphenyl)-1,4-benzoxazinimidoline: 4-(3-Ethylphenyl)-1,4-benzoxazinimidoline: 4-Benzyl-1,4-benzoxazinimidazoline: 4-(3-Methylbenzyl)-1,4-benzoxazinimidazoline: 4-(3-Chlorobenzyl)-1,4-benzoxazinimidazoline:

5. A method for preparing a 4-aryl(methyl)-1,4-benzoxazinimidazoline compound having the general structural formula (IV) as claimed in any one of claims 1 to 3, characterized in that: The method comprises the following steps: S1) reacting 3,4-dihydro-2H-1,4-benzoxazine having the structural formula (I) with 1,2-dibromoethane in the presence of a base in a first solvent to obtain N-(2-bromoethyl)-1,4-benzoxazine having the structural formula (II): S2) reacting N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II) with an aromatic amine compound having structural formula (V) in a second solvent in the presence of a base and a first catalyst to obtain an N-(2-arylaminoethyl)-1,4-benzoxazine compound having structural formula (III): S3) reacting an N-(2-arylaminoethyl)-1,4-benzoxazine compound having a general structural formula (III) in the presence of a second catalyst in a third solvent to obtain a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having a general structural formula (IV):

6. The method according to claim 5, characterized in that: In step S1): the first solvent is an organic solvent; the base is NaH; and / or In step S2), the second solvent is an organic solvent; the base is one or both of Na2CO3 and K2CO3; the first catalyst is one or both of KI and NaI; and / or In step S3), the third solvent is an organic solvent; the second catalyst is one or both of Cu(OAc)2 and Ag2CO3.

7. The method according to claim 6, characterized in that: In step S1): the first solvent is N,N-dimethylformamide; and / or In step S2): the second solvent is acetonitrile; the base is K2CO3; the first catalyst is NaI; and / or In step S3), the third solvent is N,N-dimethylformamide; the second catalyst is a mixture of Cu(OAc)2 and Ag2CO3.

8. The method according to any one of claims 5 to 7, characterized in that: In step S1), the molar ratio of the 3,4-dihydro-2H-1,4-benzoxazine having the structural formula (I), 1,2-dibromoethane and the base added is 1:8-20:4-12; and / or In step S2), the molar ratio of the N-(2-bromoethyl)-1,4-benzoxazine having the structural formula (II), the aromatic amine compound having the structural formula (V), the base, and the first catalyst is 1:1-3:1.5-4:0.8-2.5; and / or In step S3), the molar ratio of the N-(2-arylaminoethyl)-1,4-benzoxazine compound having the general structural formula (III) to the second catalyst is 1:2.5-6.

9. The method according to claim 8, characterized in that: In step S1), the molar ratio of the 3,4-dihydro-2H-1,4-benzoxazine of formula (I), 1,2-dibromoethane and the base added is 1:10-15:6-10; and / or In step S2), the molar ratio of the N-(2-bromoethyl)-1,4-benzoxazine having the structural formula (II), the aromatic amine compound having the structural formula (V), the base, and the first catalyst is 1:1.1-2:1.8-3:1-2; and / or In step S3), the molar ratio of the N-(2-arylaminoethyl)-1,4-benzoxazine compound having the general structural formula (III) to the second catalyst is 1:3-5.

10. The method according to claim 8, characterized in that: Step S1) is: adding 3,4-dihydro-2H-1,4-benzoxazine having structural formula (I) and 1,2-dibromoethane to a reaction container in proportion, then slowly adding a base under stirring in an ice-water bath, then adding a first solvent, stirring evenly, reacting in an oil bath, cooling after the reaction is completed, adding a saturated sodium chloride solution, then extracting with ethyl acetate, washing the obtained organic phase with distilled water and a saturated sodium chloride solution, respectively, drying, desolventizing under reduced pressure and separating and purifying by column chromatography to obtain N-(2-bromoethyl)-1,4-benzoxazine having structural formula (II); and / or Step S2) is: adding N-(2-bromoethyl)-1,4-benzoxazine having a structural formula (II) and a first catalyst to a reaction container in proportion, then adding a second solvent to react, cooling to room temperature after the reaction is completed, then adding an aromatic amine compound having a structural formula (V) and a base in proportion to react, cooling to room temperature after the reaction is completed, filtering, and successively performing vacuum desolventizing and column chromatography separation and purification on the filtrate to obtain an N-(2-arylaminoethyl)-1,4-benzoxazine compound having a structural formula (III); and / or Step S3) is: adding an N-(2-arylaminoethyl)-1,4-benzoxazine compound having a general structural formula (III) and a second catalyst into a reaction container in proportion, and then adding a third solvent to react. After the reaction is completed, filtering, extracting the filtrate with dichloromethane, and washing the obtained organic phase with a saturated sodium chloride solution in turn, drying, desolventizing and column chromatography separation and purification to obtain a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having a general structural formula (IV).

11. A use of a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) as claimed in any one of claims 1 to 3 or a 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) prepared by the method according to any one of claims 5 to 10, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is used to inhibit one or more of Fusarium head blight, Phytophthora spp., Rice blast, Sclerotinia sclerotiorum, Botrytis cinerea and Sheath blight.

12. The use according to claim 11, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compound having the general structural formula (IV) is used to inhibit rice blast fungus and / or phytophthora fungus.

13. A use of a 4-aryl(methyl)-1,4-benzoxazinimidazoline compound having the general structural formula (IV) as claimed in any one of claims 1 to 3 or a 4-aryl(methyl)-1,4-benzoxazinimidazoline compound having the general structural formula (IV) prepared by the method according to any one of claims 5 to 10, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compound with the general structural formula (IV) is used to prepare a drug for inhibiting one or more pathogens selected from the group consisting of fusarium head blight, phytophthora, rice blast, sclerotinia, gray mold and sheath blight.

14. The use according to claim 13, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compound with the general structural formula (IV) is used to prepare a drug for inhibiting rice blast fungus and / or phytophthora.

15. A use of the 4-aryl(methyl)-1,4-benzoxazinimidazoline compound as claimed in claim 4, characterized in that: The 4-aryl(methyl)-1,4-benzoxazinimidazoline compound is used to inhibit one or more of fusarium head blight, phytophthora, rice blast, sclerotinia, gray mold and sheath blight.

16. The use according to claim 15, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compound is used to inhibit rice blast fungus and / or phytophthora oryzae fungus.

17. A use of the 4-aryl(methyl)-1,4-benzoxazinimidazoline compound as claimed in claim 4, characterized in that: The 4-aryl(methyl)-1,4-benzoxazinimidazoline compounds are used to prepare drugs for inhibiting one or more pathogens selected from Fusarium fusiformis, Phytophthora spp., Rice blast, Sclerotinia sclerotiorum, Botrytis cinerea and Sheath blight.

18. The use according to claim 17, characterized in that: The 4-aryl(methyl)-1,4-benzoxazine imidazoline compounds are used to prepare drugs for inhibiting rice blast fungus and / or phytophthora.

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