A benzoxazine spiro compound, and a preparation method and application thereof

Abstract

The application provides a benzoxazine spiro compound and a preparation method and application thereof, and belongs to the technical field of chemical synthesis. 1 H or CH3; R2 is H or t-Bu.The 2-isocyano phenoxy diene, 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy) benzene and 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy) benzene provided by the application are subjected to three-component tandem cyclization reaction with o-phenylphenol and acetone respectively, the reaction sites of isonitrile and phenol and acetone are combined, and the spiro derivative can be efficiently synthesized, thereby providing a new idea for new drug research and development and natural product research.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, and particularly relates to a benzoxazine spirocyclic compound, its preparation method, and its application. Background Technology

[0002] Isonitriles contain a relatively stable divalent carbon structure, where the carbon atom exhibits both nucleophilic and electrophilic properties; it functions as both a carbene and a free radical acceptor. Therefore, isonitriles are perhaps one of the most unique and diverse functional groups in chemical reactions. For a long time, the chemical reactions involving isonitriles have been best known for multicomponent reactions such as Ugi and Passerini reactions. With in-depth research, isonitrile compounds have been widely used in many synthetic reactions, including natural product synthesis, asymmetric catalysis, and the synthesis of nitrogen-containing heterocycles. Simultaneously, these compounds have also been used as precursors for heterocyclic compounds in many fields, including pharmaceuticals, pesticides, and chemical dyes.

[0003] As one-carbon synthons, conventional isonitriles often do not involve the nitrogen atom in their isocyanate group in heterocycle construction during many reactions. Therefore, conventional isonitrile chemistry is insufficient for constructing more complex nitrogen-containing heterocycles. However, with in-depth research into isonitrile chemistry, chemists have discovered that introducing highly reactive functional groups at the ortho position of the isocyanate group can not only increase the overall reactivity of the functionalized isonitriles but also allow the nitrogen atom and the functional group to participate in the construction of multi-component heterocycles. This leads to novel transformations that deviate from traditional reaction pathways, resulting in more complex heterocyclic or fused-ring compounds.

[0004] Spirocyclic compounds are a very important class of heterocyclic compounds. Because the carbon atoms in the spirocycle fix the conformation of the compound, they possess strong rigidity, which can reduce drug resistance and enhance metabolic stability, leading to their wide application in insecticides, antibacterial agents, antivirals, anticancer agents, anti-inflammatory agents, and plant growth regulators. Therefore, spirocyclic compounds hold an important position in the fields of biomedicine and chemical synthesis, and the efficient synthesis of spirocyclic compounds has become one of the important tasks in organic synthesis. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a benzoxazine spirocyclic compound, its preparation method and application. This invention provides a novel approach for the synthesis of spirocyclic compounds by a three-component tandem cyclization reaction of functionalized isonitriles, phenol and acetone under certain conditions.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a benzoxazine spirocyclic compound, represented by the following general formula (1):

[0008]

[0009] Among them, R 1 R2 is H or CH3; R2 is H or t-Bu.

[0010] Preferably, the benzoxazine spirocyclic compound is selected from the following compounds:

[0011]

[0012] This invention also provides a method for preparing the above-mentioned benzoxazine spirocyclic compounds, selected from the following synthetic routes:

[0013]

[0014]

[0015] The specific synthesis steps are as follows:

[0016] 1) React any one of compounds VI, VII and VIII with o-phenylphenol, cesium carbonate and acetone solution. After the reaction is complete, a reaction solution is obtained.

[0017] 2) The reaction solution obtained in step 1) is filtered, dried and separated to obtain the organic phase;

[0018] 3) Concentrate and purify the organic phase obtained in step 2) to obtain any one of the target products I, II and III.

[0019] Preferably, the synthetic route of compound VI is as follows:

[0020]

[0021] Preferably, the synthetic route for compound VII is as follows:

[0022]

[0023]

[0024] Preferably, the synthetic route for compound VIII is as follows:

[0025]

[0026] Preferably, the specific synthesis steps of compound VI are as follows:

[0027] 1) After dissolving o-hydroxybenzamide, react it with potassium carbonate and 3-bromopropyne. After the reaction is complete, filter and purify the reaction solution to obtain the product o-oxypropynebenzamide IV.

[0028] 2) Dissolve compound IV from step 1) in dichloromethane and react it with Et3N and POCl3. After the reaction is complete, quench the reaction solution, then extract, dry and separate. Concentrate the obtained organic phase and purify it to obtain the target product 2-isocyanophenoxypropyne V.

[0029] 3) Dissolve compound V from step 2) in THF and react with potassium tert-butoxide. After the reaction is complete, filter the reaction solution, concentrate the resulting organic phase and separate and purify it to obtain the target product 2-isocyanophenoxyalene VI.

[0030] Preferably, the specific synthesis steps of compound VII are as follows:

[0031] 1) N-(2-hydroxy-4-methylphenyl)formamide was dissolved and reacted with potassium carbonate and 3-bromopropyne. After the reaction was completed, the reaction solution was filtered, purified and separated to obtain the product N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide.

[0032] 2) The compound N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide described in step 1) is dissolved in dichloromethane and reacted with Et3N and POCl3. After the reaction is completed, the reaction solution is quenched, then extracted, dried and separated. The obtained organic phase is concentrated and purified to obtain the target product 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene.

[0033] 3) The compound 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene described in step 2) was dissolved in THF and reacted with potassium tert-butoxide. After the reaction was completed, the reaction solution was filtered, and the resulting organic phase was concentrated and purified to obtain the target product 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy)benzene VII.

[0034] Preferably, the specific synthesis steps of compound VIII are as follows:

[0035] 1) N-(5-(tert-butyl)-2-hydroxyphenyl)formamide was dissolved and reacted with potassium carbonate and 3-bromopropyne. After the reaction was completed, the reaction solution was filtered, purified and separated to obtain the product N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide.

[0036] 2) The compound N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide described in step 2) was dissolved in dichloromethane and reacted with Et3N and POCl3. After the reaction was completed, the reaction solution was quenched, then extracted, dried and separated. The obtained organic phase was concentrated and purified to obtain the target product 4-(tert-butyl)-2-isocyano-1-(prop-2-yn-1-yloxy)benzene.

[0037] 3) The compound 4-(tert-butyl)-2-isocyano-1-(prop-2-acetylen-1-yloxy)benzene described in step 2) was dissolved in THF and reacted with potassium tert-butoxide. After the reaction was completed, the reaction solution was filtered, and the resulting organic phase was concentrated and purified to obtain the target product 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy)benzene VIII.

[0038] The present invention also provides the application of the above-mentioned benzoxazine spirocyclic compounds in the preparation of insecticidal, antibacterial, antiviral, anticancer, and anti-inflammatory drugs.

[0039] This invention involves a three-component tandem cyclization reaction of 2-isocyanophenoxyalene, 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy)benzene, and 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy)benzene with o-phenylphenol and acetone, respectively. By combining the reaction sites of isonitriles with phenol and acetone, spirocyclic derivatives can be synthesized efficiently. The benzoxazine spirocyclic compounds synthesized in this invention have high antibacterial activity. Attached Figure Description

[0040] Figure 1 The hydrogen NMR spectrum of compound I of this invention (CDCl3, 298K);

[0041] Figure 2 The image shows the carbon NMR spectrum (CDCl3, 298K) of compound I of this invention.

[0042] Figure 3 The hydrogen NMR spectrum (CDCl3, 298K) of compound II of this invention is shown below.

[0043] Figure 4 The carbon NMR spectrum (CDCl3, 298K) of compound II of this invention is shown below.

[0044] Figure 5 The hydrogen NMR spectrum (CDCl3, 298K) of compound III of this invention is shown below.

[0045] Figure 6 The image shows the carbon NMR spectrum (CDCl3, 298K) of compound III of this invention.

[0046] Figure 7 This is a test diagram showing the antibacterial effect of compound I of the present invention. Detailed Implementation

[0047] This invention provides a benzoxazine spirocyclic compound, represented by the following general formula (1):

[0048]

[0049] Among them, R 1 R2 is H or CH3; R2 is H or t-Bu.

[0050] In this invention, the benzoxazine spirocyclic compound is preferably selected from the following compounds:

[0051]

[0052] This invention also provides a method for preparing the above-mentioned benzoxazine spirocyclic compounds, preferably from the following synthetic route:

[0053]

[0054] The specific synthesis steps are as follows:

[0055] 1) React any one of compounds VI, VII and VIII with o-phenylphenol, cesium carbonate and acetone solution. After the reaction is complete, a reaction solution is obtained.

[0056] 2) The reaction solution obtained in step 1) is filtered, dried and separated to obtain the organic phase;

[0057] 3) Concentrate and purify the organic phase obtained in step 2) to obtain any one of the target products I, II and III.

[0058] In this invention, the reaction is preferably stirred at 80-100°C for 3-5 hours, and more preferably at 90°C for 4 hours.

[0059] In this invention, it is preferable to monitor the reaction using a TLC plate to determine whether the reaction is complete.

[0060] In this invention, the drying separation is preferably performed using anhydrous sodium sulfate to obtain the organic phase.

[0061] In this invention, the purification and separation is preferably carried out by column chromatography after organic phase concentration.

[0062] In this invention, the target products I, II and III are yellow solids.

[0063] In this invention, the preferred synthetic route for compound VI is as follows:

[0064]

[0065] In this invention, the preferred synthetic route for compound VII is as follows:

[0066]

[0067] In this invention, the preferred synthetic route for compound VIII is as follows:

[0068]

[0069]

[0070] In this invention, the preferred synthesis steps for compound VI are as follows:

[0071] 1) After dissolving o-hydroxybenzamide, react it with potassium carbonate and 3-bromopropyne. After the reaction is complete, filter and purify the reaction solution to obtain the product o-oxypropynebenzamide IV.

[0072] 2) Dissolve compound IV from step 1) in dichloromethane and react it with Et3N and POCl3. After the reaction is complete, quench the reaction solution, then extract, dry and separate. Concentrate the obtained organic phase and purify it to obtain the target product 2-isocyanophenoxypropyne V.

[0073] 3) Dissolve compound V from step 2) in THF and react with potassium tert-butoxide. After the reaction is complete, filter the reaction solution, concentrate the resulting organic phase and separate and purify it to obtain the target product 2-isocyanophenoxyalene VI.

[0074] In this invention, the o-hydroxybenzamide is preferably dissolved in tetrahydrofuran, and then potassium carbonate is added. The reaction solution is preferably carried out in an oil bath at 80°C. 3-bromopropyne is preferably added to the reaction solution in batches. After the reaction is completed, the reaction solution is filtered, the filtrate is collected and concentrated under vacuum, and finally purified and separated by column chromatography (PE / EA = 5:1) to obtain a white solid, which is the target product o-oxypropyne benzamide IV.

[0075] In this invention, compound IV is preferably dissolved in dichloromethane, and Et3N is added at room temperature. POCl3 is added slowly after stirring the reaction solution. The reaction process is monitored using a TLC plate. After the reaction is complete, the reaction is quenched with saturated sodium bicarbonate solution. Extraction is performed, and the organic phase is obtained by drying with anhydrous sodium sulfate. The obtained organic phase is concentrated and purified by column chromatography (eluent: PE / EA = 30 / 1) to obtain a pale yellow solid, which is the target product 2-isocyanophenoxypropyne V.

[0076] In this invention, 2-isocyanophenoxypropyne V is preferably dissolved in THF, stirred at room temperature, and potassium tert-butoxide is slowly added while the reaction progress is monitored using a TLC plate. After the reaction is complete, the reaction solution is vacuum filtered, and the resulting organic phase is concentrated under vacuum and then purified by column chromatography (PE / EA = 10 / 1) to obtain a black solid, which is the target product 2-isocyanophenoxyalkene VI.

[0077] In this invention, the preferred synthesis steps for compound VII are as follows:

[0078] 1) N-(2-hydroxy-4-methylphenyl)formamide was dissolved and reacted with potassium carbonate and 3-bromopropyne. After the reaction was completed, the reaction solution was filtered, purified and separated to obtain the product N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide.

[0079] 2) The compound N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide described in step 1) is dissolved in dichloromethane and reacted with Et3N and POCl3. After the reaction is completed, the reaction solution is quenched, then extracted, dried and separated. The obtained organic phase is concentrated and purified to obtain the target product 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene.

[0080] 3) The compound 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene described in step 2) was dissolved in THF and reacted with potassium tert-butoxide. After the reaction was completed, the reaction solution was filtered, and the resulting organic phase was concentrated and purified to obtain the target product 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy)benzene VII.

[0081] In this invention, the N-(2-hydroxy-4-methylphenyl)formamide is preferably dissolved in tetrahydrofuran, and then potassium carbonate is added. The reaction solution is preferably carried out in an oil bath at 80°C. 3-bromopropyne is preferably added to the reaction solution in batches. After the reaction is completed, the reaction solution is filtered, the filtrate is collected and concentrated under vacuum, and finally purified and separated by column chromatography (PE / EA = 5:1) to obtain a white solid N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide.

[0082] In this invention, preferably, the above-mentioned white solid N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide is dissolved in dichloromethane, and Et3N is added at room temperature. Preferably, POCl3 is slowly added after stirring the reaction solution. Preferably, the reaction progress is monitored using a TLC plate. After the reaction is completed, the reaction is quenched with saturated sodium bicarbonate solution. Extraction is performed, and the organic phase is obtained by drying with anhydrous sodium sulfate. The obtained organic phase is concentrated and purified by column chromatography (eluent: PE / EA = 30 / 1) to obtain a pale yellow solid, which is the target product 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene.

[0083] In this invention, 1-isocyano-4-methyl-2-(prop-2-adien-1-yloxy)benzene is preferably dissolved in THF, stirred at room temperature, and potassium tert-butoxide is slowly added while the reaction progress is monitored using a TLC plate. After the reaction is complete, the reaction solution is vacuum filtered, and the resulting organic phase is concentrated under vacuum and purified by column chromatography (PE / EA = 10 / 1) to obtain a black solid, which is the target product 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy)benzene VII.

[0084] In this invention, the preferred synthesis steps for compound VIII are as follows:

[0085] 1) N-(5-(tert-butyl)-2-hydroxyphenyl)formamide was dissolved and reacted with potassium carbonate and 3-bromopropyne. After the reaction was completed, the reaction solution was filtered, purified and separated to obtain the product N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide.

[0086] 2) The compound N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide described in step 1) is dissolved in dichloromethane and reacted with Et3N and POCl3. After the reaction is completed, the reaction solution is quenched, then extracted, dried and separated. The obtained organic phase is concentrated and purified to obtain the target product 4-(tert-butyl)-2-isocyano-1-(prop-2-yn-1-yloxy)benzene.

[0087] 3) The compound 4-(tert-butyl)-2-isocyano-1-(prop-2-acetylen-1-yloxy)benzene described in step 2) was dissolved in THF and reacted with potassium tert-butoxide. After the reaction was completed, the reaction solution was filtered, and the resulting organic phase was concentrated and purified to obtain the target product 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy)benzene VIII.

[0088] In this invention, the N-(5-(tert-butyl)-2-hydroxyphenyl)formamide is preferably dissolved in tetrahydrofuran, and then potassium carbonate is added. The reaction solution is preferably carried out in an oil bath at 80°C. 3-bromopropyne is preferably added to the reaction solution in batches. After the reaction is completed, the reaction solution is filtered, the filtrate is collected and concentrated under vacuum, and finally purified and separated by column chromatography (PE / EA = 5:1) to obtain a white solid N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide.

[0089] In this invention, preferably, the above-mentioned white solid N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide is dissolved in dichloromethane, and Et3N is added at room temperature. Preferably, POCl3 is slowly added after stirring the reaction solution. Preferably, the reaction progress is monitored using a TLC plate. After the reaction is completed, the reaction is quenched with saturated sodium bicarbonate solution. Extraction is performed, and the organic phase is obtained by drying with anhydrous sodium sulfate. The obtained organic phase is concentrated and purified by column chromatography (eluent: PE / EA = 30 / 1) to obtain a pale yellow solid, which is the target product 4-(tert-butyl)-2-isocyano-1-(prop-2-yn-1-yloxy)benzene.

[0090] In this invention, preferably, 4-(tert-butyl)-2-isocyano-1-(prop-2-dien-1-yloxy)benzene is dissolved in THF, stirred at room temperature, and potassium tert-butoxide is slowly added while the reaction progress is monitored using a TLC plate. After the reaction is complete, the reaction solution is vacuum filtered, and the resulting organic phase is concentrated under vacuum and purified by column chromatography (PE / EA = 10 / 1) to obtain a black solid, which is the target product 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy)benzene VIII.

[0091] In this invention, the raw material N-(2-hydroxyphenyl)formamide used in compound I can be prepared according to the literature "Chem. Commun. 2024, 60, 2661-2664", and the raw materials N-(2-hydroxy-4-methylphenyl)formamide and N-(5-(tert-butyl)-2-hydroxyphenyl)formamide used in compounds II and III can be prepared according to the literature "Org. Biomol. Chem. 2022, 20, 6931-6940". Other small molecule raw materials can be commercially available products in the art.

[0092] The present invention also provides the application of the above-mentioned benzoxazine spirocyclic compounds in the preparation of insecticidal, antibacterial, antiviral, anticancer, and anti-inflammatory drugs.

[0093] In this invention, compound I exhibits very high antibacterial activity against Bacillus subtilis, Xanthomonas, and the fungus Candida tropicalis at a concentration of 6.25 μg / disc.

[0094] In this invention, Bacillus subtilis, Xanthomonas, and the fungus Candida tropicalis are all conventional test microorganisms used in antimicrobial tests in this field.

[0095] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0096] Example 1

[0097] Preparation process of compound IV:

[0098]

[0099] In a 250 mL three-necked flask, o-hydroxybenzamide (3.43 g, 25 mmol) was dissolved in tetrahydrofuran (150 mL), followed by the addition of potassium carbonate (8.64 g, 62.5 mmol). The reaction solution was placed in an 80 °C oil bath, and 3-bromopropyne (4.46 g, 37.5 mmol) was added to the reaction solution in portions. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and concentrated under vacuum, and finally purified and separated by column chromatography (PE / EA = 5:1) to obtain a white solid, which was the target product o-oxypropyne benzamide IV, with a yield of 70%-80%.

[0100] Example 2

[0101] Preparation process of compound V:

[0102]

[0103] Compound IV (2.63 g, 15 mmol) was dissolved in 50 mL of dichloromethane. Et3N (4.55 g, 45 mmol) was added at room temperature. After stirring the reaction mixture for 10 minutes, POCl3 (3.45 g, 22.5 mmol) was slowly added. The reaction was immediately monitored using a TLC plate. After the reaction was complete, it was quenched with saturated sodium bicarbonate solution. Extraction was performed, and the organic phase was obtained by drying with anhydrous sodium sulfate. The obtained organic phase was concentrated and purified by column chromatography (eluent: PE / EA = 30 / 1) to obtain a pale yellow solid, which was the target product 2-isocyanophenoxypropyne V, in a yield of 45%-55%.

[0104] Example 3

[0105] Preparation process of target product VI:

[0106]

[0107] 0.79 g (5 mmol) of 2-isocyanophenoxypropyne V was dissolved in 100 mL of THF and stirred at room temperature for 5 minutes. Potassium tert-butoxide (0.56 g, 5 mmol) was slowly added, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered under vacuum. The resulting organic phase was concentrated under vacuum and purified by column chromatography (PE / EA = 10 / 1) to obtain the black solid, which was the target product 2-isocyanophenoxyalkene VI, in a yield of 50%-60%.

[0108] Example 4

[0109] Preparation process of target product VII:

[0110]

[0111] 1-Isocyano-4-methyl-2-(prop-2-dien-1-yloxy) (0.86 g, 5 mmol) was dissolved in THF (100 mL), stirred at room temperature for 5 minutes, and potassium tert-butoxide (0.56 g, 5 mmol) was slowly added while monitoring the reaction progress using TLC. After the reaction was complete, the reaction solution was filtered under vacuum, and the resulting organic phase was concentrated under vacuum and purified by column chromatography (PE / EA = 10 / 1) to obtain a black solid, which was the target product 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy)benzene VII, with a yield of 50%-60%.

[0112] Example 5

[0113] Preparation process of target product VIII:

[0114]

[0115] 4-(tert-butyl)-2-isocyano-1-(prop-2-dien-1-yloxy) (1.07 g, 5 mmol) was dissolved in THF (100 mL), stirred at room temperature for 5 minutes, and potassium tert-butoxide (0.56 g, 5 mmol) was slowly added while the reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered under vacuum, and the resulting organic phase was concentrated under vacuum and purified by column chromatography (PE / EA = 10 / 1) to obtain a black solid, which was the target product 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy)benzene VIII, with a yield of 50%-60%.

[0116] Example 6

[0117] Preparation process of target product I:

[0118]

[0119] In a 10 mL sealed tube, target product VI (0.126 g, 0.8 mmol), reactant o-phenylphenol (0.068 g, 0.4 mmol), cesium carbonate (0.13 g, 0.4 mmol), and acetone (2.5 mL) solution were added. The mixture was stirred at 90 °C for 4 hours, and the reaction was monitored using a TLC plate. After the reaction was complete, the reaction solution was filtered and dried over anhydrous sodium sulfate to obtain the organic phase. The obtained organic phase was concentrated and purified by column chromatography (eluting agent: PE / EA = 10 / 1) to obtain a yellow solid, which was target product I, with a yield of 73%. 1 H NMR(400MHz,Chloroform-d)δ7.36(d,J=4.3Hz,4H),7.34–7.32(m,1H),7.32–7.29(m,2H),7.15(ddd,J=7.8,6.6,1.7Hz,1H),6.92–6.84(m,2H),6. 82–6.75(m,1H),6.70(dd,J=8.1,1.6Hz,1H),5.19(s,1H),3.51(s,1H),2. 39–2.30(m,1H),2.29–2.06(m,3H),1.91–1.75(m,1H),1.74–1.58(m,2H). 13 C NMR(101MHz,Chloroform-d)δ208.94,153.17,141.06,138.05,132.64,130.77,129.95,129.67,128.71,127.77,127. 08,123.35,122.51,120.58,118.12,117.32,117.26,97.34,57.49,47.60,40.74,29.05,20.19.HRMS(ESI):Calcd.For C 25 H 23 NO3[M+H] + :386.1751,Found:386.1762.

[0120] Example 7

[0121] Preparation process of target product II:

[0122]

[0123] In a 10 mL sealed tube, target product VII (0.137 g, 0.8 mmol), reactant o-phenylphenol (0.068 g, 0.4 mmol), cesium carbonate (0.13 g, 0.4 mmol), and acetone (2.5 mL) solution were added. The mixture was stirred at 90 °C for 4 hours, and the reaction was monitored using a TLC plate. After the reaction was complete, the reaction solution was filtered and dried over anhydrous sodium sulfate to obtain the organic phase. The obtained organic phase was concentrated and purified by column chromatography (eluent: PE / EA = 10 / 1) to obtain a yellow solid, which was target product II, with a yield of 64%. 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J=2.2Hz,2H),7.34(m,3H),7.32(m,2H),7.31–7.28(m,2H),7.18–7.11(m,1H),6.68(ddt,J=4.4,1.9,1.0H z,2H),6.63(d,J=8.4Hz,1H),5.19(s,1H),3.31(s,1H),2.39–2.27(m,1H ),2.24(s,3H),2.23–2.08(m,3H),1.93–1.73(m,2H),1.72–1.56(m,2H). 13 C NMR(101MHz,Chloroform-d)δ208.96,153.26,141.21,138.08,132.63,130.83,130.76,129.66,128.71,127.75,127. 05,123.27,123.16,118.81,117.69,117.15,97.34,57.41,47.27,40.72,29.19,20.66,20.19.HRMS(ESI):Calcd.For C 26 H 25 NO3[M+H] + :400.1907,Found:400.1913.

[0124] Example 8

[0125] Preparation process of target product III:

[0126]

[0127] In a 10 mL sealed tube, target product VIII (0.170 g, 0.8 mmol), reactant o-phenylphenol (0.068 g, 0.4 mmol), cesium carbonate (0.13 g, 0.4 mmol), and acetone (2.5 mL) solution were added. The mixture was stirred at 90 °C for 4 hours, and the reaction was monitored using a TLC plate. After the reaction was complete, the reaction solution was filtered and dried over anhydrous sodium sulfate to obtain the organic phase. The obtained organic phase was concentrated and purified by column chromatography (eluent: PE / EA = 10 / 1) to obtain a yellow solid, which was the target product III, with a yield of 56%. 1 HNMR(400MHz,Chloroform-d)δ7.35(d,J=1.3Hz,1H),7.34(s,3H),7.33–7.32(m, 1H),7.32–7.31(m,2H),7.30(d,J=1.1Hz,1H),7.14(ddd,J=7.6,6.4,2.0Hz,1H), 6.82–6.79(m,2H),6.73(dd,J=1.9,0.7Hz,1H),5.18(s,1H),3.45(s,1H),2.41–2 .30(m,1H),2.29–2.08(m,3H),2.00–1.67(m,2H),1.75–1.58(m,2H),1.28(s,9H). 13 C NMR(101MHz,Chloroform-d)δ209.30,153.34,145.70,138.89,138.25,132.77,130.91,129.83,129.26,128.84,127.88,127 .19,123.42,117.97,117.35,116.85,115.43,97.53,57.75,47.76,40.92,34.30,31.61,29.28,20.39.HRMS(ESI):Calcd.For C 29 H 31 NO3[M+H] + :442.2377,Found:442.2386.

[0128] Example 9

[0129] Antibacterial effect test of compound I

[0130] We selected Gram-positive and Gram-negative bacteria Bacillus subtilis and Xanthomonas aeruginosa, as well as the fungus Candida tropicalis at a concentration of 6.25 μg / disc. Antimicrobial tests were conducted at concentrations ranging from 1.5 to 100 μg / disc. Compound I exhibited very high antimicrobial activity against all three species. This demonstrates that our synthesized compound I has a truly effective antimicrobial effect.

[0131] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A benzoxazine spirocyclic compound, represented by the following general formula (1): in, R 1 R2 is H or CH3; t- Bu.

2. The benzoxazine spirocyclic compound according to claim 1, characterized in that, It is selected from the following compounds: 。 3. The method for preparing the benzoxazine spirocyclic compound according to claim 1 or 2, characterized in that, Selected from the following synthesis routes: ； ； The specific synthesis steps are as follows: 1) React any one of compounds VI, VII, and VIII with o-phenylphenol, cesium carbonate, and acetone solution. After the reaction is complete, a reaction solution is obtained. 2) Filter the reaction solution obtained in step 1), dry and separate it to obtain the organic phase; 3) Concentrate and purify the organic phase obtained in step 2) to obtain any one of the target products I, II and III.

4. The method for preparing benzoxazine spirocyclic compounds according to claim 3, characterized in that, The synthetic route for compound VI is as follows: ； ； 。 5. The method for preparing benzoxazine spirocyclic compounds according to claim 3, characterized in that, The synthetic route for compound VII is as follows: 。 6. The method for preparing benzoxazine spirocyclic compounds according to claim 3, characterized in that, The synthetic route for compound VIII is as follows: 。 7. The method for preparing benzoxazine spirocyclic compounds according to claim 4, characterized in that, The specific synthesis steps of compound VI are as follows: 1) After dissolving o-hydroxybenzamide, react it with potassium carbonate and 3-bromopropyne. After the reaction is complete, filter and purify the reaction solution to obtain the product o-oxypropynebenzamide IV. 2) Dissolve compound IV from step 1) in dichloromethane and react it with Et3N and POCl3. After the reaction is complete, quench the reaction solution, then extract, dry and separate. Concentrate the obtained organic phase and purify it to obtain the target product 2-isocyanophenoxypropyne V. 3) Dissolve compound V from step 2) in THF and react with potassium tert-butoxide. After the reaction is complete, filter the reaction solution, concentrate the resulting organic phase and separate and purify it to obtain the target product 2-isocyanophenoxyalkene VI.

8. The method for preparing benzoxazine spirocyclic compounds according to claim 5, characterized in that, The specific synthesis steps of compound VII are as follows: 1) N-(2-hydroxy-4-methylphenyl)formamide was dissolved and reacted with potassium carbonate and 3-bromopropyne. After the reaction was completed, the reaction solution was filtered, purified and separated to obtain the product N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide. 2) The compound N-(4-methyl-2-(prop-2-yn-1-yloxy)phenyl)formamide described in step 1) was dissolved in dichloromethane and reacted with Et3N and POCl3. After the reaction was completed, the reaction solution was quenched, then extracted, dried and separated. The obtained organic phase was concentrated and purified to obtain the target product 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene. 3) The compound 1-isocyano-4-methyl-2-(prop-2-yn-1-yloxy)benzene described in step 2) is dissolved in THF and reacted with potassium tert-butoxide. After the reaction is completed, the reaction solution is filtered, and the resulting organic phase is concentrated and purified to obtain the target product 1-isocyano-4-methyl-2-(prop-1,2-dien-1-yloxy)benzene VII.

9. The method for preparing benzoxazine spirocyclic compounds according to claim 6, characterized in that, The specific synthesis steps of compound VIII are as follows: 1) N-(5-(tert-butyl)-2-hydroxyphenyl)formamide was dissolved and reacted with potassium carbonate and 3-bromopropyne. After the reaction was completed, the reaction solution was filtered, purified and separated to obtain the product N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide. 2) The compound N-(5-(tert-butyl)-2-(prop-2-yn-1-yloxy)phenyl)formamide described in step 1) was dissolved in dichloromethane and reacted with Et3N and POCl3. After the reaction was completed, the reaction solution was quenched, then extracted, dried and separated. The obtained organic phase was concentrated and purified to obtain the target product 4-(tert-butyl)-2-isocyano-1-(prop-2-yn-1-yloxy)benzene. 3) The compound 4-(tert-butyl)-2-isocyano-1-(prop-2-acetylen-1-yloxy)benzene described in step 2) was dissolved in THF and reacted with potassium tert-butoxide. After the reaction was completed, the reaction solution was filtered, and the resulting organic phase was concentrated and purified to obtain the target product 4-(tert-butyl)-2-isocyano-1-(prop-1,2-dien-1-yloxy)benzene VIII.

10. The use of the benzoxazine spirocyclic compound according to claim 1 or 2 in the preparation of antibacterial drugs.

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