Benzopyran derivative, synthetic method and application

Abstract

Trifluoroacetone with benzene rings and different heterocyclic rings and substituted salicylaldehyde are used as raw materials, DMSO is used as a solvent, reflux reaction is performed to generate benzopyran derivative crude products with different substituent groups, the crude products are post-processed to obtain the benzopyran derivative, TLC or liquid phase tracking reaction is performed to obtain the benzopyran derivative, and the benzopyran derivative with different substituent groups is obtained. The reaction process is simple and easy to operate. Antifungal activity experiments are carried out on the synthesized eighteen compounds, the antibacterial rates of the compounds on fusarium graminearum, rhizoctonia solani, fusarium moniliforme and fusarium oxysporum are determined, and the inhibition rate of the thiophenedibromo pyrone on rhizoctonia solani at 200 ppm is the highest and is 98.84%; the unsubstituted dichloropyrone has the highest inhibition rate on fusarium graminearum, and the inhibition rate is 66.08%; the inhibition rate of the pyridine dichloro pyrone on fusarium oxysporum is the highest, and is 71.07%; the inhibition rate of the pyridine dichloro pyrone on fusarium moniliforme is the highest, and is 69.12%. The benzopyran derivative synthesized by the method has a good application prospect in various fields of medicines, organic synthesis, biosensing, photoelectric materials and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a benzopyran derivative, a synthesis method and an application thereof. Background Art

[0002] Pathogenic plant fungi refer to fungi that can cause plant diseases. They parasitize on plants, destroy the normal physiological functions of plants, and cause various disease symptoms in plants. They can harm plants in a variety of ways, including directly invading plants, secreting toxins, and affecting plant nutrient absorption, causing a variety of plant diseases. These diseases can cause symptoms such as lesions, wilting and rotting on the leaves, stems, roots and other parts of plants, and eventually lead to plant death. These pathogenic plant fungi have various transmission routes, including airborne transmission, rainwater transmission, insect transmission, etc. They can reproduce and produce toxins in plants, causing varying degrees of damage to plants.

[0003] The toxins secreted by some fungi are harmful to both humans and plants. For example, toxin is a common fungal toxin that can cause poisoning and death in animals, and can also affect the growth and development of plants, leading to a decrease in plant yields. In addition, fungi can also affect the plant's nutrient absorption by invading the plant's body. Some fungi can form mycorrhizae on the roots of plants, which can affect the plant's absorption of water and nutrients. These fungi can also secrete enzymes that damage the plant's cell walls, causing plant cell death, which in turn affects the growth and development of the plant. In short, fungi can cause many kinds of harm to plants, including causing diseases, secreting toxins, and affecting the plant's nutrient absorption. In order to protect the health and growth of plants, effective measures need to be taken to control the growth and reproduction of fungi.

[0004] When pathogenic fungi encounter their hosts, they produce various cell wall degrading enzymes, such as glycanases and proteases, to fragment plant cell wall polymers to facilitate penetration into host cells. In plants, the fungal proteolytic machinery is responsible for the removal of abnormal or nonfunctional proteins, activation / inactivation of specific proteins, and autolytic processes. In addition, proteases increase the permeability of plant plasma membranes, suggesting that they may play a key role in plant pathogenesis.

[0005] Chitin is a polysaccharide mainly found in the exoskeleton of insects, crustaceans and fungal cell walls. Chitinase is an enzyme that catalyzes the hydrolysis of chitin to produce N-acetylglucosamine. The enzyme was first discovered by Kahler and Hofmann in 1929 from the gastric juice (midgut gland secretion) of snails (Helix pomatia). Later, the enzyme was also found in the secretion of insect molting glands, the peel of almonds and mold fungi.

[0006] Chitinase plays a variety of roles in organisms. First, it is mainly involved in the degradation and decomposition of chitin. Secondly, chitinase plays a role in maintaining the integrity and stability of the cell wall. In organisms such as fungi and insects, chitinase participates in the metabolism and remodeling of the cell wall, helping to rebuild and repair the cell wall. In addition, chitinase also has a certain defensive effect, which can degrade chitin in the cell walls of parasites and pathogens, destroy their structure, and thus resist external invasion. Over the past few decades, people have been paying attention to the role of chitinase in plants. There is strong evidence that they are antifungal proteins, but they may also play a role in nonspecific stress responses and can be developmentally regulated. Therefore, by synthesizing compounds that can interact with chitinase, it is theoretically possible to destroy the structure of pathogenic fungi and thus protect crops.

[0007] In order to control the damage of fungi to plants, many antifungal drugs have been developed. The synthesis of antifungal drugs mainly relies on organic synthetic chemistry and can be divided into many categories. Among the large number of fluorinated compounds used in the pharmaceutical and agrochemical industries, nitrogen-containing heterocycles with fluorine atoms or trifluoromethyl groups are common. These drugs have different mechanisms of action and adapt to the range of diseases. The synthesis process of these drugs includes steps such as synthesizing precursors, constructing drug skeletons, and introducing active groups. Among them, the selection and preparation of synthetic precursors are crucial because they determine the structure and properties of the drugs.

[0008] Benzopyran, also known as chromene, is an important oxygen-containing heterocyclic compound formed by the fusion of benzene and pyran. It mainly exists in natural products such as alkaloids, flavonoids, tocopherols and anthocyanins, and its basic structure is benzopyran. The core unit of benzopyran exists in many natural products, such as tocopherol, α-tocotrienol and γ-tocotrienol, and the pyran ring contains a phytyl chain. Benzopyran derivatives are essential to human life, and their derivatives play a vital role in pharmaceutical chemistry. It has good pharmacological and biological activities, such as antioxidant activity, antibacterial activity, anticoagulation, anticancer activity, antitumor activity, etc., and is widely used in various drugs such as anticoagulants, anticancer drugs, antiallergic drugs, etc. It was also found that benzopyran compounds can interact with chitinase, thereby having activity against fungal diseases in farmland.

[0009] There are many methods for synthesizing benzopyran compounds, but traditional synthesis methods have defects such as limited reaction conditions, low reaction efficiency, and environmental pollution. Therefore, it is a major challenge to quickly synthesize a large number of various biologically active and stable benzopyran compounds. Safer, more effective, rapid and simple synthesis methods are under continuous research.

[0010] In view of this, the present invention is proposed. Summary of the invention

[0011] The purpose of the present invention is to provide a benzopyran derivative, a synthesis method and an application thereof, wherein cheap and readily available trifluoroacetone is used as a raw material to carry out a Knoevenagel condensation reaction with a substituted salicylaldehyde to generate a benzopyrone compound with antibacterial activity, which is of great significance to the healthy growth of crops.

[0012] To achieve the above object, the present invention adopts the following technical solutions:

[0013] The synthesis method of benzopyran derivatives of the present invention comprises the following steps: using trifluoroacetone with a benzene ring and different heterocycles and substituted salicylaldehyde as raw materials, DMSO as a solvent, and ammonium acetate as a catalyst, and performing a reflux reaction to generate crude benzopyran derivatives with different substituents, and then post-treating the crude products to obtain benzopyran derivatives;

[0014] The structural formula of the trifluoroacetone with a benzene ring and different heterocycles is shown below:

[0015]

[0016] R1 is one of H or 4-Cl;

[0017] The structural formula of substituted salicylaldehyde is as follows: R2 is one of F, Cl, Br, I, OCH3, and NO2 substituted at the 5-position or one of F, Cl, Br, and I substituted at the 3,5-position.

[0018] Further, the reaction route is as follows:

[0019]

[0020] R1 is one of H or 4-Cl; R2 is one of F, Cl, Br, I, OCH3, NO2 substituted at the 5-position or one of F, Cl, Br, I substituted at the 3,5-position.

[0021] Further, the reaction route is as follows:

[0022]

[0023] R1 is H; R2 is Cl substituted at the 5-position or Cl substituted at the 3,5-position or Br substituted at the 3,5-position.

[0024] Further, the reaction route is as follows:

[0025]

[0026] R1 is H; R2 is Cl or Br substituted at the 3,5 position.

[0027] Further, the reaction route is as follows:

[0028]

[0029] R1 is H; R2 is Cl substituted at the 3,5 positions.

[0030] Furthermore, the molar ratio of trifluoroacetone having a benzene ring and different heterocyclic rings to substituted salicylaldehyde is 1:1.

[0031] Furthermore, the reflux reaction temperature is 80-150° C., and the reflux reaction is carried out until the reaction is complete.

[0032] Furthermore, the post-treatment operation steps of the crude product are as follows: the crude product is transferred to a separatory funnel, extracted with 20 ml of ethyl acetate and 20 ml of saturated brine, the ester layer is washed three times with 15 ml of saturated brine, the water layer is combined and washed three times with 10 ml of ethyl acetate, all ester layers are combined, and then washed three times with 10 ml of saturated brine, and finally the combined ester layers are dried over anhydrous sodium sulfate, filtered and transferred to a 100 ml round-bottom flask, and the remaining 3-5 ml is concentrated by rotary evaporation, 5 ml of petroleum ether is added for recrystallization, and a solid is obtained after filtration, and the solid is naturally dried to obtain the product.

[0033] The present invention also provides the use of the benzopyran derivatives obtained by the synthesis method in the preparation of drugs for preventing and controlling plant fungi.

[0034] Furthermore, the plant fungi are Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum, and Rhizoctonia solani.

[0035] Beneficial effects of the present invention: The present invention utilizes trifluoroacetone with a benzene ring and different heterocycles to react with substituted salicylaldehyde to generate benzopyran derivatives with different substituents. 1 H spectroscopy, NMR 13 C spectrum and high-resolution mass spectrometry were used to characterize the compound, indicating that the target product was successfully synthesized. Then, the reaction conditions were explored to a certain extent through high-performance liquid chromatography analysis, and the conditions that can effectively accelerate the reaction rate and increase the reaction yield were found to be 105°C under the catalysis of ammonium acetate in the solvent DMSO for 8 hours, with a yield of 76.25%.

[0036] The antifungal activity of the 18 synthesized compounds was tested. The mycelium growth rate method was used to determine the antifungal rates of the compounds against Fusarium graminearum, Rhizoctonia solani, Fusarium moniliforme, and Fusarium oxysporum. It was found that at 200 ppm, thiophene dibromopyrone had the highest inhibition rate against Rhizoctonia solani, which was 98.84%; unsubstituted dichloropyrone had the highest inhibition rate against Fusarium graminearum, which was 66.08%; pyridine dichloropyrone had the highest inhibition rate against Fusarium oxysporum, which was 71.07%; and pyridine dichloropyrone had the highest inhibition rate against Fusarium moniliforme, which was 69.12%. The half-dilution method was used to test the EC for substances with an inhibition rate of more than 80%. 50 Activity test, EC 50 The value is 223.284ppm, R2=0.935. The synthesized compounds will show good application prospects in various fields such as medicine, organic synthesis, biosensors and optoelectronic materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0038] Figure 1 The liquid chromatogram of the raw material benzoyltrifluoroacetone;

[0039] Figure 2 This is the liquid chromatogram of the raw material 5-chlorosalicylaldehyde;

[0040] Figure 3 is the liquid chromatogram of the target product;

[0041] Figure 4 is the liquid chromatogram of the reaction under the most suitable conditions;

[0042] Figure 5 is the H NMR spectrum of unsubstituted chloropyrone;

[0043] Figure 6 is the C NMR spectrum of unsubstituted chloropyrone;

[0044] Figure 7 It is a high-resolution mass spectrum of unsubstituted chloropyrone;

[0045] Figure 8 This is the single crystal diffraction pattern of the unsubstituted iodinated pyrone of Example 7;

[0046] Fig. 9 This is the single crystal diffraction pattern of thiophene dichloropyrone of Example 14;

[0047] Fig.10 This is a comparison chart of the inhibition rate against Rhizoctonia solani (200ppm);

[0048] Fig.11 This is a comparison chart of the inhibition rate against Fusarium graminearum (200ppm);

[0049] Fig.12 This is a comparison chart of the inhibition rate against Fusarium oxysporum (200ppm);

[0050] Fig.13 This is a comparison chart of the inhibition rate against Fusarium moniliforme (200ppm);

[0051] Fig.14 This is a comparison of the inhibition rates of different concentrations of 3o against Rhizoctonia solani. DETAILED DESCRIPTION

[0052] The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention, and those skilled in the art in this field can make some non-essential improvements and adjustments based on the content of the above invention.

[0053] The invention uses trifluoroacetone with a benzene ring or a heterocyclic ring and substituted salicylaldehyde as raw materials to synthesize 18 new benzopyrone derivatives. The compounds are characterized by nuclear magnetic resonance H spectrum, nuclear magnetic resonance C spectrum and high-resolution mass spectrum, and it can be seen that the target products are successfully synthesized.

[0054] The specific reaction route is as follows:

[0055]

[0056] Example 1

[0057]

[0058] The synthesis method of the unsubstituted chloropyrone (3c) in this example is as follows: 5 mmol (1.0808 g) of benzoyltrifluoroacetone and 5 mmol (0.7829 g) of 5-chlorosalicylaldehyde are dissolved in 10 ml of DMSO, and heated at 105°C for reaction. After the reaction is completed by thin layer chromatography, the reaction solution is transferred to a separatory funnel, saturated brine is added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove part of the solvent, an appropriate amount of petroleum ether is added, and the solid is precipitated by cooling. The product is obtained by suction filtration and drying, and the yield is 61.05%.

[0059] Its H NMR spectrum shows Figure 5 , NMR C spectrum such as Figure 6 , high resolution mass spectrometry Figure 7 It can be seen that the unsubstituted chloropyrone was successfully synthesized.

[0060] Characterization by H NMR spectrum: The molecular formula of unsubstituted chloropyrone is C 17 H 10 ClF3O3, the compound contains 10 hydrogens, and the measured hydrogen spectrum also has 10 hydrogens. The absorption peak with chemical shift δ=9.33ppm is the H on the double bond carbon of the benzopyran ring, the absorption peaks with chemical shifts δ=7.87ppm, δ=7.85ppm, δ=7.72ppm, δ=7.61ppm, and δ=7.59ppm are the H on the benzene ring of benzoyltrifluoroacetone, the absorption peaks with chemical shifts δ=7.49ppm, δ=7.46ppm, and δ=7.17ppm are the H on the chlorobenzene ring, and the absorption peak with chemical shift δ=7.38ppm is the H of -OH connected to the adjacent carbon of the trifluoromethyl group.

[0061] NMR C spectrum characterization: 13 C NMR(101MHz,Chloroform-d)δ197.49,150.47,138.55,135.47,134.45,133.69,130. 13,129.04,128.73,127.59,122.59,117.86,117.65,96.35,96.15(q,J=33.7Hz,1C). Figure 6 The number of C's shown in the C' NMR spectrum is consistent with the number of C's in the molecular formula of the target product compound.

[0062] The high-resolution mass spectrometry shows that the theoretical molar mass of unsubstituted chloropyrone is minus the hydroxyl group [M-OH] + :338.0316, the molar mass of the target compound minus the hydroxyl group [M-OH] + :338.0322, the two values ​​are almost the same, indicating that the target product, unsubstituted chloropyrone, was successfully synthesized.

[0063] Example 2

[0064]

[0065] The synthesis of unsubstituted fluoropyrone (3a) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0066] Unsubstituted fluoropyrone (3a), mp 175℃~180℃; yield, 71.65%; 1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.84(d,J=7.2Hz,2H),7.71(t,J=7.5Hz,1H),7.56(t,J=7.7Hz,2 H),7.19(s,1H),7.12(td,J=8.5,8.1,2.9Hz,1H),7.05(dd,J=9.0,4.4Hz,1H),6.91(dd,J=7.7,2.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ197.44,158.85,148.02,138.73,135.56,134.42,130.13,129.03,122.49(q,J =286.0Hz,1C),120.84,120.61,117.55,115.15,114.92,96.12(q,J=34.9Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.forC 17 H9F4O2 + :321.0533; found:321.0538.

[0067] Example 3

[0068]

[0069] The synthesis of unsubstituted difluoropyrone (3b) in this example is the same as in Example 1 except that the reaction raw materials are different. Unsubstituted difluoropyrone (3b), mp 161°C~162°C; yield, 48.00%; 1 H NMR (400MHz, Chloroform-d) δ7.89-7.81(m,3H),7.73(t,J=7.4Hz,1H),7.58(t,J=7.6Hz,2H),7.18(s,1H),7.00(t,J=10.5Hz,1H),6.76(d,J=7.4Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ196.99,151.39,150.20,137.68,135.35,134.63,130.16,123.70,123.05,12 2.27(q,J=290.6Hz,1C),119.14,97.27,96.18(q,J=35.4Hz,1C),85.01,84.86.HRMS(ESI-TOF):m / z[M+Na] + calcd.for C17 H9F5O3Na + :379.0370; found:379.0373.

[0070] Example 4

[0071]

[0072] The synthesis of unsubstituted dichloropyrone (3d) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0073] Unsubstituted dichloropyrone (3d), mp75℃~83℃; yield, 96.23%; 1 H NMR (400MHz, Chloroform-d) δ7.88-7.83(m,2H),7.73(t,J=7.5Hz,1H),7.57(t,J=7.8Hz,2H),7.47(d,J=2.4Hz,1H),7.17-7.10(m,2H). 13 C NMR(101MHz,Chloroform-d)δ197.04,146.55,137.51,135.24,134.70,133.54,130.20,129.12,127.44,127.17, 123.69,123.42,122.52,122.24(q,J=290.0Hz,1C),118.88,96.74(q,J=35.4Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.for C 17 H8Cl2F3O2 + :371.9926; found:371.9940.

[0074] Example 5

[0075]

[0076] The synthesis of unsubstituted bromopyrone (3e) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0077] Unsubstituted brominated pyrone (3e), mp 153℃~155℃; yield, 75.64%; 1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.86-7.82(m,2H),7.71(q,J=7.6Hz,1H),7.57(t,J=7 .7Hz,2H),7.50(dd,J=8.7,2.4Hz,1H),7.34(d,J=2.3Hz,1H),7.19(s,1H),6.99(d,J=9.1Hz,1H). 13 CNMR(101MHz,Chloroform-d)δ197.49,151.02,138.46,136.58,135.48,131.70,129.05,122.54,122 .45(q,J=289.0Hz,1C),118.41,118.05,114.66,96.17(q,J=25..3Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.for C 17 H9BrF3O2 + :380.9733; found:380.9731.

[0078] Example 6

[0079]

[0080] The synthesis of unsubstituted dibromopyrone (3f) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0081] Unsubstituted dibromopyrone (3f), mp 122℃~123℃; yield, 25.70%; 1 H NMR (400MHz, Chloroform-d) δ7.91 (s, 1H), 7.84 (d, J = 8.2Hz, 2H), 7.77-7.69 (m, 2H), 7.57 (t, J = 7.6Hz, 2H), 7.30 (s, 1H), 7.14 (s, 1H). 13 C NMR(101MHz,Chloroform-d)δ196.64,148.02,138.88,137.22,135.33,134.60,130.71,130.16,129.06,123. 68,122.11(q,J=289.0Hz,1C).,114.59,111.11,97.00,96.61(q,J=35.5Hz,1C)..HRMS(ESI-TOF):m / z[M-OH] + calcd.forC 17H8Br2F3O2 + :459.8916; found:459.8942.

[0082] Example 7

[0083]

[0084] The synthesis of unsubstituted iodinated pyrone (3 g) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0085] Unsubstituted iodine pyrone (3g), single crystal diffraction pattern as shown Fig.11 As shown, mp135℃~138℃; yield, 54.34%; 1 H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.83(d,J=7.4Hz,2H),7.71(t,J=7.5Hz,1H),7.67(dd ,J=8.7,2.1Hz,1H),7.56(t,J=7.7Hz,2H),7.52(d,J=2.0Hz,1H),7.18(s,1H),6.90-6.84(m,1H). 13 C NMR(101MHz,Chloroform-d)δ197.50,151.81,142.44,138.41,137.68,135.49,134.44,130.12,129.04, 122.45(q,J=289.0Hz,1C),122.31,119.00,118.41,96.11(q,J=35.0Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.forC 17 H9IF3O2 + :428.9594; found:428.9596.

[0086] Example 8

[0087]

[0088] The synthesis of unsubstituted diiodopyrone (3h) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0089] Unsubstituted diiodopyrone (3h), mp 167℃~178℃; yield, 48.8%; 1H NMR(400MHz,Chloroform-d)δ8.12(d,J=1.9Hz,1H),7.94(s,1H),7.86-7.80(m,2H ),7.72(t,J=7.5Hz,1H),7.56(t,J=7.8Hz,2H),7.48(d,J=1.9Hz,1H),7.09(s,1H). 13 C NMR(101MHz,Chloroform-d)δ196.99,151.39,150.20,137.68,135.35,134.63,130.16,123.70,123.05,12 2.49(q,J=286.0Hz,1C),119.14,97.09(q,J=35.5Hz,1C),96.91,85.01,84.86.HRMS(ESI-TOF):m / z[M-OH] + calcd.for C 17 H8I2F3O2 + :554.8560; found:554.8558.

[0090] Example 9

[0091]

[0092] The synthesis of unsubstituted methoxypyrone (3i) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0093] Unsubstituted methoxypyrone (3i), mp 135℃~136℃; yield, 34.53%; 1 H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.84(d,J=7.2Hz,2H),7.70(t,J=7.5Hz,1H),7 .56(t,J=7.7Hz,2H),7.24(s,1H),7.05-6.96(m,2H),6.68(d,J=2.7Hz,1H),3.76(s,3H). 13 C NMR(101MHz,Chloroform-d)δ197.85,154.77,140.40,135.91,134.12,130.08,128.95,122.62(q,J=276.0H z,1C),122.02,120.68,117.08,116.91,112.92,96.23,96.06(q,J=35.0Hz,1C).HRMS(ESI-TOF):m / z[M-OH] +calcd.for C 18 H 12 F3O3 + :333.0733; found:333.0731.

[0094] Example 10

[0095]

[0096] The synthesis of unsubstituted nitropyrone (3j) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0097] Unsubstituted nitropyrone (3j), mp 220℃~222℃; yield, 56.22%; 1 H NMR(400MHz, DMSO-d6)δ8.30(dd,J=9.0,2.6Hz,1H),8.17(d,J=2.6Hz,1H),8.00(s,1H),7.90- 7.83(m,2H),7.75(t,J=7.5Hz,1H),7.59(t,J=7.8Hz,2H),7.30(s,1H),7.21(d,J=9.0Hz,1H). 13 CNMR(101MHz,Chloroform-d)δ196.99,156.25,142.84,137.22,135.02,134.91,130.24,12 9.22,128.97,125.15,123.59,116.86,96.87(q,J=53.0Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.for C 18 H9NF3O4 + :348.0478; found:348.0480.

[0098] Embodiment 11

[0099]

[0100] The synthesis of chlorodibromopyrone (3k) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0101] Chlorodibromopyrone (3k), mp 196℃~197℃; yield, 23.40%; 1H NMR (400MHz, Chloroform-d) δ7.80(s,1H),7.78(s,1H),7.76(d,J=2.2Hz,1H),7.70(s,1H),7.54(d,J=8.6Hz,2H),7.30(d,J=2.2Hz,1H),7.12(s,1H). 13 C NMR(101MHz,Chloroform-d)δ195.60,148.09,141.52,139.20,137.38,133.51,131.50,130.82,129.55, 123.15,122.16(q,J=289.0Hz,1C).,114.73,111.21,96.74(q,J=35.4Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.for C 17 H7Br2ClF3O2 + :493.8526; found:493.8561.

[0102] Example 12

[0103]

[0104] The synthesis of chloro-chloro-pyrone (31) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0105] Chlorochloropyrone (3l), mp 142℃~143℃; yield, 56.30%; 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=8.5Hz,2H),7.55(d,J=8.5Hz,2H),7.37( dd,J=8.8,2.5Hz,1H),7.20(d,J=2.5Hz,1H),7.16(s,1H),7.04(d,J=8.8Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ196.08,150.45,141.25,138.38,133.89,133.74,131.46,129.47,128.75,127 .71,123.83,122.46,122.39(q,J=288.0Hz,1C)117.73,96.08(q,J=35.0Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.for C 17 H8Cl2F3O2+ :371.9926; found:371.9939.

[0106] Example 13

[0107]

[0108] The synthesis of thiophene chloropyrone (3m) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0109] Thiophene chloropyrone (3m), mp 142℃~146℃; yield, 72.20%; 1 H NMR(400MHz,Chloroform-d)δ7.89(d,J=4.9Hz,1H),7.79(d,J=3.8Hz,1H),7.62(s,1H),7.39( s,1H),7.36(dd,J=8.7,2.5Hz,1H),7.27(s,1H),7.25(d,J=2.0Hz,1H),7.04(d,J=8.7Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ187.93,150.28,141.24,137.18,136.43,136.18,133.46,128.77,128.56,127 .62,122.30(q,J=289.0Hz,1C),117.81.,117.69,96.09,95.92(q,J=35.0Hz,1C).HRMS(ESI-TOF):m / z[M+Na] + calcd.for C 15 H8SClF3O3Na + :382.9732; found:382.9738.

[0110] Embodiment 14

[0111]

[0112] The synthesis of thiophene dichloropyrone (3n) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0113] Thiophene dichloropyrone (3n), single crystal diffraction pattern is shown in Figure 12, mp 185℃~189℃; yield, 84.12%; 1H NMR(400MHz,Chloroform-d)δ7.81(dd,J=4.9,1.0Hz,1H),7.70(d,J=3.8Hz,1H ),7.57(s,1H),7.37(d,J=2.4Hz,1H),7.19-7.15(m,1H),7.08(d,J=2.4Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ187.45,146.36,141.07,137.53,136.39,135.49,133.32,128.86 ,127.45,127.00,123.92,123.22,122.10(q,J=289.0Hz,1C).,118.84,96.47(q,J=35.0Hz,1C).

[0114] Embodiment 15

[0115]

[0116] The synthesis of thiophene dibromopyrone (3o) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0117] Thiophene dibromopyrone (3o), mp 143℃~145℃; yield, 47.12%; 1 H NMR(400MHz,Chloroform-d)δ7.89(d,J=4.9Hz,1H),7.78(d,J=3.7Hz,1H),7.66(s,1 H),7.45(d,J=2.3Hz,1H),7.34(s,1H),7.24(d,J=4.7Hz,1H),7.16(d,J=2.2Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ187.39,146.37,141.14,137.49,136.37,135.41,133.30 ,128.86,127.45,124.06,122.08(q,J=288.0Hz,1C).,96.66,96.49(q,J=35.0Hz,1C).

[0118] Example 16

[0119]

[0120] The synthesis of furanyl dichloropyrone (3p) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0121] Furandichloropyrone (3p), mp 131℃~138℃; yield, 79.80%; 1 H NMR (400MHz, Chloroform-d) δ7.89(s,1H),7.81(s,1H),7.58(s,1H),7.45(dd,J=13.6,2.8Hz,2H),7.21(d,J=2.0Hz,1H),6.71(d,J=3.5Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ197.04,146.55,137.51,135.24,134.70,133.54,130.20,129.12,127.44,127.17 ,123.69,123.42,122.80(q,J=288.0Hz,1C),118.88,96.74,96.51(q,J=35.3Hz,1C).HRMS(ESI-TOF):m / z[M+Na] + calcd.for C 15 H7Cl2F3O3 + :

[0122] Embodiment 17

[0123]

[0124] The synthesis of furanyl dibromopyrone (3q) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0125] Furandibromopyrone (3q), mp109℃~111℃; yield, 53.66%; 1 H NMR (400MHz, Chloroform-d) δ7.84(s,1H),7.80(s,1H),7.76(d,J=2.2Hz,1H),7.57(s,1H),7.43(d,J=3.6Hz,1H),7.39(d,J=2.2Hz,1H),6.71(s,1H). 13 C NMR(101MHz,Chloroform-d)δ181.43,150.77,149.22,148.05,138.98,136.70,130.85,122.96,122.52,121 .04(q,J=297.0Hz,1C),114.66,113.33,111.11,77.37,77.05(q,J=64.0Hz,1C).HRMS(ESI-TOF):m / z[M-OH] + calcd.for C15 H7Br2F3O3 + :449.8709; found:449.8733.

[0126] Embodiment 18

[0127]

[0128] The synthesis of pyridinedichloropyrone (3r) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0129] Pyridine dichloropyrone (3r), mp 129℃~130℃; yield, 47.60%; 1 H NMR(400MHz,Chloroform-d)δ9.04(s,1H),8.92(d,J=3.2Hz,1H),8.16(dd,J=7.9,1.9Hz,1H ),7.80(s,1H),7.54(dd,J=7.8,4.9Hz,1H),7.48(s,1H),7.19(s,1H),7.13(d,J=2.3Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ194.96,150.84,146.58,138.04,137.36,133.96,131.27,127.71,127.30,12 4.03,123.58,121.70(q,J=288.0Hz,1C),118.64,96.59,96.77(q,J=36.0Hz,1C).HRMS(ESI-TOF):m / z[M+H] + calcd.for C 16 H9Cl2NF3O3 + :389.9912; found:389.9918.

[0130] Application example: Antifungal activity test of benzopyran derivatives

[0131] 1. Required experimental reagents and instruments

[0132] Reagents: distilled water, glucose, agar, Tween 80, dimethyl sulfoxide.

[0133] Instruments: 50mL conical flask, kraft paper, signature pen, pipette, medium-sized pipette tip, large-sized pipette tip, hole puncher, lighter, inoculation spatula, sealing film, high-pressure steam sterilizer, alcohol lamp, rubber band, SW-CJ-2D double-person single-sided clean workbench, LRH-259 biochemical incubator.

[0134] 2. Experimental operation part

[0135] (1) Preparation of culture medium: Weigh 200g of peeled potatoes and cut them into appropriate small pieces. Put the prepared potato pieces into a pot containing 1000ml of distilled water, add cold water, boil over high heat, reduce to minimum heat and continue to cook for 30 minutes before turning off the induction cooker. Filter the boiled potato water with gauze into a 1000ml beaker, add distilled water just to the 1000ml mark, then add the weighed 20g of glucose and 18g of agar to the solution while hot, and stir quickly with a glass rod to prevent the solution from solidifying. Stir the solution until the glucose and agar are completely dissolved. Finally, dispense the prepared PDA culture medium into clean 50ml conical bottles with 30mL of culture solution per bottle, and seal the conical bottles with sealing film, kraft paper and rubber bands.

[0136] (2) Sterilization: Wrap the medium-sized pipette tip, large-sized pipette tip, inoculation spatula and hole punch with newspaper to isolate the air, seal the conical flasks containing 250 mL and 100 mL of distilled water with sealing film and kraft paper, and then put them together with the sealed conical flasks of culture medium into a high-pressure steam sterilizer for sterilization for 2 hours.

[0137] (3) Preparation of drugs: Weigh 6.6 mg of each drug, add 0.3 mL of DMSO in a double-person single-sided clean bench with the lighting and fan turned on. After the drug is dissolved, add 2.5 mL of Tween 80 to a conical flask containing 250 mL of distilled water using a pipette and a sterilized pipette tip. Add 10 mL of DMSO to 100 mL of distilled water, and use a pipette to transfer 3.0 mL of Tween water to the drug bottle to prepare a 200 ppm solution. For the blank control, only 0.3 mL of DMSO and 3 mL of Tween water were added.

[0138] (4) Ultraviolet sterilization: Place the prepared medicines, culture dishes marked with a signature pen, and an alcohol lamp into a two-person single-sided clean workbench and sterilize with ultraviolet light for 30 minutes.

[0139] (5) Pour the plate: After the UV sterilization is completed, turn off the UV lamp and turn on the lighting and fan. Wear gloves, disinfect your hands with alcohol, enter the double-person single-sided clean workbench, and light the alcohol lamp after the remaining alcohol on your hands evaporates. Take the conical flask containing the culture medium out of the sterilizer, remove the sealing film and kraft paper, pour the prepared medicine into the culture medium, shake it well, burn the mouth of the conical flask with an alcohol lamp to sterilize it, and pour the culture medium evenly into three culture dishes near the outer flame of the alcohol lamp.

[0140] (6) Ultraviolet sterilization: After the culture dish is poured, turn off the alcohol lamp, turn off the lighting and fan, turn on the ultraviolet lamp, put the culture dish, punch and inoculation spatula into the double-person single-sided clean workbench, and sterilize with ultraviolet light for 30 minutes.

[0141] (7) Inoculation of bacterial strains: After UV sterilization, turn off the UV lamp and turn on the lighting and fan. Wear gloves, disinfect your hands with alcohol, enter the double-person single-sided clean workbench, and light the alcohol lamp after the remaining alcohol on your hands evaporates. After burning and sterilizing the puncher with an alcohol lamp, punch a circle of holes on the outermost edge of the hyphae of the pre-cultured bacterial strain, burn and sterilize the inoculation shovel with an alcohol lamp, pick up the beaten bacterial cake with the inoculation shovel and place it on the culture medium, with the bacterial side touching the culture dish, and seal the culture dish with a sealing film.

[0142] (8) Cultivation: The inoculated culture dish was placed upside down in a biochemical incubator set at 26.5°C and cultured until the fungi in the blank control group grew to almost cover the entire culture dish.

[0143] (9) Measurement and calculation: Take out the culture dishes that have grown well, measure the diameter of the hyphae in each culture dish using the cross method, and take photos of the ones that are relatively round and free of foreign bacteria. After the measurement is completed, calculate the antibacterial rate. The calculation method of the antibacterial rate is: Antibacterial rate = (average diameter of hyphae in the control group - average diameter of the sample group) / (average diameter of hyphae in the control group - diameter of the puncher) (diameter of the puncher: 5 mm).

[0144] 3. Test results and analysis of antifungal activity of benzopyrone derivatives

[0145] The mycelium growth rate method was used to determine the antifungal activities of 18 target products against Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum, and Rhizoctonia solani, as shown in Tables 1-4, Figure 10-13 shown.

[0146] Table 1 Inhibition rate of target products against Rhizoctonia solani

[0147]

[0148]

[0149] Table 2 Inhibition rate of target products against Fusarium graminearum

[0150]

[0151] Table 3 Inhibition rate of target product on Fusarium oxysporum

[0152]

[0153] Table 4 Inhibition rate of target product on Fusarium moniliforme

[0154]

[0155]

[0156] Thiophene dibromopyrone with an inhibition rate of more than 80% against Rhizoctonia solani was selected for EC50 The half-dilution method was used to obtain the antibacterial rates at different concentrations, as shown in Table 5 and Fig.14 EC was obtained by SPSS software analysis. 50 The value is 223.284ppm, and the linear regression equation is y=1.49+0.64x, R 2 =0.935.

[0157] Table 5 Inhibition rate of thiophene dibromopyrone to Rhizoctonia solani at different concentrations

[0158]

[0159] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing benzopyran derivatives, characterized in that: Using trifluoroacetone with a benzene ring and different heterocycles and substituted salicylaldehyde as raw materials, DMSO as solvent, reflux reaction to generate crude benzopyran derivatives with different substituents, and post-treating the crude products to obtain benzopyran derivatives; The structural formula of the trifluoroacetone with a benzene ring and different heterocycles is shown below: R1 is one of H or 4-Cl; The structural formula of substituted salicylaldehyde is as follows: R2 is one of F, Cl, Br, I, OCH3, and NO2 substituted at the 5-position or one of F, Cl, Br, and I substituted at the 3,5-position.

2. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The reaction route is as follows: R1 is one of H or 4-Cl; R2 is one of F, Cl, Br, I, OCH3, NO2 substituted at the 5-position or one of F, Cl, Br, I substituted at the 3,5-position.

3. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The reaction route is as follows: R1 is H; R2 is Cl substituted at the 5-position or Cl substituted at the 3,5-position or Br substituted at the 3,5-position.

4. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The reaction route is as follows: R1 is H; R2 is Cl or Br substituted at the 3,5 position.

5. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The reaction route is as follows: R1 is H; R2 is Cl substituted at the 3,5 positions.

6. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The molar ratio of trifluoroacetone with a benzene ring and different heterocyclic rings to substituted salicylaldehyde is 1:

1.

7. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The reflux reaction temperature is 80°C-150°C, and the reflux reaction is carried out until the reaction is complete.

8. The method for synthesizing benzopyran derivatives according to claim 1, characterized in that: The steps for post-treatment of the crude product are as follows: transfer the crude product to a separatory funnel, extract with 20 ml of ethyl acetate and 20 ml of saturated brine, wash the ester layer three times with 15 ml of saturated brine, combine the water layers and wash three times with 10 ml of ethyl acetate, combine all ester layers, and then wash three times with 10 ml of saturated brine, finally combine the ester layers, dry them over anhydrous sodium sulfate, filter and transfer to a 100 ml round-bottom flask, concentrate by rotary evaporation to leave 3-5 ml, add 5 ml of petroleum ether for recrystallization, filter to obtain a solid, and dry the solid naturally to obtain the product.

9. Use of the benzopyran derivatives obtained by the synthesis method according to any one of claims 1 to 8 in the preparation of drugs for preventing and controlling plant fungi.

10. The use according to claim 9, characterized in that: The plant fungi are Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum and Rhizoctonia solani.

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