Benzopyran derivatives, synthesis methods and applications

Abstract

The present invention discloses a benzopyran derivative, a synthesis method, and an application thereof. Trifluoroacetone containing a benzene ring and different heterocycles and a substituted salicylaldehyde are used as raw materials, DMSO is used as a solvent, and a reflux reaction is performed to generate a crude benzopyran derivative with different substituents. The crude product is post-treated to obtain the benzopyran derivative. The reaction is tracked by TLC or liquid chromatography, and the reaction process is simple and easy to operate. Eighteen synthesized compounds were subjected to antifungal activity experiments to determine the antifungal activity of the compounds against Fusarium graminearum, Rhizoctonia solani, Fusarium moniliforme, and Fusarium oxysporum. At 200 ppm, thiophene dibromopyrone had the highest inhibition rate against Fusarium graminearum, at 98.84%; unsubstituted dichloropyrone had the highest inhibition rate against Fusarium graminearum, at 66.08%; pyridine dichloropyrone had the highest inhibition rate against Fusarium oxysporum, at 71.07%; and pyridine dichloropyrone had the highest inhibition rate against Fusarium moniliforme, at 69.12%. The benzopyran derivatives synthesized by the present invention will show good application prospects in various fields such as medicine, organic synthesis, biosensing and optoelectronic materials.

Description

Technical Field

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

[0002] Pathogenic plant fungi are those that can cause plant diseases. By parasitizing plants, they disrupt their normal physiological functions, leading to various disease symptoms. They can harm plants through various pathways, including direct invasion, secretion of toxins, and interference with nutrient absorption, causing a variety of plant diseases. These diseases can cause symptoms such as lesions, wilting, and rotting on leaves, stems, roots, and other parts of plants, ultimately leading to plant death. These pathogenic plant fungi spread through various pathways, including airborne, rainwater-borne, and insect-borne. They can reproduce within plants and produce toxins, causing varying degrees of damage.

[0003] Some fungi secrete toxins that are harmful to both humans and plants. For example, toxins are a common fungal toxin that can cause poisoning and death in animals, while also affecting plant growth and development, leading to reduced yields. Furthermore, fungi can affect a plant's nutrient absorption by invading its body. Some fungi can form mycorrhizae within plant roots, which can affect the plant's absorption of water and nutrients. These fungi also secrete enzymes that damage plant cell walls, causing cell death and, in turn, affecting plant growth and development. In short, fungi can cause multiple harms to plants, including causing disease, secreting toxins, and affecting nutrient absorption. To protect plant health and growth, effective measures are needed 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, thereby facilitating penetration into host cells. In plants, the fungal proteolytic machinery is responsible for the removal of abnormal or nonfunctional proteins, the activation / inactivation of specific proteins, and autolytic processes. Furthermore, proteases increase the permeability of plant plasma membranes, suggesting that they may play a key role in plant pathogenesis.

[0005] Chitin is a polysaccharide found primarily in the exoskeletons of insects, crustaceans, and fungal cell walls. Chitinase, an enzyme that catalyzes the hydrolysis of chitin to produce N-acetylglucosamine, was first discovered by Kahler and Hofmann in 1929 in the gastric juice (midgut gland secretion) of the snail Helix pomatia. The enzyme has since been found in the molting gland secretions of insects, the peel of almonds, and mold fungi.

[0006] Chitinases play multiple roles in organisms. First, they primarily participate in the degradation and breakdown of chitin. Second, chitinases play a role in maintaining the integrity and stability of cell walls. In organisms such as fungi and insects, chitinases participate in cell wall metabolism and remodeling, aiding in cell wall reconstruction and repair. Furthermore, chitinases have a defensive role, degrading chitin in the cell walls of parasites and pathogens, disrupting their structure and thus protecting against external invasion. Over the past few decades, interest in the role of chitinases in plants has been intense. While there is strong evidence that they are antifungal proteins, they may also play a role in nonspecific stress responses and regulate development. Therefore, by synthesizing compounds that interact with chitinases, it is theoretically possible to disrupt the structure of pathogenic fungi and thus protect crops.

[0007] To control fungal damage to plants, numerous antifungal drugs have been developed. Their synthesis relies primarily on organic synthetic chemistry and can be categorized into several groups. Among the numerous fluorinated compounds used in the pharmaceutical and agrochemical industries, nitrogen-containing heterocycles with fluorine atoms or trifluoromethyl groups are common. These drugs have diverse mechanisms of action and a range of disease targets. The synthesis of these drugs involves synthesizing precursors, constructing the drug backbone, and introducing active groups. The selection and preparation of synthetic precursors are crucial, as they determine the drug's structure and properties.

[0008] Benzopyrans, also known as chromenes, are an important class of oxygen-containing heterocyclic compounds formed by the fusion of benzene and pyran. They are primarily found in natural products such as alkaloids, flavonoids, tocopherols, and anthocyanins, and their basic structure is benzopyran. The benzopyran core unit, present in a variety of natural products such as tocopherol, α-tocotrienol, and γ-tocotrienol, contains a phytyl chain on the pyran ring. Benzopyran derivatives are essential to human life and play a crucial role in pharmaceutical chemistry. They possess excellent pharmacological and biological activities, such as antioxidant, antibacterial, anticoagulant, anticancer, and antitumor activities, and are widely used in a variety of pharmaceuticals, including anticoagulants, anticancer drugs, and antiallergic agents. Benzopyran compounds have also been found to interact with chitinase, thereby exerting activity against fungal diseases in agricultural fields.

[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, the rapid synthesis of a large number of various biologically active and stable benzopyran compounds is a major challenge. 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 present invention aims to provide a benzopyran derivative, a synthesis method and an application thereof. The Knoevenagel condensation reaction of trifluoroacetone, a cheap and readily available raw material, with substituted salicylaldehyde is carried out 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 having a benzene ring and different heterocycles and substituted salicylaldehyde as raw materials, DMSO as solvent, and ammonium acetate as catalyst, performing a reflux reaction to generate crude benzopyran derivatives having different substituents, and 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 scheme is shown below:

[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 scheme is shown below:

[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 scheme is shown below:

[0025]

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

[0027] Further, the reaction scheme is shown below:

[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 heterocycles 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 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 aqueous 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 the combined ester layers are finally dried over anhydrous sodium sulfate, filtered and transferred to a 100 ml round-bottom flask, and the remaining 3 to 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 benzopyran derivatives obtained by the synthesis method in the preparation of drugs for preventing and treating 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, nuclear magnetic resonance 13 C spectroscopy and high-resolution mass spectrometry confirmed the successful synthesis of the target product. High-performance liquid chromatography analysis then explored the reaction conditions and found that the most effective conditions for accelerating the reaction rate and improving the yield were 105°C in DMSO under the catalysis of ammonium acetate for 8 hours, yielding 76.25%.

[0036] The antifungal activity of the 18 synthesized compounds was tested using the mycelial growth rate method to determine the antifungal activity 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, at 98.84%; unsubstituted dichloropyrone had the highest inhibition rate against Fusarium graminearum, at 66.08%; pyridine dichloropyrone had the highest inhibition rate against Fusarium oxysporum, at 71.07%; and pyridine dichloropyrone had the highest inhibition rate against Fusarium oxysporum, at 69.12%. The EC test was performed on substances with an inhibition rate of more than 80% using the half-dilution method. 50 Activity test, EC 50 The synthesized compound has a promising application prospect in various fields such as medicine, organic synthesis, biosensor 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 following briefly introduces the drawings required for use in the embodiments or the description of the prior art. 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 any creative work.

[0038] Figure 1 This is 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 This 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] Figure 9 This is the single crystal diffraction pattern of thiophene dichloropyrone in Example 14;

[0047] Figure 10 The figure is a comparison of the inhibition rate against Rhizoctonia solani (200ppm);

[0048] Figure 11 The figure is a comparison of the inhibition rate against Fusarium graminearum (200ppm);

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

[0050] Figure 13 The figure is a comparison of the inhibition rate against Fusarium moniliforme (200ppm);

[0051] Figure 14 The figure shows the comparison of the inhibition rate of different concentrations of 3o against Rhizoctonia solani. DETAILED DESCRIPTION

[0052] The present invention will be further described below with reference to specific examples. It should be understood that the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention, and that those skilled in the art may make non-essential improvements and adjustments based on the contents of the above invention.

[0053] The present invention uses trifluoroacetone with a benzene ring or a heterocyclic ring and a substituted salicylaldehyde as raw materials to synthesize 18 new benzopyrone derivatives. The compounds are characterized by H nuclear magnetic resonance spectroscopy, C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry, indicating 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 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 were dissolved in 10 ml of DMSO and heated at 105°C. After completion of the reaction, as monitored by thin-layer chromatography, the reaction solution was transferred to a separatory funnel, added with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to remove some of the solvent. An appropriate amount of petroleum ether was added, and the precipitated solid was cooled. Filtered and dried to obtain the product in a yield of 61.05%.

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

[0060] H NMR spectrum characterization: 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 the -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 atoms shown in the C NMR spectrum is consistent with the number of C atoms in the molecular formula of the target product compound.

[0062] The high-resolution mass spectrometry shows that the theoretical molar mass of the unsubstituted chloropyrone is reduced by 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 for the different reaction starting materials.

[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 for the different starting materials. 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 was the same as in Example 1 except for the different reaction starting materials.

[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 was the same as in Example 1 except for the different reaction starting materials.

[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 was the same as in Example 1 except for the different reaction starting materials.

[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 iodopyrone (3 g) in this example was the same as in Example 1 except for the different reaction starting materials.

[0085] Unsubstituted iodine pyrone (3g), single crystal diffraction pattern as shown Figure 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 for the different reaction starting materials.

[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 for the different reaction starting materials.

[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 for the different reaction starting materials.

[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] Example 11

[0099]

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

[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-chloropyrone (31) in this example is the same as in Example 1 except that the reaction raw materials are different.

[0105] Chloropyrone (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 was the same as in Example 1 except for the different reaction starting materials.

[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] Example 14

[0111]

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

[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] Example 15

[0115]

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

[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 furanyldichloropyrone (3p) in this example was the same as in Example 1 except for the different reaction starting materials.

[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] Example 17

[0123]

[0124] The synthesis of furanyl dibromopyrone (3q) in this example was the same as in Example 1 except for the different reaction starting materials.

[0125] Furandibromopyrone (3q), mp 109℃~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] Example 18

[0127]

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

[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 testing of benzopyran derivatives

[0131] 1. Required experimental reagents and instruments

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

[0133] Instruments: 50 mL conical flask, kraft paper, signature pen, pipette, medium-sized pipette tip, large-sized pipette tip, hole punch, lighter, inoculation spatula, sealing film, high-pressure steam sterilizer, alcohol lamp, rubber band, SW-CJ-2D double-person single-sided clean bench, 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. Place the prepared potato pieces in a pot containing 1000ml of distilled water, add cold water, bring to a 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 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 flasks at 30ml per bottle, and seal the conical flasks with sealing film, kraft paper and rubber bands.

[0136] (2) Sterilization: Wrap the medium-sized pipette tip, large-sized pipette tip, inoculation spatula, and punch with newspaper to isolate the air. Seal the Erlenmeyer flasks containing 250 mL and 100 mL of distilled water with sealing film and kraft paper. Then, place them together with the sealed Erlenmeyer flasks containing culture medium in a high-pressure steam sterilizer and sterilize for 2 h.

[0137] (3) Preparation of drugs: Weigh 6.6 mg of each drug and add 0.3 mL of DMSO to a double-person, single-sided clean bench with the lights and fan 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 pipette 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) UV sterilization: Place the prepared medicines, culture dishes marked with a signature pen, and an alcohol lamp into a double-person single-sided clean workbench and sterilize with UV 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) UV sterilization: After the culture dish is poured, turn off the alcohol lamp, turn off the lighting and fan, turn on the UV lamp, and place the culture dish, punch and inoculation spatula together in a double-person single-sided clean workbench for UV sterilization for 30 minutes.

[0141] (7) Inoculation: 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 the punch with the alcohol lamp to sterilize it, punch a circle of holes on the outermost edge of the mycelium of the pre-cultured strain, burn the inoculation shovel with the alcohol lamp to sterilize it, and pick up the punched 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 sealing film.

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

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

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

[0145] The mycelial 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 against 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 Figure 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 basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended 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 is carried out to generate crude benzopyran derivatives with different substituents. The crude product is post-treated to obtain benzopyran derivatives; the structural formula of the benzopyran derivatives is shown below: 、 、 、 ； 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, NO2 substituted at the 5-position or one of F, Cl, Br, I substituted at the 3,5-position.

2. The method for synthesizing benzopyran derivatives according to claim 1, wherein: 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, wherein: 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, wherein: 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, wherein: 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, wherein: The molar ratio of trifluoroacetone with a benzene ring and different heterocycles to substituted salicylaldehyde is 1:

1.

7. The method for synthesizing benzopyran derivatives according to claim 1, wherein: 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, wherein: 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 aqueous layers and wash three times with 10 ml of ethyl acetate, combine all the ester layers, and then wash three times with 10 ml of saturated brine. Finally, the combined ester layers are dried over anhydrous sodium sulfate, filtered and transferred to a 100 ml round-bottom flask, concentrated by rotary evaporation to a remaining 3-5 ml, added with 5 ml of petroleum ether for recrystallization, filtered to obtain a solid, and dried naturally to obtain the product.

9. Use of a benzopyran derivative obtained by the synthesis method according to any one of claims 1 to 8 in the preparation of a drug 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.

Images