Phenolic derivatives containing a phthalide structure, and methods of making and using the same

Abstract

The present application belongs to the technical field of pesticides, and relates to a phenolic derivative containing a phthalide structure, and a preparation method and application thereof. The present application combines and modifies phthalide and phenol to synthesize the phenolic derivative containing the phthalide structure. The present application uses, for example, ortho-carboxybenzaldehyde, phthalide, phenolic compounds, and the like as raw materials, and synthesizes the phenolic derivative containing the phthalide structure through condensation, nucleophilic substitution, and the like. The reaction condition is mild, the acid reagent, the basic reagent, and the Lewis acid used are easy to obtain, and the product is easy to purify. The phenolic derivative containing the phthalide structure has good prevention and treatment effects on tobacco mosaic virus, pepper virus, wheat virus, and the like, solves the problems of a lack of types of existing anti-plant virus agents and insufficient activity, and is expected to be developed into a new anti-plant virus agent which is efficient, safe, economical, and environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of pesticide technology and relates to phenolic derivatives containing phthalide structures, their preparation methods and applications. Background Technology

[0002] Plant viruses are significant pathogens affecting crops, characterized by their high damage and difficulty in control. Tobacco mosaic virus (TMV) is one of the most widely studied plant viruses, capable of infecting a variety of plants, including tobacco, tomato, pepper, cucumber, potato, and some ornamental flowers. The use of antiviral agents is a crucial measure for controlling plant viral diseases and can effectively reduce crop yield losses. Currently, only a few commercially available agents are used to control plant viral diseases. However, the efficacy of these commonly used agents (such as ningnanmycin and ribavirin) is generally below 60%, and there is a severe shortage of highly effective antiviral agents in production. Therefore, the development of highly effective, safe, economical, and environmentally friendly green antiviral agents has become a focus of attention in the current pesticide field.

[0003] Phenylphthalide compounds are widely found in bioactive natural products and drug molecules, exhibiting broad biological activity. In the pesticide field, phthalide structures are present in many existing pesticides (such as the organochlorine fungicide tetrachlorophthalide) and active compounds. For example, Zhang Peng et al. (CN202110633349.9) isolated the compounds tennalide A and tennalide from the tobacco endophytic fungus *Aspergillus tennesseensis* 1022LEF. B, which has significant inhibitory activity against tobacco mosaic virus; Chinese patent (CN202211462135.0) provides the application of butenyl phthalide in the control of fall armyworm; Chinese patent (CN202210351561.0) discloses the application of butenyl phthalide and butyl phthalide in the control of crop white mold; Chinese patent (CN202410021506.4) discloses the application of butenyl phthalide as a fungicide synergist in the control of peanut root rot; Chinese patent (CN201911344621.0) discloses the application of a phthalide derivative in the control of plant viruses, fungicide, insecticide and acaricide, some phthalide compounds show certain antiviral activity, but only comparable to the commercial variety ribavirin.

[0004] In summary, phthalide compounds have potential applications in the pesticide field, but their research and development as antiviral agents for plants remains relatively limited, and their antiviral activity needs further improvement. On the other hand, phenolic compounds (such as guaiacol, thymol, and carawayol) are important natural products and industrial raw materials, possessing advantages such as wide availability and low cost. Therefore, by organically combining and rationally modifying the phthalide and phenolic structures, novel phenolic derivatives containing phthalide structures are designed and synthesized, and their antiviral activity is systematically studied. This is of great significance for developing new pesticides with independent intellectual property rights. Summary of the Invention

[0005] To address the problems and deficiencies in the existing technologies, this invention provides phenolic derivatives containing phthalide structures, their preparation methods, and applications. This invention organically combines and modifies phthalide and phenol structures, successfully synthesizing a series of phenolic derivatives containing phthalide structures. These compounds exhibit significant inhibitory effects against plant viruses.

[0006] In a first aspect, the present invention provides phenolic derivatives containing a phthalide structure, having a structure as shown in formula (I), or stereoisomers, tautomers, isotopic derivatives thereof, or pesticide-acceptable salts thereof.

[0007]

[0008] Among them, R 0 Each of the following groups is independently selected from hydrogen, halogen, amino, amide, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted benzene ring, optionally substituted aromatic heterocycle, optionally substituted aryloxy.

[0009] R 1 It is selected from any one of acyl, ester, aminoacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted benzene ring, optionally substituted aromatic heterocycle, optionally substituted aryloxy group;

[0010] R 2 R 3 R 4 R 5 Each group is independently selected from any one of hydrogen, halogen, amino, amide, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino;

[0011] m is selected from 0 or 1;

[0012] n is an integer between 0 and 4;

[0013] The optional substitution is unsubstituted, or substituted by any one or more groups selected from halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, and aryl.

[0014] Furthermore, in the phenolic derivatives containing a phthalide structure provided by the present invention, the alkyl group, alkylthio group, and alkylamine group have 1 to 8 carbon atoms in the alkyl group;

[0015] The alkoxy group has 1 to 8 carbon atoms;

[0016] The halogen is selected from any one of fluorine, chlorine, bromine, and iodine;

[0017] The aromatic heterocycle is a C1-C10 aromatic heterocycle containing nitrogen, sulfur, or oxygen;

[0018] The aromatic heterocycle is selected from any one of pyrrole, thiophene, furan, pyridine, pyran, imidazole, thiazole, oxazole, isoxazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, indole, oxadiazole, thiadiazole, triazole, and tetraazole.

[0019] Furthermore, the phenolic derivatives containing a phthalide structure provided by the present invention have the structure shown in formula (I-a), or its stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts thereof.

[0020]

[0021] Among them, R 1 It is selected from any one of acyl, ester, aminoacyl, C1~C8 alkyl, C1~C8 alkenyl, C1~C8 alkynyl, substituted benzene ring, C1~C10 nitrogen-containing heterocycle, C1~C10 oxygen-containing heterocycle, C1~C10 sulfur-containing heterocycle, and C1~C10 aryloxy group;

[0022] R 2 R 3 R 4 R 5 Each group is independently selected from any one of hydrogen, halogen, amino, acylamino, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, C1-C8 alkyl, C1-C8 haloalkane, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkylthio, and C1-C8 alkylamino.

[0023] The halogen is selected from any one of fluorine, chlorine, bromine, and iodine;

[0024] The substituents are selected from any one or more of the following groups: halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, and aryl.

[0025] Furthermore, in the phenolic derivatives containing a phthalide structure provided by the present invention, the phenolic derivatives containing a phthalide structure are selected from the following structures:

[0026]

[0027]

[0028] .

[0029] Secondly, the present invention provides a method for preparing phenolic derivatives containing a phthalide structure, comprising:

[0030] Route 1:

[0031] ;

[0032] Route 2:

[0033] ;

[0034] Where X is fluorine, chlorine, bromine or iodine.

[0035] Furthermore, in the preparation method of the phenolic derivative containing the phthalide structure provided by the present invention, route 1 includes: using o-carboxybenzaldehyde compound II and phenolic compound III as raw materials, condensing them under acidic conditions to generate phenolic compound IV; after purification, phenolic compound IV undergoes a nucleophilic substitution reaction with halogenated compound V under alkaline conditions to generate phenolic derivative I containing the phthalide structure;

[0036] Furthermore, in the preparation method of the phenolic derivative containing a phthalide structure provided by the present invention, route 2 includes: using phenolic compound III and halogenated compound V as raw materials, a nucleophilic substitution reaction is carried out under alkaline conditions to generate phenolic compound VI; after purification, phenolic compound VI is condensed with 3-halogenated phthalide compound VII under Lewis acid catalysis to generate phenolic derivative I containing a phthalide structure.

[0037] Furthermore, in the method for preparing phenolic derivatives containing phthalide structures provided by the present invention, the acid in the acidic condition is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Amberlyst, and ZnCl2;

[0038] The base used in the alkaline conditions is selected from any one of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydride, triethylamine, pyridine, and 1,8-diazacyclic [5.4.0]undec-7-ene (DBU);

[0039] The Lewis acid is selected from any one of tin tetrachloride, boron trifluoride ether, and anhydrous aluminum trichloride.

[0040] Thirdly, the present invention provides a pesticide composition, characterized in that the active ingredient of the pesticide composition includes the above-mentioned phenolic derivative containing a phthalide structure.

[0041] Fourthly, the present invention provides the application of phenolic derivatives or pesticide compositions containing phthalide structures in the treatment of plant viruses, including tobacco mosaic virus, pepper virus, wheat virus, rice virus, tomato virus, sweet potato virus, potato virus, cucurbit virus, and maize dwarf mosaic virus.

[0042] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages:

[0043] This invention successfully synthesized a series of novel phenolic derivatives containing phthalide structures by organically combining and rationally modifying the structures of phthalide and phenol. Bioactivity tests showed that these phenolic derivatives exhibited significant inhibitory effects against plant viruses such as tobacco mosaic virus (TMV). Regarding the synthetic method, optimal reaction conditions were established through systematic optimization. This method has advantages such as short steps, readily available raw materials, and high yield. The antiviral activity of the phenolic derivatives containing phthalide structures was evaluated using the half-leaf necrotic spot method. The results showed that within the application concentration range of 100–500 μg / mL, they exhibited excellent comprehensive antiviral activity against TMV, including significant inactivation, therapeutic, and protective activities. Compared with existing commercial antiviral agents for plants, the compounds provided by this invention have novel structures, a simple and efficient synthetic process, and are both highly efficient and environmentally friendly. Based on these characteristics, phenolic derivatives containing phthalide structures hold promise for development into a new generation of highly efficient, safe, economical, and environmentally friendly antiviral agents for plants. Detailed Implementation

[0044] The technical solution of the present invention will be described below with reference to embodiments. However, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental methods and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials can be purchased commercially.

[0045] In this invention, the alkyl groups in alkylthio and alkylamine groups refer to monovalent saturated aliphatic hydrocarbon groups, containing 1 to 20, 1 to 18, 1 to 16, 1 to 12, or 1 to 10 carbon atoms; preferably, straight-chain or branched groups with 1 to 8 carbon atoms (C1 to C8 alkyl, specifically 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms), more preferably straight-chain or branched groups with 1 to 6 carbon atoms (i.e., C1 to C6 alkyl, specifically 1, 2, 3, 4, 5, or 6 carbon atoms). Specific embodiments include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0046] In this invention, alkoxy groups specifically refer to alkyl-O- groups; alkylthio groups specifically refer to alkyl-S- groups; and alkylamine groups specifically refer to alkyl-NH- or dialkyl-N- groups. The alkyl group in the dialkyl-N- group may be selected from the same group or from different groups.

[0047] The halogens involved in this invention refer to fluorine, chlorine, bromine, and iodine.

[0048] The phenolic derivatives containing a phthalide structure described in this invention include the compound shown in formula (I) and its stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts thereof. The stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts of the compound are obtained using conventional techniques in the art, and exert the same or similar biological effects in vitro and in vivo through a mechanism of action substantially consistent with that of the compound shown in formula (I).

[0049] ,

[0050] Among them, R 0 Each of the following groups is independently selected from hydrogen, halogen, amino, amide, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted benzene ring, optionally substituted aromatic heterocycle, optionally substituted aryloxy.

[0051] R 1 It is selected from any one of acyl, ester, aminoacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted benzene ring, optionally substituted aromatic heterocycle, optionally substituted aryloxy group;

[0052] R 2 R 3 R4 R 5 Each group is independently selected from any one of hydrogen, halogen, amino, amide, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino;

[0053] n is an integer between 0 and 4;

[0054] The optional substitution is unsubstituted, or substituted by any one or more groups selected from halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, and aryl.

[0055] Stereoisomers are isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may exist in this compound. Optical isomers are substances with identical molecular structures and similar physicochemical properties, but different optical rotations. The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, where “R” and “S” are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. A compound containing asymmetrically substituted carbon atoms is racemic if the number of R configurations and S configurations of the asymmetrically substituted carbon atoms in the compound are equal. Having an excess of atoms in one configuration (relative to another) results in a higher quantity of that configuration, preferably an excess of about 85% to 90%, more preferably an excess of about 95% to 99%, and even more preferably an excess greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0056] Tautomers are structural isomers with different energies that can interconvert through low energy barriers. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomers. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0057] Isotope derivatives refer to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, 80 Br and 125 I. Compounds containing these and / or other isotopes are within the scope of this invention. The isotopically labeled compounds of this invention can be prepared using general methods well known to those skilled in the art.

[0058] The pesticide-acceptable salt refers to the salt obtained by reacting the phenolic derivative containing the phthalide structure of this invention with a chemically acceptable acid. The chemically acceptable acid can be an inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid) or an organic acid (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, or benzoic acid). The pesticide-acceptable salt can also be the salt obtained by reacting the phenolic derivative containing the phthalide structure of this application with a chemically acceptable base, wherein the chemically acceptable base can be an inorganic base (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) or an organic base (such as trimethylamine, triethylamine, etc.). Further, the pesticide-acceptable salt can be a potassium salt, sodium salt, ammonium salt, calcium salt, pyridine salt, choline salt, hydrochloride salt, phosphate salt, acetate salt, benzenesulfonate salt, or oxalate salt.

[0059] Example 1

[0060] The compound I-1 (R) described in this embodiment 1 =Methyl, R 2 =Methoxy, R 3 =R 4 =R 5 The synthesis method of (=hydrogen, m=1) is as follows:

[0061]

[0062] (1) Synthesis of compound IV-1: Compound II-1 (0.15 g, 1.0 mmol), Amberlyst 15 (hydrogen form, 0.22 g, 0.7 mmol), 1,2-dichloroethane (2 mL), and compound III-1 (guaiacol, 0.19 g, 1.5 mmol) were placed in a reaction flask, mixed at room temperature, and refluxed at 90 °C for 12 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was diluted with dichloromethane (10 mL) and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give compound IV-1 (0.14 g, yield 56.3%) as a white solid.

[0063] (2) Synthesis of compound I-1: Compound IV-1 (0.20 g, 0.7 mmol), anhydrous potassium carbonate (0.29 g, 2.1 mmol), and N,N-dimethylformamide (2 mL) were mixed, and bromoethane (0.11 g, 1.0 mmol) was added. The mixture was stirred at 40 °C for 6 h, and the reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water (10 mL) and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound I-1 (0.10 g, yield 37.6%) as a white solid.

[0064] The detection results for compound I-1 are as follows:

[0065] mp = 101.7–115.2 ℃;

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 7.7, 1.0 Hz, 1H), 6.84(d, J = 1.8 Hz, 2H), 6.68 (d, J = 1.8 Hz, 1H), 6.36 (s, 1H), 4.09 (q, J = 6.9Hz, 2H), 3.80 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H);

[0067] 13C NMR (101 MHz, CDCl3) δ 170.7, 149.8, 149.7, 149.3, 134.4, 129.5,128.5, 125.9, 125.7, 123.1, 120.2, 112.4, 110.3, 83.1, 64.4, 56.1, 14.8;

[0068] ESI-MS calculated for C 17 H 16 O4[M + Na] + , 307.0941; found, 307.0950.

[0069] Example 2

[0070] The compound I-2 (R) described in this embodiment 1 =Vinyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0071]

[0072] The synthesis method of compound I-2 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 3-bromopropene to obtain compound I-2 (white solid, 0.18 g, yield 31.8%).

[0073] The detection results for compound I-2 are as follows:

[0074] mp = 75.3–78.7 ℃;

[0075] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J= 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 7.6, 0.9 Hz, 1H), 6.86(d,J = 8.2 Hz, 1H), 6.82 (dd, J = 8.3, 2.0 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6.35 (s, 1H), 6.06 (ddd, J= 22.7, 10.6, 5.4 Hz, 1H), 5.39 (dd, J = 17.2, 1.6Hz, 1H), 5.28 (dd, J = 10.4, 1.4 Hz, 1H), 4.61 (d, J = 5.4 Hz, 2H), 3.80 (s,3H);

[0076] 13 C NMR (101 MHz, CDCl3) δ 170.6, 149.9, 149.7, 149.0, 134.4, 133.1,129.5, 129.0, 125.9, 125.7, 123.1, 120.0, 118.4, 113.3, 110.5, 83.0, 70.0,56.1.

[0077] Example 3

[0078] The compound I-3 (R) described in this embodiment 1 =Ethynyl group, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0079]

[0080] The synthesis method of compound I-3 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 3-bromopropyne to obtain compound I-3 (brown solid, 0.98 g, yield 17.2%).

[0081] The detection results for compound I-3 are as follows:

[0082] mp = 119.5–123.6 ℃;

[0083] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.35 (dd, J = 7.6, 0.9 Hz, 1H), 7.03(d, J = 8.3 Hz, 1H), 6.87 (dd, J = 8.3, 2.1 Hz, 1H), 6.72 (d, J = 2.0 Hz,1H), 6.36 (s, 1H), 4.76 (d, J = 2.3 Hz, 2H), 3.80 (s, 3H), 2.51 (t, J = 2.4Hz, 1H);

[0084] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.2, 149.7, 147.7, 134.4, 130.2,129.5, 125.9, 125.8, 123.1, 119.9, 114.2, 110.5, 82.8, 78.3, 76.2, 56.8,56.1.

[0085] Example 4

[0086] The compound I-4 (R) described in this embodiment 1 =Phenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0087]

[0088] The synthesis method of compound I-4 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with benzyl bromoethane to obtain compound I-4 (brown solid, 0.17 g, yield 25.3%).

[0089] The detection results for compound I-4 are as follows:

[0090] mp = 145.5–150.4 ℃;

[0091] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J = 7.4,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 6.9 Hz, 2H), 7.39 – 7.29(m, 4H), 6.86 (d, J = 8.2 Hz, 1H), 6.79 (dd, J = 8.2, 2.1 Hz, 1H), 6.71 (d, J= 2.1 Hz, 1H), 6.35 (s, 1H), 5.16 (s, 2H), 3.82 (s, 3H);

[0092] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.1, 149.7, 149.1, 136.9, 134.4,129.5, 129.2, 128.7 (2C), 128.1, 127.3 (2C), 125.9, 125.7, 123.1, 120.1,113.8, 110.5, 83.0, 71.0, 56.2.

[0093] Example 5

[0094] The compound I-5 (R) described in this embodiment 1 =4-Fluorophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0095]

[0096] The synthesis method of compound I-5 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-fluorobenzyl bromide to obtain compound I-5 (yellow solid, 0.21 g, yield 29.1%).

[0097] The detection results for compound I-5 are as follows:

[0098] mp = 147.9–151.4 ℃;

[0099] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 – 7.36 (m, 2H), 7.33 (dd, J =7.7, 1.0 Hz, 1H), 7.08 – 7.00 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.80 (dd, J= 8.2, 2.1 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 6.35 (s, 1H), 5.10 (s, 2H), 3.81 (s, 3H);

[0100] 13 C NMR (101 MHz, CDCl3) δ 170.6, 162.6 (d, J = 246.1 Hz), 150.2,149.7, 148.9, 134.4, 132.6 (d, J = 3.4 Hz), 129.5, 129.4, 129.3 (d, J = 8.2Hz, 2C), 125.9, 125.8, 123.1, 120.0, 115.6 (d, J = 21.7 Hz, 2C), 113.9, 110.5, 82.9, 70.5, 56.2.

[0101] Example 6

[0102] The compound I-6 (R) described in this embodiment 1 =4-Chlorophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0103]

[0104] The synthesis method of compound I-6 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-chlorobenzyl bromide to obtain compound I-6 (white solid, 0.25 g, yield 34.4%).

[0105] The detection results for compound I-6 are as follows:

[0106] mp = 167.5–176.7 ℃;

[0107] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.6,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.38 – 7.29 (m, 5H), 6.83 (d, J = 8.4Hz, 1H), 6.79 (dd, J = 8.3, 2.0 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 6.35 (s,1H), 5.11 (s, 2H), 3.81 (s, 3H);

[0108] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.2, 149.7, 148.8, 135.4, 134.4,133.9, 129.5 (2C), 128.9 (2C), 128.7 (2C), 125.9, 125.8, 123.1, 120.0, 113.9,110.6, 82.9, 70.4, 56.2;

[0109] ESI-MS calculated for C 22 H 17 ClO4[M + Na] + , 403.0708; found, 403.0717.

[0110] Example 7

[0111] The compound I-7 (R) described in this embodiment 1 =2-Chlorophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0112]

[0113] The synthesis method of compound I-7 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with o-chlorobenzyl bromide to obtain compound I-7 (pale yellow oily liquid, 0.23 g, yield 86.2%).

[0114] The detection results for compound I-7 are as follows:

[0115] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.7Hz, 1H), 7.55 (m, 3H), 7.38 (dd, J = 6.7, 2.7 Hz, 1H), 7.34 (d, J = 7.7 Hz,1H), 7.26 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 8.3, 2.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.36 (s, 1H), 5.25 (s, 2H), 3.83 (s, 3H);

[0116] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.2, 149.7, 148.9, 134.6, 134.4,132.4, 129.6, 129.5, 129.5, 129.1, 128.7, 127.2, 125.9, 125.8, 123.1, 120.2,113.9, 110.8, 82.9, 68.2, 56.3.

[0117] Example 8

[0118] The compound I-8 (R) described in this embodiment 1 =3-Chlorophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0119]

[0120] The synthesis method of compound I-8 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with m-chlorobenzyl bromide to obtain compound I-8 (white solid, 0.14 g, yield 59.1%).

[0121] The detection results for compound I-8 are as follows:

[0122] mp = 113.6–128.3 ℃;

[0123] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.6,1.2 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 7.7 Hz,1H), 7.29 (s, 3H), 6.84 (d, J = 8.3 Hz, 1H), 6.80 (dd, J = 8.2, 2.0 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.35 (s, 1H), 5.11 (s, 2H), 3.82 (s, 3H);

[0124] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.3, 149.7, 148.9, 139.0, 134.7,134.4, 130.0, 129.7, 129.5, 128.3, 127.4, 125.9, 125.8, 125.4, 123.1, 120.1,114.1, 110.7, 82.9, 70.4, 56.2.

[0125] Example 9

[0126] The compound I-9 (R) described in this embodiment 1 =3,4-Dichlorophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0127]

[0128] The synthesis method of compound I-9 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 3,4-dichlorobenzyl bromide to obtain compound I-9 (pale yellow oily liquid, 0.10 g, yield 48.5%).

[0129] The detection results for compound I-9 are as follows:

[0130] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.43 (d, J =8.2 Hz, 1H), 7.34 (dd, J = 7.6, 0.9 Hz, 1H), 7.26 (s, 1H), 6.81 (d, J = 3.0Hz, 2H), 6.72 (d, J = 1.8 Hz, 1H), 6.35 (s, 1H), 5.08 (s, 2H), 3.82 (s, 3H);

[0131] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.3, 149.6, 148.7, 137.2, 134.5,132.9, 132.2, 130.8, 130.0, 129.6, 129.3, 126.6, 125.9, 125.8, 123.1, 120.0,114.2, 110.7, 82.8, 69.9, 56.2.

[0132] Example 10

[0133] The compound I-10 (R) described in this embodiment 1 =2,4-Dichlorophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0134]

[0135] The synthesis method of compound I-10 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 2,4-dichlorobenzyl bromide to obtain compound I-10 (pale yellow oily liquid, 0.08 g, yield 36.2%).

[0136] The detection results for compound I-10 are as follows:

[0137] 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz, 1H), 7.66 (t, 1H), 7.57(t, J = 7.5 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.34(d, J = 7.7 Hz, 1H), 7.26 (s, 1H), 6.82 (s, 2H), 6.73 (s, 1H), 6.36 (s, 1H), 5.19 (s, 2H), 3.83 (s, 3H);

[0138] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.3, 149.7, 148.7, 134.4, 134.3,133.3, 133.0, 129.9, 129.6, 129.6, 129.3, 127.5, 125.9, 125.8, 123.1, 120.1,114.0, 110.8, 82.9, 67.7, 56.3.

[0139] Example 11

[0140] The compound I-11 (R) described in this embodiment 1 =4-Bromophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0141]

[0142] The synthesis method of compound I-11 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-bromochlorobenzyl to obtain compound I-11 (pale yellow oily liquid, 0.45 g, yield 54.8%).

[0143] The detection results for compound I-11 are as follows:

[0144] mp = 152.5–163.3 ℃;

[0145] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J = 7.6,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.33 (dd, J =7.6, 0.9 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.2 Hz, 1H), 6.79(dd, J = 8.2, 1.9 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 6.35 (s, 1H), 5.09 (s,2H), 3.81 (s, 3H);

[0146] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.1, 149.6, 148.8, 135.9, 134.4(2C), 131.9 (2C), 129.5, 129.0 (2C), 125.9, 125.8, 123.0, 122.0, 120.0,113.9, 110.5, 82.9, 70.4, 56.2.

[0147] Example 12

[0148] The compound I-12 (R) described in this embodiment 1 =4-Trifluoromethylphenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0149]

[0150] The synthesis method of compound I-12 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-trifluoromethylbenzyl chloride to obtain compound I-12 (yellow solid, 0.2 g, yield 25.4%).

[0151] The detection results for compound I-12 are as follows:

[0152] mp = 97.5–103.5 ℃;

[0153] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 6.9 Hz, 3H), 7.33 (dd, J= 7.7, 1.0 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 8.2, 1.9 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.35 (s, 1H), 5.20 (s, 2H), 3.83 (s, 3H);

[0154] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.1, 149.6, 148.7, 141.0, 134.4,130.2 (q, J = 32.6 Hz), 129.7, 129.5, 127.3 (2C), 125.8, 125.8, 125.7 (q, J =3.5 Hz, 2C), 124.2 (q, J = 272.0 Hz), 123.0, 120.0, 113.8, 110.6, 82.9, 70.3,56.2.

[0155] Example 13

[0156] The compound I-13 (R) described in this embodiment 1 =4-Methoxyphenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0157]

[0158] The synthesis method of compound I-13 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-methoxybenzyl chloride to obtain compound I-13 (brown solid, 0.22 g, yield 30.9%).

[0159] The detection results for compound I-13 are as follows:

[0160] mp = 106.5–111.8 ℃;

[0161] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.65 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.37 – 7.31 (m, 3H), 6.91 – 6.85 (m,3H), 6.79 (dd, J = 8.2, 2.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.34 (s, 1H),5.07 (s, 2H), 3.80 (s, 6H);

[0162] 13 C NMR (101 MHz, CDCl3) δ 170.7, 159.5, 150.1, 149.7, 149.2, 134.4,129.5, 129.1, 129.1 (2C), 128.9, 125.9, 125.7, 123.1, 120.1, 114.1 (2C),113.9, 110.5, 83.0, 70.9, 56.2, 55.4.

[0163] Example 14

[0164] The compound I-14 (R) described in this embodiment 1 =4-Trifluoromethoxyphenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0165]

[0166] The synthesis method of compound I-14 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-trifluoromethoxybenzyl chloride to obtain compound I-14 (white solid, 0.17 g, yield 20.2%).

[0167] The detection results for compound I-14 are as follows:

[0168] mp = 97.7–98.9 ℃;

[0169] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.34 (dd, 6.35 (s, 1H), 5.13 (s, 2H), 3.82 (s, 3H);

[0170] 13 C NMR (101 MHz, CDCl3) δ 170.5, 150.1, 149.6, 148.9 (q, J = 1.9 Hz), 148.8, 135.5, 134.3, 129.5, 129.4, 128.7 (2C), 125.8, 125.7, 122.9, 121.2(2C), 120.5 (q, J = 257.1 Hz), 119.9, 113.7, 110.4, 82.8, 70.2, 56.1.

[0171] Example 15

[0172] The compound I-15 (R) described in this embodiment 1 =4-tert-butylphenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0173]

[0174] The synthesis method of compound I-15 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with 4-tert-butylbenzyl chloride to obtain compound I-15 (brown solid, 0.36 g, yield 46.3%).

[0175] The detection results for compound I-15 are as follows:

[0176] mp = 147.3–152.3 ℃;

[0177] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J = 7.5,1.2 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.42 – 7.30 (m, 5H), 6.89 (d, J = 8.2Hz, 1H), 6.80 (dd, J = 8.3, 2.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.35 (s,1H), 5.11 (s, 2H), 3.81 (s, 3H), 1.31 (s, 9H);

[0178] 13 C NMR (101 MHz, CDCl3) δ 170.7, 151.1, 150.1, 149.7, 149.3, 134.4,133.8, 129.5, 129.0, 127.3 (2C), 125.9, 125.7, 125.7 (2C), 123.1, 120.1,113.6, 110.5, 83.0, 70.9, 56.2, 34.7, 31.4 (3C).

[0179] Example 16

[0180] The compound I-16 (R) described in this embodiment 1 =4-Methylbenzoate group, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0181]

[0182] The synthesis method of compound I-16 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with methyl 4-chloromethylbenzoate to obtain compound I-16 (yellow solid, 0.42 g, yield 54.7%).

[0183] The detection results for compound I-16 are as follows:

[0184] mp = 125.1–133.5 ℃;

[0185] 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 8.02 (s, 1H), 7.96 (d, J = 7.7Hz, 1H), 7.65 (td, J = 7.5, 1.2 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.33 (dd, J = 7.7, 1.0 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.78 (dd, J = 8.3, 2.0 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.34 (s, 1H), 5.20 (s,2H), 3.91 (s, 3H), 3.83 (s, 3H);

[0186] 13 C NMR (101 MHz, CDCl3) δ 170.6, 167.0, 150.2, 149.6, 148.8, 142.1,134.4, 130.1 (2C), 129.8, 129.6, 129.5, 126.9 (2C), 125.9, 125.8, 123.1,120.0, 113.9, 110.6, 82.9, 70.5, 56.2, 52.3.

[0187] Example 17

[0188] The compound I-17 (R) described in this embodiment 1 =4-Methylbenzoate tert-butyl ester, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0189]

[0190] The synthesis method of compound I-17 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with tert-butyl p-chloromethylbenzoate to obtain compound I-17 (brown solid, 0.11 g, yield 13.2%).

[0191] The detection results for compound I-17 are as follows:

[0192] mp = 114.7–119.2 ℃;

[0193] 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.96 (d, J = 7.4 Hz, 2H), 7.65 (td, J = 7.5, 1.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 8.7 Hz,2H), 7.32 (dd, J = 7.6, 0.9 Hz, 1H), 6.80 (d, J =8.2 Hz, 1H), 6.77 (dd, J =8.4, 1.9 Hz, 1H), 6.71 (d, J = 1.8 Hz, 1H), 6.34 (s, 1H), 5.21 (s, 2H), 3.83 (s, 3H), 1.58 (s, 9H);

[0194] 13 C NMR (101 MHz, CDCl3) δ 170.6, 165.6, 150.1, 149.7, 148.8, 141.5,134.4, 131.7, 129.9 (2C), 129.5 (2C), 126.7 (2C), 125.9, 125.8, 123.1, 120.0,113.9, 110.6, 82.9, 81.2, 70.5, 56.2, 28.3 (3C);

[0195] ESI-MS calculated for C 27 H 26 O6[M + Na] + , 469.1622; found, 469.1628.

[0196] Example 18

[0197] The compound I-18 (R) described in this embodiment 1 =2-Cyanophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0198]

[0199] The synthesis method of compound I-18 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with o-cyanobenzyl chloride to obtain compound I-18 (brown solid, 0.61 g, yield 84.4%).

[0200] The detection results for compound I-18 are as follows:

[0201] mp = 144.3–148.1 ℃;

[0202] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.70 – 7.62 (m,3H), 7.57 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.33(dd, J = 7.6, 0.9 Hz, 1H), 6.81 (d, J = 1.8 Hz, 2H), 6.74 (s, 1H), 6.35 (s,1H), 5.19 (s, 2H), 3.83 (s, 3H);

[0203] 13 C NMR (101 MHz, CDCl3) δ 170.5, 150.2, 149.6, 148.5, 142.4, 134.4,132.6 (2C), 130.1, 129.6, 127.6 (2C), 125.9, 125.8, 123.0, 120.0, 118.8,114.1, 111.9, 110.7, 82.8, 70.2, 56.2.

[0204] Example 19

[0205] The compound I-19 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0206]

[0207] The synthesis method of compound I-19 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with m-cyanobenzyl chloride to obtain compound I-19 (yellow solid, 0.28 g, yield 39.0%).

[0208] The detection results for compound I-19 are as follows:

[0209] mp = 147.2–151.1 ℃;

[0210] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.67(dd, J = 7.5, 1.2 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.62 – 7.54 (m, 2H),7.48 (t, J = 7.7 Hz, 1H), 7.34 (dd, J = 7.6, 0.9 Hz, 1H), 6.85 – 6.79 (m,2H), 6.74 (d, J = 1.8 Hz, 1H), 6.36 (s, 1H), 5.15 (s, 2H), 3.83 (s, 3H);

[0211] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.3, 149.6, 148.5, 138.6, 134.5,131.8, 131.5, 130.8, 130.1, 129.6 (2C), 125.9, 125.8, 123.0, 120.0, 118.8,114.1, 112.9, 110.7, 82.8, 70.0, 56.2;

[0212] ESI-MS calculated for C 23 H 17 NO4[M + Na] + , 394.1050; found, 394.1058.

[0213] Example 20

[0214] The compound I-20 (R) described in this embodiment 1 =4-Cyanophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0215]

[0216] The synthesis method of compound I-20 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with p-cyanobenzyl chloride to obtain compound I-20 (white solid, 0.61 g, yield 84.2%).

[0217] The detection results for compound I-20 are as follows:

[0218] mp = 93.7–101.2 ℃;

[0219] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.69 (m, 3H), 7.64(td, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.42 (td, J = 7.6, 1.4 Hz, 2H), 7.35 (d,J = 7.7 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.36 (s, 1H), 5.32 (s, 2H), 3.83 (s, 3H);

[0220] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.4, 149.6, 148.5, 140.5, 134.5,133.3, 132.9, 130.3, 129.6, 128.6, 128.5, 125.8 (2C), 123.1, 120.1, 117.1,114.5, 111.0, 110.7, 82.8, 68.7, 56.2.

[0221] Example 21

[0222] The compound I-21 (R) described in this embodiment 1 =2-Nitrophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0223]

[0224] The synthesis method of compound I-21 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with o-nitrobenzyl chloride to obtain compound I-21 (brown solid, 0.62 g, yield 81.8%).

[0225] The detection results for compound I-21 are as follows:

[0226] mp = 142.1–145.3 ℃;

[0227] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 7.7Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.71 – 7.63 (m, 2H), 7.57 (t, J = 7.5 Hz,1H), 7.48 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 8.2 Hz,1H), 6.83 (dd, J = 8.3, 1.8 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.37 (s, 1H),5.55 (s, 2H), 3.84 (s, 3H);

[0228] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.2, 149.6, 148.5, 146.9, 134.5,134.3, 133.9, 130.0, 129.6, 128.6, 128.5, 125.9, 125.8, 125.2, 123.1, 120.2,114.0, 110.6, 82.8, 68.0, 56.2.

[0229] Example 22

[0230] The compound I-22 (R) described in this embodiment 1 =3-Nitrophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0231]

[0232] The synthesis method of compound I-22 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with m-nitrobenzyl chloride to obtain compound I-22 (yellow solid, 0.08 g, yield 11.7%).

[0233] The detection results for compound I-22 are as follows:

[0234] mp = 132.2–136.1 ℃;

[0235] 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.17 (dd, J = 8.7, 1.9 Hz,1H), 7.96 (dt, J = 7.7, 1.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.67 (td, J =7.5, 1.3 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.34 (dd, J = 7.7, 0.9 Hz, 1H), 6.87(d, J = 8.3 Hz, 1H), 6.82 (dd, J = 8.3, 2.0 Hz, 1H), 6.74 (d, J = 2.0 Hz,1H), 6.36 (s, 1H), 5.22 (s, 2H), 3.84 (s, 3H);

[0236] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.3, 149.6, 148.6, 148.5, 139.1,134.5, 133.3 (2C), 130.2, 129.8, 129.6, 125.8, 123.2, 123.0, 122.3, 120.0,114.3, 110.6, 82.8, 70.1, 56.2;

[0237] ESI-MS calculated for C 22 H 17 NO6[M + Na] + , 414.0948; found, 414.0958.

[0238] Example 23

[0239] The compound I-23 (R) described in this embodiment 1 =4-Nitrophenyl, R 2 =Methoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0240]

[0241] The synthesis method of compound I-23 in this embodiment is the same as that in Example 1, except that the bromoethane used in Example 1 is replaced with p-nitrobenzyl chloride to obtain compound I-23 (yellow solid, 0.25 g, yield 33.2%).

[0242] The detection results for compound I-23 are as follows:

[0243] mp = 142.9–146.6 ℃;

[0244] 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 8.7 Hz, 2H), 7.96 (d, J = 7.6Hz, 1H), 7.66 (td, J = 7.5, 1.2 Hz, 1H), 7.61 (s, 1H), 7.60 – 7.54 (m, 2H),7.33 (dd, J = 7.6, 0.9 Hz, 1H), 6.85 – 6.78 (m, 2H), 6.75 (d, J = 1.7 Hz,1H), 6.35 (s, 1H), 5.24 (s, 2H), 3.84 (s, 3H);

[0245] 13 C NMR (101 MHz, CDCl3) δ 170.6, 150.2, 149.6, 1 48.4, 147.7, 144.4,134.5, 130.1, 129.6, 127.6 (2C), 125.8, 125.8, 124.0 (2C), 123.0, 120.0,114.0, 110.6, 82.8, 69.9, 56.2.

[0246] Example 24

[0247] The compound I-24 (R) described in this embodiment 1 =Methyl, R 2 =Fluorine, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0248]

[0249] The synthesis method of compound I-24 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-fluorophenol to obtain compound I-24 (white solid, 0.03 g, yield 15.2%).

[0250] The detection results for compound I-24 are as follows:

[0251] mp = 86.5–88.3 ℃;

[0252] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.67 (td, J = 7.5,1.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.32 (dd, J = 7.6, 0.9 Hz, 1H), 7.02(d, J = 8.5 Hz, 1H), 6.98 – 6.90 (m, 2H), 6.33 (s, 1H), 4.10 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H);

[0253] 13 C NMR (101 MHz, CDCl3) δ 170.4, 152.7 (d, J = 247.4 Hz), 149.3,148.0 (d, J = 10.5 Hz), 134.5, 129.7, 129.0 (d, J = 6.0 Hz), 125.9, 125.8,123.6 (d, J = 3.6 Hz), 123.0, 115.2 (d, J = 19.6 Hz), 114.7 (d, J = 2.2 Hz), 82.1 (d, J = 1.8 Hz), 65.0, 14.8.

[0254] Example 25

[0255] The compound I-25 (R) described in this embodiment 1 =Methyl, R 2 =Chlorine, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0256]

[0257] The synthesis method of compound I-25 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-chlorophenol to obtain compound I-25 (light yellow oily liquid, 0.08 g, yield 35.5%).

[0258] The detection results for compound I-25 are as follows:

[0259] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 2.2Hz, 1H), 7.12 (dd, J = 8.5, 2.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.32 (s,1H), 4.11 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H);

[0260] 13 C NMR (101 MHz, CDCl3) δ 170.4, 155.4, 149.4, 134.6, 129.7, 129.3(2C), 127.0, 125.9 (2C), 123.5, 123.0, 113.4, 82.0, 65.0, 14.8.

[0261] Example 26

[0262] The compound I-26 (R) described in this embodiment 1 =Methyl, R 2 =Ethyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0263]

[0264] The synthesis method of compound I-26 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-ethylphenol to obtain compound I-26 (yellow solid, 0.04 g, yield 18.3%).

[0265] The detection results for compound I-26 are as follows:

[0266] mp = 63.2–69.4 ℃;

[0267] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.5Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.06 – 6.98 (m,2H), 6.78 (d, J = 8.3 Hz, 1H), 6.35 (s, 1H), 4.03 (q, J = 6.9 Hz, 2H), 2.60(q, J = 7.4 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H), 1.15 (t, J = 7.5 Hz, 3H);

[0268] 13 C NMR (101 MHz, CDCl3) δ 157.8, 152.5, 150.1, 134.3, 133.6, 129.3,128.3, 127.7, 126.2, 126.1, 125.7, 123.1, 111.2, 83.3, 63.7, 23.6, 15.0,14.1.

[0269] Example 27

[0270] The compound I-27 (R) described in this embodiment 1 =Methyl, R 2 =Isopropyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0271]

[0272] The synthesis method of compound I-27 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-isopropylphenol to obtain compound I-27 (brown solid, 0.14 g, yield 63.3%).

[0273] The detection results for compound I-27 are as follows:

[0274] mp = 63.2–67.4 ℃;

[0275] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.4Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 2.5Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.37 (s,1H), 4.02 (q, J = 7.0 Hz, 2H), 3.29 (hept, J = 6.9 Hz, 1H), 1.42 (t, J = 7.0Hz, 3H), 1.18 (d, J = 6.9 Hz, 6H);

[0276] 13 C NMR (101 MHz, CDCl3) δ 170.8, 157.2, 150.0, 137.8, 134.3, 129.3,127.8, 126.2, 125.8, 125.7, 125.7, 123.1, 111.4, 83.4, 63.8, 27.2, 22.6,22.5, 15.0.

[0277] Example 28

[0278] The compound I-28 (R) described in this embodiment 1 =Methyl, R 2 =tert-butyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0279]

[0280] The synthesis method of compound I-28 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-tert-butylphenol to obtain compound I-28 (yellow solid, 0.09 g, yield 44.6%).

[0281] The detection results for compound I-28 are as follows:

[0282] mp = 55.1–60.1 ℃;

[0283] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.66 (td, J = 7.5,1.3 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.18 (d, J =2.4 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.38(s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H), 1.36 (s, 9H);

[0284] 13 C NMR (101 MHz, CDCl3) δ 170.8, 158.7, 149.9, 138.8, 134.3, 129.3,127.4, 126.5, 126.2, 126.1, 125.7, 123.2, 112.2, 83.5, 63.6, 35.1, 29.7 (3C), 15.0.

[0285] Example 29

[0286] The compound I-29 (R) described in this embodiment 1 =Methyl, R 2 =ethoxy, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0287]

[0288] The synthesis method of compound I-29 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with o-ethoxyphenol to obtain compound I-29 (brown solid, 0.17 g, yield 77.5%).

[0289] The detection results for compound I-29 are as follows:

[0290] mp = 76.2–79.2 ℃;

[0291] 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.5Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.3Hz, 1H), 6.82 (dd, J = 8.3, 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.34 (s,1H), 4.08 (q, J = 7.0 Hz, 2H), 4.00 (q, J = 7.0 Hz, 2H), 1.41 (t, 3H), 1.40 (t, 3H);

[0292] 13 C NMR (101 MHz, CDCl3) δ 170.7, 149.8 (2C), 149.2, 134.4, 129.4,128.6, 126.0, 125.7, 123.1, 120.3, 113.2, 112.4, 83.1, 64.9, 64.7, 14.9,14.9;

[0293] ESI-MS calculated for C 18 H 18 O4[M + Na] + , 321.1097; found, 321.1102.

[0294] Example 30

[0295] The compound I-30 (R) described in this embodiment 1 =Methyl, R 2 =R 5 =Methoxy, R 3 =R 4 The structure of (=hydrogen, m=1) is as follows:

[0296]

[0297] The synthesis method of compound I-30 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2,6-dimethoxyphenol to obtain compound I-30 (white solid, 0.13 g, yield 60.2%).

[0298] The detection results for compound I-30 are as follows:

[0299] mp = 108.2–115.7 ℃;

[0300] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.65 (td, J = 7.5,1.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.7, 1.0 Hz, 1H), 6.89(s, 2H), 6.30 (s, 1H), 3.82 (q, J = 7.0 Hz, 2H), 2.24 (s, 6H), 1.40 (t, J =7.1 Hz, 3H);

[0301] 13 C NMR (101 MHz, CDCl3) δ 170.7, 157.1, 149.9, 134.4, 131.9 (2C), 131.3, 129.4, 127.7 (2C), 125.9, 125.7, 123.1, 82.9, 68.1, 16.5 (2C), 15.9;

[0302] ESI-MS calculated for C 18 H 18 O5[M + Na] + , 337.1046; found, 337.1053.

[0303] Example 31

[0304] The compound I-31 (R) described in this embodiment 1 =R 2 =R 4 =Methyl, R 3 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0305]

[0306] The synthesis method of compound I-31 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2,5-dimethylphenol to obtain compound I-31 (white solid, 0.10 g, yield 45.5%).

[0307] The detection results for compound I-31 are as follows:

[0308] mp = 121.1–127.2 ℃;

[0309] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.67 (td, J = 7.6,1.2 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.33 (dd, J = 7.7, 1.0 Hz, 1H), 6.67(s, 1H), 6.62 (s, 2H), 4.03 (q, J = 6.9 Hz, 2H), 2.44 (s, 3H), 2.06 (s, 3H), 1.41 (t, J = 6.9 Hz, 3H);

[0310] 13 C NMR (101 MHz, CDCl3) δ 170.9, 157.8, 149.8, 136.2, 134.2, 129.8,129.3, 126.7, 125.7, 125.2, 124.8, 123.2, 113.5, 80.8, 63.7, 19.5, 15.8,15.0.

[0311] Example 32

[0312] The compound I-32 (R) described in this embodiment 1 =R 2 =Methyl, R 4 =Isopropyl, R 3 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0313]

[0314] The synthesis method of compound I-32 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-methyl-5-isopropylphenol to obtain compound I-32 (white solid, 0.11 g, yield 55.2%).

[0315] The detection results for compound I-32 are as follows:

[0316] mp = 107.9–112.7 ℃;

[0317] 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 1H), 7.67 (td, J = 7.6,1.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.6, 0.9 Hz, 1H), 6.80(s, 1H), 6.75 (s, 1H), 6.52 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.41 (p, J =6.8 Hz, 1H), 2.03 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H), 1.37 (d, J = 6.9 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H);

[0318] 13 C NMR (101 MHz, CDCl3) δ 170.9, 158.3, 150.2, 147.3, 134.2, 129.8,129.2, 126.8, 125.7, 125.0, 123.9, 123.2, 108.2, 79.7, 63.7, 29.1, 24.5,24.4, 15.8, 15.0.

[0319] Example 33

[0320] The compound I-33 (R) described in this embodiment 1 =Methyl, R 2 =Isopropyl, R 4 =Methyl, R 3 =R 5 The synthesis method of (=hydrogen, m=1) is as follows:

[0321]

[0322] (1) Synthesis of compound VI-33: Compound VI-33 (thymol, 0.11 g, 0.7 mmol) and anhydrous potassium carbonate (0.21 g, 1.5 mmol) were mixed in N,N-dimethylformamide (2 mL), and bromoethane (0.11 g, 1.0 mmol) was added. The mixture was stirred at 40 °C for 6 h, and the reaction was monitored by TLC (EA:PE = 1:5). After the reaction was completed, the mixture was quenched with water (10 mL) and extracted with ethyl acetate 2-3 times. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a yellow solid compound VI-33 (0.10 g, yield 80.6%).

[0323] (2) Synthesis of compound I-33: 3-bromophthalide compound VII-1 (0.21 g, 1.0 mmol) and anhydrous tin tetrachloride (1.04 g, 4 mmol) were mixed in dichloromethane (2 mL), and compound IV-33 (0.19 g, 1.1 mmol) was added. The mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC (EA:PE = 1:2). After the reaction was complete, the mixture was quenched with water (10 mL) and extracted 2-3 times with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid compound I-33 (0.18 g, yield 44.7%).

[0324] The detection results for compound I-33 are as follows:

[0325] mp = 108.2–115.7 ℃;

[0326] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.7 Hz, 1H), 7.67 (td, J = 7.5,1.2 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 7.7, 0.8 Hz, 1H), 6.69(d, J = 3.0 Hz, 2H), 6.62 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.17 (hept, J =6.9 Hz, 1H), 2.40 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H), 1.06 (dd, J = 6.9, 3.6Hz, 6H);

[0327] 13 C NMR (101 MHz, CDCl3) δ 171.0, 157.0, 149.7, 136.2, 135.0, 134.1,129.3, 126.8, 125.9, 125.8, 125.3, 123.2, 113.9, 81.4, 63.7, 27.1, 22.6,22.4, 19.4, 15.1;

[0328] ESI-MS calculated for C 20 H 22 O3[M + Na] + , 333.1461; found, 333.1470.

[0329] Example 34

[0330] The compound I-34 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0331]

[0332] The synthesis method of compound I-34 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with phenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-34 (white solid, 0.13 g, yield 60.2%).

[0333] The detection results for compound I-34 are as follows:

[0334] mp = 108.2–115.7 ℃;

[0335] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.66 (td, J = 7.4, 1.1 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.5 Hz,1H), 7.50 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.7, 0.9 Hz, 1H), 7.20 (dt, 2H), 6.95 (dt, 2H), 6.38 (s, 1H), 5.09 (s, 2H);

[0336] 13 C NMR (101 MHz, CDCl3) δ 170.6, 159.1, 149.7, 138.4, 134.5, 131.8,131.6, 130.8, 129.6, 129.5, 129.4, 129.1 (2C), 126.0, 125.8, 123.1, 118.7,115.3 (2C), 113.0, 82.7, 68.8.

[0337] Example 35

[0338] The compound I-35 (R) described in this embodiment1 =3-Cyanophenyl, R 2 =Fluorine, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0339]

[0340] The synthesis method of compound I-35 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with o-fluorophenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-35 (white solid, 0.07 g, yield 28.8%).

[0341] The detection results for compound I-35 are as follows:

[0342] mp = 118.6–124.6℃;

[0343] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.71– 7.65 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 (t,J = 7.8 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.06 – 6.94 (m, 3H), 6.34 (s, 1H), 5.16 (s, 2H);

[0344] 13 C NMR (101 MHz, CDCl3) δ 170.3, 152.9 (d, J = 248.9 Hz), 149.2,147.1 (d, J = 10.9 Hz), 137.9, 134.6, 132.0, 131.6, 130.8, 130.6 (d, J = 6.2Hz), 129.8, 129.7, 125.9, 125.8, 123.6 (d, J = 3.6 Hz), 123.0, 118.6, 115.8(d, J = 2.2 Hz), 115.6 (d, J = 19.3 Hz), 113.0, 81.8 (d, J = 1.4 Hz), 70.2;

[0345] ESI-MS calculated for C22 H 14 FNO3[M + Na] + , 382.0850; found, 382.0858.

[0346] Example 36

[0347] The compound I-36 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =Chlorine, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0348]

[0349] The synthesis method of compound I-36 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with o-chlorophenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-36 (white solid, 0.06 g, yield 23.5%).

[0350] The detection results for compound I-36 are as follows:

[0351] mp = 124.9–129.2℃;

[0352] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.73– 7.66 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.52 (t,J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.14(dd, J = 8.5, 2.3 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.34 (s, 1H), 5.17 (s, 2H);

[0353] 13C NMR (101 MHz, CDCl3) δ 170.3, 154.5, 149.2, 137.8, 134.6, 132.0,131.3, 130.5, 130.5, 129.8, 129.7, 129.5, 127.0, 126.0, 125.8, 124.1, 123.0,118.7, 114.0, 113.0, 81.8, 69.7;

[0354] ESI-MS calculated for C 22 H 14 ClNO3[M + Na] + , 398.0554; found, 398.0562.

[0355] Example 37

[0356] The compound I-37 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =Methyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0357]

[0358] The synthesis method of compound I-37 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with o-methylphenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-37 (white solid, 0.07 g, yield 28.7%).

[0359] The detection results for compound I-37 are as follows:

[0360] mp = 131.7–132.6℃;

[0361] 1H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.65 (td, J = 7.8, 3.9 Hz, 3H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 (t, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.06 (dd, J = 8.3, 2.5 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 8.3Hz, 1H), 6.34 (s, 1H), 5.10 (s, 2H), 2.25 (s, 3H);

[0362] 13 C NMR (101 MHz, CDCl3) δ 170.7, 157.2, 149.9, 138.8, 134.4, 131.7,131.3, 130.5, 130.0, 129.6, 129.4, 128.8, 128.0, 126.3, 126.0, 125.7, 123.1,118.8, 112.9, 111.4, 82.9, 68.7, 16.6;

[0363] ESI-MS calculated for C 23 H 17 NO3[M + Na] + , 378.1101; found, 378.1111.

[0364] Example 38

[0365] The compound I-38 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =Ethyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0366]

[0367] The synthesis method of compound I-38 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-ethylphenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-38 (white solid, 0.11 g, yield 39.1%).

[0368] The detection results for compound I-38 are as follows:

[0369] mp = 141.3–143.2℃;

[0370] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.69– 7.60 (m, 3H), 7.56 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 (d,J = 7.5 Hz, 1H), 7.07 (s, 1H), 7.04 (dd, J = 8.3, 2.4 Hz, 1H), 6.82 (d, J =8.4 Hz, 1H), 6.37 (s, 1H), 5.10 (s, 2H), 2.68 (qd, J = 7.4, 3.1 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H);

[0371] 13 C NMR (101 MHz, CDCl3) δ 170.7, 162.3, 156.8, 149.9, 138.8, 134.4,133.9, 131.7, 131.3, 130.5, 129.6, 129.5, 129.0, 128.6, 126.2, 126.0, 125.7,123.1, 112.9, 111.6, 83.0, 68.8, 23.6, 14.2;

[0372] ESI-MS calculated for C 24 H 19 NO3[M + Na] + , 392.1257; found, 392.1266.

[0373] Example 39

[0374] The compound I-39 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =Isopropyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0375]

[0376] The synthesis method of compound I-39 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-isopropylphenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-39 (white solid, 0.11 g, yield 38.3%).

[0377] The detection results for compound I-39 are as follows:

[0378] mp = 141.3–143.2℃;

[0379] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.66 (td, J = 7.5, 1.3 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.5 Hz,1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.6, 0.9 Hz, 1H), 7.17 (d, J =2.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.39(s, 1H), 5.10 (s, 2H), 3.36 (hept, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H);

[0380] 13 C NMR (101 MHz, CDCl3) δ 170.7, 156.2, 149.8, 138.8, 138.2, 134.4,131.7, 131.3, 130.5, 129.6, 129.5, 129.1, 126.1, 126.0, 125.8, 125.8, 123.1,118.8, 112.9, 111.8, 83.1, 68.9, 27.2, 22.7, 22.6;

[0381] ESI-MS calculated for C 25 H 21 NO3[M + Na] + , 406.1414; found, 406.1423.

[0382] Example 40

[0383] The compound I-40 (R) described in this embodiment 1 =3-Cyanophenyl, R 2 =tert-butyl, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0384]

[0385] The synthesis method of compound I-40 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-tert-butylphenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-40 (light yellow oily liquid, 0.20 g, yield 72.5%).

[0386] The detection results for compound I-40 are as follows:

[0387] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.67(t, J = 8.1 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.52(t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 6.99(dd, J = 8.4, 2.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 5.13 (s, 2H), 1.37 (s, 9H);

[0388] 13 C NMR (101 MHz, CDCl3) δ 170.7, 157.9, 149.7, 139.2, 138.7, 134.3,131.8, 131.6, 130.8, 129.7, 129.4, 128.7, 126.8, 126.2, 126.1, 125.7, 123.1,118.7, 113.0, 112.7, 83.2, 69.2, 35.1, 29.8 (3C).

[0389] Example 41

[0390] The compound I-41 (R) described in this embodiment 1=3-Cyanophenyl, R 2 =R 5 =Methyl, R 3 =R 4 The structure of (=hydrogen, m=1) is as follows:

[0391]

[0392] The synthesis method of compound I-41 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2,6-dimethylphenol and bromoethane is replaced with m-cyanobenzyl bromide to obtain compound I-41 (yellow solid, 0.12 g, yield 41.6%).

[0393] The detection results for compound I-41 are as follows:

[0394] mp = 130.1–138.4℃;

[0395] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.72– 7.62 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.35 (d,J = 7.6 Hz, 1H), 6.94 (s, 2H), 6.32 (s, 1H), 4.82 (s, 2H), 2.26 (s, 6H);

[0396] 13 C NMR (101 MHz, CDCl3) δ 170.6, 156.1, 149.7, 139.0, 134.4, 132.2,131.7, 131.7, 131.6, 130.8, 129.4 (2C), 129.4, 127.8 (2C), 125.7 (2C), 122.9,118.7, 112.7, 82.6, 72.4, 16.5 (2C).

[0397] Example 42

[0398] The compound I-42 (R) described in this embodiment 1 =4-Chlorophenyl, R 2 =Fluorine, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0399]

[0400] The synthesis method of compound I-42 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-fluorophenol and bromoethane is replaced with 4-chlorobenzyl bromide to obtain compound I-42 (white solid, 0.10 g, yield 33.5%).

[0401] The detection results for compound I-42 are as follows:

[0402] mp = 125.3–130.4℃;

[0403] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.67 (td, J = 7.5,1.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.35 (s, 4H), 7.32 (d, J = 6.8 Hz,1H), 7.03 – 6.93 (m, 3H), 6.33 (s, 1H), 5.10 (s, 2H);

[0404] 13 C NMR (101 MHz, CDCl3) δ 170.3, 152.9 (d, J = 248.3 Hz), 149.2,147.4 (d, J = 10.5 Hz), 134.7, 134.6, 134.2, 130.0 (d, J = 5.9 Hz), 129.7,129.0 (2C), 128.9 (2C), 125.9, 125.8, 123.6 (d, J = 3.7 Hz), 123.0, 115.7 (d,J = 2.1 Hz), 115.4 (d, J = 19.6 Hz), 81.9, 70.7.

[0405] Example 43

[0406] The compound I-43 (R) described in this embodiment 1 =4-Chlorophenyl, R 2 =Chlorine, R 3 =R 4 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0407]

[0408] The synthesis method of compound I-43 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-chlorophenol and bromoethane is replaced with 4-chlorobenzyl bromide to obtain compound I-43 (white solid, 0.05 g, yield 37.4%).

[0409] The detection results for compound I-43 are as follows:

[0410] mp = 138.2–146.7℃;

[0411] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.67 (td, J = 7.5,1.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.40 – 7.30 (m, 5H), 7.27 (d, J = 2.2Hz, 1H), 7.11 (dd, J = 8.5, 2.3 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.32 (s,1H), 5.12 (s, 2H);

[0412] 13 C NMR (101 MHz, CDCl3) δ 170.3, 154.8, 149.2, 134.6, 134.6, 134.1,130.0, 129.7, 129.4, 129.0 (2C), 128.5 (2C), 127.0, 125.9, 125.8, 123.9,123.0, 114.0, 81.9, 70.2.

[0413] Example 44

[0414] The compound I-44 (R) described in this embodiment 1 =4-Chlorophenyl, R 2 =Isopropyl, R 4 =Methyl, R 3 =R 5 The structure of (=hydrogen, m=1) is as follows:

[0415]

[0416] The synthesis method of compound I-44 in this embodiment is the same as that in Example 1, except that compound III-1 used in Example 1 is replaced with 2-isopropyl-5-methylphenol and bromoethane is replaced with 4-chlorobenzyl bromide to obtain compound I-44 (white solid, 0.08 g, yield 33.6%).

[0417] The detection results for compound I-44 are as follows:

[0418] mp = 114.2–119.5℃;

[0419] 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.6 Hz, 1H), 7.68 (td, J = 7.5,1.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.37 (s, 4H), 7.35 (d, J = 7.7 Hz,1H), 6.75 (d, J = 2.6 Hz, 2H), 6.63 (s, 1H), 5.05 (s, 2H), 3.23 (hept, J =6.9 Hz, 1H), 2.40 (s, 3H), 1.08 (d, J = 3.9 Hz, 6H);

[0420] 13 C NMR (101 MHz, CDCl3) δ 170.9, 156.4, 149.6, 136.4, 135.7, 135.2,134.2, 133.8, 129.4, 128.9 (2C), 128.6 (2C), 126.8, 126.1, 126.0, 125.8,123.2, 114.2, 81.2, 69.4, 27.1, 22.6, 22.5, 19.4.

[0421] Example 45

[0422] This embodiment provides the in vivo inactivation, therapeutic and protective activities of representative compounds I-1 to I-40 against tobacco mosaic virus (TMV).

[0423] (1) Determination of the anti-TMV passivation activity of compounds I-1 to I-40

[0424] The in vitro inactivation activity of compounds I-1 to I-40 against TMV was determined using the half-leaf necrotic spot method. Healthy, vigorous tobacco leaves at the 5-6 leaf stage were selected. An equal volume of solutions of compounds I-1 to I-40 were mixed with TMV virus, and after 30 min, the mixture was inoculated into the left half of the leaf (treatment group). The right half served as a blank control, inoculated with an equal volume of distilled water and TMV virus mixture. Inoculation was performed using conventional mechanical friction. Each group consisted of 3-5 leaves, and the experiment was repeated three times. Ribavirin and ningnanmycin were used as positive control groups. After 3 days of inoculation and culture, the number of necrotic spots was recorded, and the inhibition rate was calculated.

[0425]

[0426] (2) Determination of the protective activity against TMV of compounds I-1 to I-40

[0427] The inhibitory effects of compounds I-1 to I-40 on primary TMV infection were determined using the whole-plant method. Healthy, vigorous 5-6 leaf-stage tobacco plants were selected as necrotic host plants. The whole plants were sprayed with compounds I-1 to I-40 as treatment groups, while whole-plant water treatment served as a blank control. Six hours after application, the whole plants were inoculated with TMV virus. The protective effect of compounds I-1 to I-40 against TMV infection in the heart-leaf tobacco plants was determined. Each treatment group consisted of 4-5 leaves, with 3 replicates. The positive control groups were ribavirin and ningnanmycin. After obvious necrotic spots appeared on the inoculated leaves, the number of necrotic spots was recorded, and the inhibition rate was calculated using the above formula and statistically analyzed.

[0428] (3) Determination of the anti-TMV therapeutic activity of compounds I-1 to I-40

[0429] The inhibitory effects of compounds I-1 to I-40 on the replication and proliferation of TMV virus particles in *Nicotiana siceraria* were determined using the whole-plant method. Healthy, vigorous 5-6 leaf stage *Nicotiana siceraria* plants were selected as necrotic spot hosts. The entire leaf was inoculated with TMV virus by friction. Six hours later, the leaves were treated with compounds I-1 to I-40 (treatment group), with water treatment as the blank control. Four to five leaves were treated in each group, with three replicates. The positive control group consisted of ribavirin and ningnanmycin. After obvious necrotic spots appeared on the inoculated leaves, the number of necrotic spots was recorded, and the inhibition rate was calculated using the above formula and statistically analyzed.

[0430] Table 1 shows the inhibitory effects of compounds I-1 to I-40 on tobacco mosaic virus at a concentration of 500 μg / mL.

[0431] Table 1. Inhibitory effects of compounds I-1 to I-40 on tobacco mosaic virus.

[0432]

[0433] Note: The above data are the average of three repeated experiments.

[0434] Analysis of Table 1 shows that compounds I-1 to I-40 exhibit good inhibitory activity against tobacco mosaic virus at a concentration of 500 μg / mL, and all compounds I-1 to I-40 show certain antiviral activity against tobacco mosaic virus. Compounds I-19 and I-35, at a concentration of 500 μg / mL, showed inactivation activity against tobacco mosaic virus exceeding 70%, superior to the positive control group ribavirin and comparable to ningnanmycin, while also exhibiting moderate therapeutic and protective activity. Compound I-33, at a concentration of 500 μg / mL, showed a protective activity of 68.4% against tobacco mosaic virus, superior to the positive control groups ribavirin and ningnanmycin, demonstrating good protective activity. In particular, compound I-35, at a concentration of 500 μg / mL, showed inactivation, protective, and therapeutic activities against tobacco mosaic virus of 79.6%, 62.5%, and 46.5%, respectively, exhibiting excellent antiviral activity and showing promise for development as a novel antiviral agent against plant viruses.

[0435] In summary, the phenolic derivatives containing phthalide structures prepared by chemical synthesis in this invention have antiviral activity against plant viruses, which lays the foundation for preparing pesticide formulations with phenolic derivatives containing phthalide structures as the main antiviral active ingredients against plant viruses.

[0436] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art through related deductions and substitutions based on the inventive concept, without inventive effort, are within the scope of protection of the present invention.

Claims

1. A phenolic derivative containing a phthalide structure, characterized in that, The phenolic derivative containing the phthalide structure has the structure shown in formula (I), or a pesticide-acceptable salt thereof. ； Equation (Ⅰ) is specifically selected from the following structure: 。 2. The method for preparing the phenolic derivative containing a phthalide structure according to claim 1, characterized in that, Includes: Route 1: ； Route 2: ； Where X is fluorine, chlorine, bromine or iodine.

3. The method for preparing phenolic derivatives containing a phthalide structure according to claim 2, characterized in that, Route 1 includes: using o-carboxybenzaldehyde compound II and phenol compound III as raw materials, condensing them under acidic conditions to generate phenol compound IV; after purification, phenol compound IV undergoes a nucleophilic substitution reaction with halogenated compound V under alkaline conditions to generate phenol derivative I containing a phthalide structure.

4. The method for preparing phenolic derivatives containing a phthalide structure according to claim 2, characterized in that, Route 2 includes: using phenolic compound III and halogenated compound V as raw materials, a nucleophilic substitution reaction is carried out under alkaline conditions to generate phenolic compound VI; after purification, phenolic compound VI is condensed with 3-halogenated phthalide compound VII under Lewis acid catalysis to generate phenolic derivative I containing phthalide structure.

5. The method for preparing phenolic derivatives containing a phthalide structure according to claim 3, characterized in that, The acid used in the acidic conditions is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and Amberlyst. The base used in the alkaline conditions is selected from any one of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydride, triethylamine, and pyridine.

6. The method for preparing phenolic derivatives containing a phthalide structure according to claim 4, characterized in that, The base used in the alkaline conditions is selected from any one of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydride, triethylamine, and pyridine. The Lewis acid is selected from any one of tin tetrachloride, boron trifluoride ether, and anhydrous aluminum trichloride.

7. A pesticide composition, characterized in that, The active ingredient of the pesticide composition includes the phenolic derivative containing a phthalide structure as described in claim 1.

8. The use of the phenolic derivative containing a phthalide structure as described in claim 1 or the pesticide composition as described in claim 7 in the treatment of tobacco mosaic virus.

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