2, 3-disubstituted naphthoquinone compound as well as application and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary drugs, and particularly relates to a 2, 3-disubstituted naphthoquinone compound as well as application and a preparation method thereof, the general formula of the 2, 3-disubstituted naphthoquinone compound is # imgabs0 #, and X is selected from C, NH, O and S; wherein when X is selected from C, an X-R1 substituent is represented as an aryl substituent; when X is selected from NH, R1 is selected from a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, substituted aryl, substituted benzyl and substituted acyl; when X is selected from O, R1 is selected from a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, substituted benzyl and substituted acyl; when X is selected from S, R1 is selected from C1-6 alkyl, substituted aryl and substituted benzyl; r2 is selected from C1-16 alkyl, substituted aryl, Ra-(CH2) n-, and Ra-CO-(CH2) n-; the series of compounds are novel in structure and good in antibody ectoparasite activity, are successfully applied to the field of veterinary drugs, and solve the long-standing problems of safety and toxicity; the synthesis process is simple, the conditions are mild, and various 2, 3-disubstituted naphthoquinone compounds can be efficiently prepared.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drugs, and specifically relates to a 2,3-disubstituted naphthoquinone compound, a use thereof, and a preparation method thereof. Background Art

[0002] External parasites are common parasitic diseases in livestock and pets, which can cause symptoms such as severe itching of animal skin, depilation, eczematous dermatitis, etc., causing animals to become thin, weak, anemic, and even cause death. Therefore, external parasites can have a serious impact on the output of meat, milk, and eggs of animals, affect the quality of fur and the ability of draft animals to serve, which not only directly endangers the healthy development and production efficiency of animal husbandry, but also affects related industries such as leather processing, causing huge economic losses. And some external parasites, such as ticks, are also the vectors of zoonotic infectious diseases (such as viruses, bacteria, fungi and protozoa, etc.), which directly endanger human health. Therefore, external parasitic diseases not only hinder the development of animal husbandry, causing huge economic losses, but are also the most common and serious public health problems.

[0003] At present, chemical drugs are still the dominant way to prevent and treat animal ectoparasitic diseases, mainly organophosphorus, organochlorine, macrolide, pyrethrum and pyrethroids, etc. These drugs are widely used due to their high efficacy, rapid action and convenience. However, long-term and irrational use has led to increasingly poor clinical efficacy, and the "3R" problems such as residues, drug resistance and recurrence have brought about potential threats to ecological environment protection, public health and food safety. Moreover, in the past decade or so, there have been basically no major breakthroughs and innovations in the technology and products for the prevention and treatment of ectoparasitic diseases. Therefore, the discovery of a new, safe and efficient acaricidal compound is of great significance for the prevention and treatment of animal ectoparasitic diseases.

[0004] Naphthoquinone compounds are widely present in nature and are the main active ingredients of many important traditional Chinese medicines. They have a wide range of biological activities and have been widely studied in the fields of antibacterial, antifungal, anticancer, anti-insect, anti-inflammatory, and antiviral. For example, natural products such as flavonoids, lanselquinone, juglone, and shikonin all show good activity against external parasites. Moreover, antiparasitic drugs developed based on naphthoquinone structures have been widely used, such as atovaquone, a broad-spectrum antiprotozoal drug, and bupavaquone, which can treat bovine Theileria pyroximate and is currently the most effective drug for the treatment of bovine Theileria pyroximate. In addition, naphthoquinone compounds have also been studied and applied in the field of plant insecticides, such as the pesticide cypermethrin, which is widely used in foreign countries for the prevention and control of fruit and vegetable pests. However, how to introduce it into the field of live veterinary drugs, safety and toxicity have always been technical problems that have troubled technicians in this field for many years. Therefore, naphthoquinone structures have important research value in the field of developing new veterinary drugs for animal-specific external parasites.

[0005] At present, with the rapid development of my country's animal husbandry industry and the steady growth of pet ownership, the existing drugs used to prevent and treat animal ectoparasites (ticks, mites) are difficult to meet the increasing use requirements. Therefore, it is urgent to develop a new veterinary drug with better activity and higher safety against animal ectoparasites. Summary of the invention

[0006] The present invention aims to provide a novel 2,3-disubstituted naphthoquinone compound with novel structure, good insect-resistant effect and safety, a preparation method and application thereof, which can be used to prepare drugs for preventing and controlling animal external parasites (ticks and mites) in the field of veterinary medicine to meet the growing demand for use.

[0007] To achieve the above object, the present invention is implemented according to the following technical solutions:

[0008] A 2,3-disubstituted naphthoquinone compound,

[0009] The general formula of the compound is shown in Formula I,

[0010] Wherein, X is selected from C, NH, O, S; wherein, when X is selected from C, the X-R1 substituent is an aryl substituent; wherein the aryl substituent is 3-monosubstituted, 4-monosubstituted, 3,4-disubstituted, 3,5-disubstituted; wherein the aryl substituent is one or two of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0011] When X is selected from NH, the R1 is selected from hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, substituted aryl, substituted benzyl, substituted acyl;

[0012] When X is selected from O, the R1 is selected from hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, substituted benzyl, substituted acyl;

[0013] When X is selected from S, the R1 is selected from C1-6 alkyl, substituted aryl, substituted benzyl;

[0014] The R2 is selected from C1-16 alkyl, substituted aryl, Ra-(CH2)n-, Ra-CO-(CH2)n-.

[0015] Further, the C1-6 alkyl in R1 is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino;

[0016] Wherein, the C3-6 cycloalkyl in R1 is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl;

[0017] Wherein, the substituted aryl in R1 is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0018] Wherein, the substituted benzyl in R1 is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0019] Wherein, the substituted acyl group in R1 is an acyl group substituted with C1-6 alkyl, an acyl group substituted with C3-6 cycloalkyl, a benzoyl group substituted with an aryl, an acyl group substituted with Ph-(CH2)n- (n=1-4), or an acyl group substituted with tert-butyloxy; wherein, the C1-6 alkyl group is an alkyl substituent with 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino; wherein , the cycloalkyl group is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl; wherein the aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, and 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, and I;

[0020] Wherein, the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups;

[0021] The aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I;

[0022] Wherein, Ra is a substituted aromatic group or a 5-6-membered heterocyclic molecule; wherein the heterocyclic molecule is a monocyclic or cyclic molecule containing one or two of the three heteroatoms of nitrogen, sulfur and oxygen; wherein, the number of CH2, n, is 1-10.

[0023] Furthermore, two substituents cannot be aryl groups at the same time.

[0024] Further, the compound is one of the compounds Naph-01 to Naph-80 shown below:

[0025]

[0026] The present invention also discloses the use of the 2,3-disubstituted naphthoquinone compound. The compound is applied to the field of veterinary medicine for animals, and is specifically used for the prevention and treatment of animal external parasites. The animal external parasites include arthropod parasites such as itch mites, scabies mites, demodex mites and ticks. The animal is one of common livestock such as cattle, sheep, pigs, rabbits, cats, dogs, etc.

[0027] The present invention also discloses a method for preparing the above 2,3-disubstituted naphthoquinone compound.

[0028] The preparation method comprises the following steps:

[0029] When X is C, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula:

[0030]

[0031] The specific preparation steps of the above reaction equation are as follows:

[0032] S1. Arylation:

[0033] Dissolving 1,4-naphthoquinone and substituted phenol or substituted aryl boronic acid in a solvent in a certain ratio, reacting them under the catalytic action of a metal catalyst and an additive, and obtaining 2-aryl naphthoquinone after purification;

[0034] S2, decarboxylation alkylation:

[0035] Under the catalytic action of metal catalysts and additives, 2-aryl naphthoquinone and corresponding carboxylic acid are dissolved in a solvent in a certain proportion for decarboxylation and alkylation, and the reaction is carried out at a temperature-insulated state, and the target compound is obtained after purification.

[0036] Wherein, the aromatic substituent R is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the aromatic substituent is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0037] The substituent Rb is a C1-16 alkyl group, Ra-(CH2)n-, or Ra-CO-(CH2)n-; wherein the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups;

[0038] In the reaction step S1, the molar ratio of 1,4-naphthoquinone to substituted phenol or substituted aryl boronic acid is 1:1.5-3.0;

[0039] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 1-10:1;

[0040] The dosage ratio of 1,4-naphthoquinone to solvent or mixed solvent is 1 mol: 1.5-1.8 L;

[0041] The metal catalyst is one or two of FeCl3, FeNO2, FeSO4|, Pd(acac)2, Pd(OAc)2, Cu(BF4)2, Cu(OTf)2, [Cp*RhCl2]2, and the molar ratio of the amount to the feed of 1,4-naphthoquinone is 0.1-3.0:1;

[0042] The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, TBHP, dppben, dppe, dppb, dppp, and dppethy, and the molar ratio of the additive to the feed of 1,4-naphthoquinone is 0.1-5:1;

[0043] The insulation reaction temperature is 25-75°C, and the insulation reaction time is 10-24 hours;

[0044] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:1.

[0045] In the reaction step S2, the molar ratio of the 2-aryl naphthoquinone to the corresponding carboxylic acid is 1:3.0-5.0;

[0046] The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to the 2-aryl naphthoquinone is 0.1-0.5:1;

[0047] The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to the 2-aryl naphthoquinone is 1.2-2.5:1;

[0048] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0049] The dosage ratio of the 2-aryl naphthoquinone to the solvent or mixed solvent is 1 mol: 1.0-1.3 L;

[0050] The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours;

[0051] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:1.

[0052] Furthermore, when X is NH, the general structural formula of the 2,3-disubstituted naphthoquinone compound is (III), prepared via the following chemical reaction equation:

[0053]

[0054] The specific preparation steps of the above reaction equation are as follows:

[0055] A. Preparation of naphthoquinone derivatives, as shown in reaction equation a);

[0056] S1. Amination: dissolving 1,4-naphthoquinone or 2-aryl naphthoquinone and an amino derivative in a solvent in a certain ratio, reacting them under the catalytic action of a catalyst, and obtaining a naphthoquinone derivative after purification;

[0057] S2. Boc protection: When Rd = H or BzO-, a 2-aminonaphthoquinone derivative with Re = H is obtained, which is dissolved with Boc2O in a certain ratio, and then reacted in the presence of a catalyst, and then purified to obtain a naphthoquinone derivative.

[0058] B. Preparation of 2-aminonaphthoquinone derivatives, as shown in reaction equation b);

[0059] S1. Decarboxylation alkylation: under the catalytic action of metal catalysts and additives, the amino-substituted naphthoquinone derivative and the corresponding carboxylic acid are dissolved in a solvent in a certain ratio for decarboxylation alkylation, the reaction is kept warm, and the naphthoquinone derivative is obtained after purification;

[0060] S2. Deprotection: When Rf = Boc-, the reaction is carried out under the action of an acidic catalyst and then a 2-aminonaphthoquinone derivative is obtained after purification.

[0061] C. Preparation of 2,3-disubstituted naphthoquinone derivatives, as shown in reaction equation c);

[0062] Acylation and alkylation: Under the catalytic action of an alkaline catalyst, 2-amino-3-substituted naphthoquinone derivatives and corresponding acyl chlorides or halogenated hydrocarbons are dissolved in a solvent in a certain proportion to carry out acylation or alkylation reaction, and the reaction is kept warm. After purification, 2,3-disubstituted naphthoquinone derivatives are obtained.

[0063] Wherein, the substituent Rc is H or substituted aryl; the substituent Rd is H, substituted aryl, substituted benzyl and BzO-; the substituent Re is H, substituted aryl and substituted benzyl; the substituent Rf is Boc-, substituted aryl and substituted benzyl; the substituent Rb is C1-16 alkyl, Ra-(CH2)n-, Ra-CO-(CH2)n-; the substituent Rg is C1-6 alkyl, C3-6 cycloalkyl, substituted aryl, Ph-(CH2)n- (n=1-4); the substituent Rh is C1-6 alkyl and C3-6 cycloalkyl;

[0064] Wherein, the substituted aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0065] The substituted benzyl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I;

[0066] Wherein, the C1-6 alkyl group is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino;

[0067] Wherein, the C3-6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl;

[0068] In the reaction step S1.1, the molar ratio of the 1,4-naphthoquinone or 2-aryl naphthoquinone to ammonia water or an amino derivative is 1:1.5-3.0;

[0069] The catalyst is one of BiCl3, Bi(OTf)3, BF3·OEt2, AcOH, AlCl3, Cu(OAc)2·H2O, CuI, t-BuOK, NaOH, K2CO3, Et3N, iPr2EtN, and the molar ratio of the amount to the feed of 1,4-naphthoquinone is 0.1-1.5:1;

[0070] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, EtOH, HFIP, EtOAc, CHCl3, DMF, DMAC, DMSO, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0071] The ratio of the 1,4-naphthoquinone or 2-aryl naphthoquinone to the solvent or mixed solvent is 1 mol: 0.85-1.0 L;

[0072] The insulation reaction temperature is 30-90°C, and the insulation reaction time is 10-24 hours;

[0073] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0074] In the reaction step S1.2, the molar ratio of the 2-aminonaphthoquinone derivative to Boc2O is 1:1.5-3.0;

[0075] The catalyst is one of DMAP, Et3N, Pyridine, and iPr2EtN, and the molar ratio of the amount to the 2-aminonaphthoquinone derivative is 0.1-1.5:1;

[0076] The solvent is one of CH3CN, DCM, THF, and CHCl3;

[0077] The insulation reaction temperature is 25-90°C, and the insulation reaction time is 5-12 hours;

[0078] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0079] In the reaction step S2.1, the molar ratio of the amino-substituted naphthoquinone derivative to the corresponding carboxylic acid is 1:3.0-5.0;

[0080] The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to the amino-substituted naphthoquinone derivative is 0.1-0.5:1;

[0081] The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to the amino-substituted naphthoquinone derivative is 1.2-2.5:1;

[0082] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0083] The ratio of the amino-substituted naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.0-1.3 L;

[0084] The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours;

[0085] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:1.

[0086] In the reaction step S2.2, the acid catalyst is one of H2SO4, TFA, H3PO4, HCl, and acetic acid, and the molar ratio of the amount used to the Boc-substituted aminonaphthoquinone derivative is 1.5-3.0:1;

[0087] The solvent is one of CH3CN, DCM, THF, CHCl3, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0088] The amount ratio of the Boc-substituted aminonaphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.5-1.8 L;

[0089] The insulation reaction temperature is 25-30°C, and the insulation reaction time is 1-6 hours;

[0090] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0091] In the reaction step S3, the molar ratio of the 2-amino-3-substituted naphthoquinone derivative to the corresponding acyl chloride or halogenated hydrocarbon is 1:2.0-3.5;

[0092] The base catalyst is one of Et3N, Pyridine, iPr2EtN, K2CO3, Na2CO3, NaHCO3, KHCO3, and KH2PO4, and the molar ratio of the base catalyst to the 2-amino-3-substituted naphthoquinone derivative is 1.2-2.5:1;

[0093] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, DMF, DMAC, DMSO, and acetone;

[0094] The insulation reaction temperature is 30-120°C, and the insulation reaction time is 6-24 hours;

[0095] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0096] Furthermore, the preparation method comprises the following steps:

[0097] When X is O, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula:

[0098]

[0099] The specific preparation steps of the above reaction equation are as follows:

[0100] A. Preparation of 2-hydroxynaphthoquinone, as shown in reaction equation a);

[0101] S1. Acylation: add 1,4-naphthoquinone and acetic anhydride in a certain proportion, drop a catalyst, keep warm for reaction, crystallize, and filter to obtain an acylate;

[0102] S2, hydrolysis and acidification: dissolve the acylate and the base in a solvent in a certain proportion, keep the reaction warm for a period of time, filter the generated solid, add it to hot water to dissolve, filter it while hot, cool the filtrate, add acid to acidify, stir it in an ice bath, filter the precipitated solid, wash it with water until it is neutral, and dry it to obtain 2-hydroxy-naphthoquinone.

[0103] B. Preparation of 2-hydroxy-3-substituted naphthoquinone derivatives, as shown in reaction equation b);

[0104] S1. Alkylation: dissolving 2-hydroxy-naphthoquinone, a catalyst, an additive and a corresponding aldehyde in a solvent in a certain proportion, keeping the temperature for reaction, adding water to quench after the reaction, separating the organic phase, concentrating it, and purifying it to obtain a 2-hydroxy-3-substituted naphthoquinone derivative;

[0105] S2. When Ri = substituted aryl, the obtained 2-hydroxy-3-substituted benzyl naphthoquinone derivative is dissolved in a solvent, reacted under the action of an oxidant and an additive, and purified to obtain a 2-hydroxy-3-substituted aryl naphthoquinone derivative;

[0106] S3. Decarboxylation and alkylation: Under the catalytic action of metal catalysts and additives, 2-hydroxy-naphthoquinone and corresponding carboxylic acids are dissolved in a solvent in a certain ratio for decarboxylation and alkylation, and the reaction is kept warm. After purification, 2-hydroxy-3-substituted naphthoquinone derivatives are obtained.

[0107] C. Preparation of 2,3-disubstituted naphthoquinone derivatives, as shown in reaction equation c);

[0108] Acylation and alkylation: Under the catalytic action of an alkaline catalyst, 2-hydroxy-3-substituted naphthoquinone derivatives and corresponding acyl chlorides or halogenated hydrocarbons are dissolved in a solvent in a certain proportion to carry out acylation or alkylation reaction, and the reaction is kept warm. After purification, 2,3-disubstituted naphthoquinone derivatives are obtained.

[0109] Wherein, the substituent Ri is a substituted aryl, a substituted benzyl and a C1-16 alkyl; the substituent Rb is a C1-16 alkyl, Ra-(CH2)n-, Ra-CO-(CH2)n-; the substituent Rg is a C1-6 alkyl, a C3-6 cycloalkyl, a substituted aryl, Ph-(CH2)n- (n=1-4); the substituent Rh is a C1-6 alkyl and a C3-6 cycloalkyl;

[0110] Wherein, the substituted aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0111] The substituted benzyl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I;

[0112] Wherein, the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups;

[0113] Wherein, the C1-6 alkyl group is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino;

[0114] Wherein, the C3-6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl;

[0115] In A, the molar ratio of 1,4-naphthoquinone to acetic anhydride in reaction step S1 is 1:6.0-10.0;

[0116] The catalyst is at least one of protonic acid sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, perchloric acid, phosphoric acid, and nitric acid, and the molar ratio of the catalyst to the 1,4-naphthoquinone is 0.3-1.0:1;

[0117] The dropping temperature is 10-40°C, and the dropping method is dropwise addition;

[0118] The insulation reaction temperature is 0-15°C, and the insulation reaction time is 1-2.5 hours;

[0119] The crystallization method is to add cold water 1-2 times the volume of the solvent into the reaction system, cool down to crystallize, and then filter to obtain the acylated derivative.

[0120] In A, the molar ratio of the acylated derivative to the base in reaction step S2 is 1:1.2-3.0;

[0121] The base is at least one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium methoxide, and sodium ethoxide;

[0122] The solvent is one of dioxane, THF, MeOH, EtOH, nBuOH, iPrOH, HFIP, DMF, and DMSO;

[0123] The insulation reaction temperature is 0-5°C, and the insulation reaction time is 0.5-4.5 hours;

[0124] The hot water temperature is 90-100° C., the acidified acid is at least one of concentrated hydrochloric acid, acetic acid, formic acid, perchloric acid, and phosphoric acid, and the acidification degree is pH 1-2;

[0125] The purification method is to filter by suction, then wash with water whose volume is 5-10 times of the solvent, and vacuum dry at 65-75° C. for 8-12 hours to obtain 2-hydroxy-naphthoquinone.

[0126] In B, the molar ratio of the 2-hydroxy-naphthoquinone and the corresponding aldehyde in the reaction step S1 is 1:1.2-2.0;

[0127] The catalyst is at least one of L-alanine, L-lysine, L-leucine, L-phenylalanine, L-tryptophan, L-tyrosine, L-proline, L-arginine, L-histidine and L-leucine, and the molar ratio of the catalyst to 2-hydroxy-naphthoquinone is 0.2-0.5:1;

[0128] The additive is at least one of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid dimethyl ester, 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid didodecyl ester, and the molar ratio of the additive to the 2-hydroxy-naphthoquinone is 1-1.05:1;

[0129] The solvent is one of CH3CN, dioxane, THF, MeOH, EtOH, iPrOH, DCM, and CHCl3;

[0130] The insulation reaction temperature is 25-35°C, and the insulation reaction time is 6-8 hours;

[0131] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0132] In B, the molar ratio of the 2-hydroxy-3-substituted benzyl naphthoquinone derivative and the oxidant in reaction step S2 is 1:1.5-2.5;

[0133] The oxidant is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, TBHP, and KMnO4;

[0134] The additive is at least one of NaOH, KOH, LiOH, CsOH, tBuOK and tBuONa, and the molar ratio of the additive to the 2-hydroxy-3-substituted benzyl naphthoquinone derivative is 8.0-16.0:1;

[0135] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-5:1;

[0136] The ratio of the 2-hydroxy-3-substituted benzyl naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.0-1.2 L;

[0137] The insulation reaction temperature is 25-30°C, and the insulation reaction time is 10-24 hours;

[0138] The purification method is filtering, acidifying the filtrate with 10-20% HCl aqueous solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0139] In B, the molar ratio of 2-hydroxy-naphthoquinone to the corresponding carboxylic acid in reaction step S3 is 1:3.0-5.0;

[0140] The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to 2-hydroxy-naphthoquinone is 0.1-0.5:1;

[0141] The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to 2-hydroxy-naphthoquinone is 1.2-2.5:1;

[0142] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0143] The dosage ratio of the 2-hydroxy-naphthoquinone to the solvent or mixed solvent is 1 mol: 1.0-1.3 L;

[0144] The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours;

[0145] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:1.

[0146] In C, the molar ratio of the 2-hydroxy-3-substituted naphthoquinone derivative to the corresponding acyl chloride or halogenated hydrocarbon is 1:2.0-3.5;

[0147] The base catalyst is one of Et3N, Pyridine, iPr2EtN, K2CO3, Na2CO3, NaHCO3, KHCO3, and KH2PO4, and the molar ratio of the base catalyst to the 2-hydroxy-3-substituted naphthoquinone derivative is 1.2-2.5:1;

[0148] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, DMF, DMAC, DMSO, and acetone;

[0149] The insulation reaction temperature is 30-120°C, and the insulation reaction time is 6-24 hours;

[0150] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0151] Furthermore, the preparation method comprises the following steps:

[0152] When X is S, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula:

[0153]

[0154] The specific preparation steps of the above reaction equation are as follows:

[0155] S1. Thioetherification:

[0156] 1,4-naphthoquinone, a catalyst and corresponding arylthiophenol or thiol are dissolved in a solvent in a certain proportion, and the reaction is carried out at a warm temperature. After purification, a 2-substituted thioether naphthoquinone derivative is obtained.

[0157] S2, Arylation:

[0158] According to a certain ratio, a 2-substituted thioether naphthoquinone derivative, a catalyst and a corresponding aryl hydrazine are dissolved in a solvent, and the mixture is heated to react. After purification, a 2-substituted thioether-3-aryl naphthoquinone derivative is obtained.

[0159] S3, decarboxylation alkylation:

[0160] Under the catalytic action of metal catalysts and additives, 2-substituted thioether naphthoquinone derivatives and corresponding carboxylic acids are dissolved in a solvent in a certain proportion for decarboxylation and alkylation, and the reaction is carried out at a warm temperature. After purification, 2-substituted thioether-3-substituted naphthoquinone derivatives are obtained.

[0161] Wherein, the substituent Rj is C1-6 alkyl, substituted aryl and substituted benzyl; the substituent Rb is C1-16 alkyl, Ra-(CH2)n-, Ra-CO-(CH2)n-;

[0162] Wherein, the C1-6 alkyl group is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino;

[0163] Wherein, the substituted aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I;

[0164] The substituted benzyl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I;

[0165] Wherein, the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups;

[0166] In the reaction step S1, the molar ratio of the 1,4-naphthoquinone to the corresponding arylthiophenol or thiol is 1:1.2-2.5;

[0167] The catalyst is at most one of BiCl3, Bi(OTf)3, BF3·OEt2, AcOH, and AlCl3, and the molar ratio of the amount to the feed of 1,4-naphthoquinone is 0.05-0.3:1;

[0168] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, EtOH, iPrOH, nBuOH, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0169] The dosage ratio of 1,4-naphthoquinone to solvent or mixed solvent is 1 mol: 0.85-1.0 L;

[0170] The insulation reaction temperature is 25-35°C, and the insulation reaction time is 10-24 hours;

[0171] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0172] In the reaction step S2, the molar ratio of the 2-substituted thioether naphthoquinone derivative to the corresponding aryl hydrazine is 1:2.0-3.5;

[0173] The catalyst is one of PIDA, PIFA, TBAI, I2, and pyridine, and the molar ratio of the amount to the 2-substituted thioether naphthoquinone derivative is 0.05-0.5:1;

[0174] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, iPrOH, TFE, HFIP, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-5:1;

[0175] The ratio of the 2-substituted thioether naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.5-1.8 L;

[0176] The insulation reaction temperature is 25-70°C, and the insulation reaction time is 15-36 hours;

[0177] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:1.

[0178] In the reaction step S3, the molar ratio of the 2-substituted thioether naphthoquinone derivative to the corresponding carboxylic acid is 1:3.0-5.0;

[0179] The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to the 2-substituted thioether naphthoquinone derivative is 0.1-0.5:1;

[0180] The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to the 2-substituted thioether naphthoquinone derivative is 1.2-2.5:1;

[0181] The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1;

[0182] The ratio of the 2-substituted thioether naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.0-1.3 L;

[0183] The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours;

[0184] The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:1.

[0185] Compared with the prior art, the present invention has the following beneficial effects:

[0186] The present invention provides a 2,3-disubstituted naphthoquinone compound, use and preparation method. The series of compounds have novel structures and good to excellent anti-ectoparasitic activity. It is particularly worth mentioning that the series of compounds are introduced into the field of living veterinary drugs, overcoming the technical difficulties that have long troubled technicians in this field for many years - namely, the safety and toxicity of the compounds. The series of compounds have a simple synthesis process and mild reaction conditions, and can efficiently prepare diverse 2,3-disubstituted naphthoquinone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0187] Figure 1 1H NMR spectrum of tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate

[0188] Figure 2 1H NMR spectrum of Naph-13

[0189] Figure 3 1H NMR spectrum of Naph-14

[0190] Figure 4 1H NMR spectrum of Naph-16

[0191] Figure 5 1H NMR spectrum of Naph-17

[0192] Figure 6 1H NMR spectrum of Naph-19

[0193] Figure 7 1H NMR spectrum of Naph-20

[0194] Figure 8 1H NMR spectrum of Naph-21

[0195] Fig. 9 1H NMR spectrum of Naph-44

[0196] Fig.10 1H NMR spectrum of Naph-45

[0197] Fig.11 1H NMR spectrum of Naph-46

[0198] Fig.12 1H NMR spectrum of Naph-48

[0199] Fig.13 1H NMR spectrum of Naph-51

[0200] Fig.14 1H NMR spectrum of Naph-52

[0201] Fig.15 1H NMR spectrum of Naph-58

[0202] Fig.16 1H NMR spectrum of Naph-59

[0203] Fig.17 1H NMR spectrum of Naph-60

[0204] Fig.18 1H NMR spectrum of Naph-62

[0205] Fig.19 1H NMR spectrum of Naph-63

[0206] Fig. 20 1H NMR spectrum of Naph-70

[0207] Fig.21 1H NMR spectrum of Naph-71

[0208] Fig. 22 1H NMR spectrum of Naph-73

[0209] Fig.23 1H NMR spectrum of Naph-74

[0210] Fig.24 1H NMR spectrum of Naph-75 DETAILED DESCRIPTION

[0211] The following examples can help those skilled in the art to better understand the present invention, but they do not limit the present invention in any way. The raw materials used in the present invention are all known compounds, which can be purchased from the market or prepared by methods known in the art.

[0212] Example 1: Preparation of compound Naph-01

[0213] Step 1: Preparation of 2-phenylnaphthoquinone

[0214] In a 250 mL round-bottom flask, after adding a magnetic bar, potassium persulfate (100 mmol, 27.03 g) and ferric nitrate (2.5 mmol, 604.6 mg) were weighed and added to the round-bottom flask, and then 1,4-naphthoquinone (25 mmol, 3.95 g) and phenylboric acid (50 mmol, 6.09 g) were added. After adding 200 mL of a mixed solvent of toluene: water (1:1) to dissolve, the room temperature was gradually raised to 70°C and the reaction was kept warm for 20 hours.

[0215] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 10:1). After evaporating the solvent, 4.45 g of a yellow solid was obtained with a yield of 76%.

[0216] 1H NMR (400MHz, CDCl3) δ8.17-8.15(m,1H),8.13-8.11(m,1H),7.80-7.77(m,2H),7.59-7.55(m,2H),7.48-7.47(m.3H),7.06(s,1H).

[0217] Step 2: Preparation of Naph-01

[0218] In a 250mL round-bottom flask, after adding a magnetic particle, weigh 2-phenylnaphthoquinone (9mmol, 2.10g) and add it to the round-bottom flask. Add 100mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver sulfate (1.35mmol, 420.9mg) and acetic acid (36mmol, 2.16g). After stirring at room temperature for ten minutes, dissolve ammonium persulfate (22.5mmol, 5.13g) in 60mL of a mixed solvent of acetonitrile: water (3:1), add it dropwise into the reaction system, and heat to 90°C for 18 hours.

[0219] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 10:1). After evaporating the solvent, 1.07 g of a yellow solid was obtained with a yield of 48%.

[0220] 1H NMR (400MHz, CDCl3) δ 8.16-8.10 (m, 2H), 7.75-7.70 (m, 2H), 7.50-7.39 (m, 3H), 7.23 (d, J = 8.3Hz, 2H), 2.08 (s, 3H).

[0221] Example 2: Preparation of compound Naph-02

[0222] Step 1: Preparation of 2-(4-hydroxyphenyl)naphthoquinone

[0223] In a 250mL round-bottom flask, after adding a magnetic bar, weigh 1,4-naphthoquinone (25mmol, 3.95g) and phenol (50mmol, 4.71g) and add them to the round-bottom flask, add 160mL of dichloromethane to dissolve, then add potassium persulfate (75mmol, 20.27g), then add ferric chloride (62.5mmol, 10.14g) into the reaction system in five portions, and react at room temperature for 18 hours.

[0224] After the TLC reaction was completed, water was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine and then dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 9:1), and the solvent was evaporated to obtain 4.56 g of a yellow solid with a yield of 73%.

[0225] 1H NMR (400MHz, CDCl3) δ9.00(brs,1H),8.13–8.11(m,1H),8.06–8.04(m,1H),7.73–7.70(m,2H),7.46(d,J=8.0,2H),6.98(s,1H),6.90(d,J=8.0,2H).

[0226] Step 2: Preparation of Naph-02

[0227] In a 250mL round-bottom flask, after adding a magnetic particle, weigh 2-(4-hydroxyphenyl) naphthoquinone (9mmol, 2.25g) and add it to the round-bottom flask. Add 100mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver nitrate (1.8mmol, 305.8mg) and acetic acid (36mmol, 2.16g). After stirring at room temperature for ten minutes, dissolve ammonium persulfate (22.5mmol, 5.13g) in 60mL of a mixed solvent of acetonitrile: water (3:1), add it dropwise into the reaction system, and heat to 90°C for 18 hours.

[0228] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether:ethyl acetate=9:1). After evaporating the solvent, 1.02 g of a yellow solid was obtained with a yield of 43%.

[0229] 1H NMR (400MHz, CDCl3) δ9.05 (brs, 1H), 8.15–8.03 (m, 2H), 7.76–7.71 (m, 2H), 7.48 (d, J = 8.0, 2H), 6.88 (d, J = 8.0, 2H), 2.10 (s, 3H).

[0230] Example 3: Preparation of compound Naph-03

[0231] Step 1: Preparation of 2-phenylnaphthoquinone

[0232] In a 250 mL round-bottom flask, after adding a magnetic bar, weigh ammonium persulfate (100 mmol, 22.82 g) and ferric sulfate (2.5 mmol, 429.8 mg) and add them to the round-bottom flask, then add 1,4-naphthoquinone (25 mmol, 3.95 g) and phenylboric acid (50 mmol, 6.09 g), add 200 mL of a mixed solvent of toluene: water (1:1) to dissolve, gradually raise the room temperature to 75 ° C, and keep the reaction for 22 hours.

[0233] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether:ethyl acetate=10:1). After evaporating the solvent, 4.15 g of a yellow solid was obtained with a yield of 71%.

[0234] 1H NMR (400MHz, CDCl3) δ8.17-8.15(m,1H),8.13-8.11(m,1H),7.80-7.77(m,2H),7.59-7.55(m,2H),7.48-7.47(m.3H),7.06(s,1H).

[0235] Step 2: Preparation of Naph-03

[0236] In a 250mL round-bottom flask, after adding a magnetic particle, weigh 2-phenylnaphthoquinone (9mmol, 2.10g) and add it to the round-bottom flask. Add 100mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver nitrate (1.35mmol, 229.3mg) and heptanoic acid (36mmol, 4.69g). After stirring at room temperature for ten minutes, potassium persulfate (22.5mmol, 6.08g) is dissolved in 60mL of a mixed solvent of acetonitrile: water (3:1), and added dropwise into the reaction system. Heat to 95°C and keep the reaction for 22 hours.

[0237] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 10:1). After evaporating the solvent, 1.12 g of a yellow oily liquid was obtained with a yield of 39%.

[0238] 1H NMR (400MHz, CDCl3) δ8.23-8.04(m,2H),7.86-7.68(m,2H),7.61-7.37(m,3H),7.35 -7.18(m,2H),2.59-2.37(m,2H),1.59-1.38(m,2H),1.37-1.08(m,6H),0.84(s,3H).

[0239] Example 4: Preparation of Compound Naph-13

[0240] Step 1: Preparation of 2-aminonaphthoquinone

[0241] In a 250mL round-bottom flask, after adding a magnet, benzyloxyamine hydrochloride (37.5mmol, 5.99g) was weighed and added to the round-bottom flask. After adding 60mL of anhydrous ethanol and Et3N (25mmol, 2.53g) to dissolve the compound, the round-bottom flask was placed in an ice bath and stirred for ten minutes. Then, 1,4-naphthoquinone (25mmol, 3.95g) was dissolved in 50mL of anhydrous ethanol and added dropwise to the round-bottom flask in an ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was kept warm for 10 hours.

[0242] After the TLC reaction was completed, the mixture was cooled to room temperature, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=2:1). After the solvent was evaporated, 3.81 g of a red solid was obtained with a yield of 88%.

[0243] 1H NMR (400MHz, CDCl3) δ 8.05 (d, J = 11.5, 2H), 7.71 (d, J = 7.6, 1H), 7.62 (d, J = 7.6, 1H), 6.00 (s, 1H), 5.31 (brs, 2H).

[0244] Step 2: Preparation of tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate

[0245] In a 100 mL round-bottom flask, after adding a magnetic bar, weigh 2-aminonaphthoquinone (9 mmol, 1.56 g), di-tert-butyl dicarbonate (13.5 mmol, 2.95 g) and DMAP (0.9 mmol, 110.0 mg) and add them to the round-bottom flask. After adding 50 mL of THF to dissolve, heat to 75 °C and reflux for 8 hours.

[0246] After the TLC reaction was completed, the mixture was cooled to room temperature, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=10:1). After the solvent was evaporated, 1.67 g of a yellow solid was obtained with a yield of 68%.

[0247] 1H NMR (400MHz,CDCl3)δ8.17–8.05(m,2H),7.80–7.67(m,3H),7.48(s,1H),1.54(s,9H). [1HNMR spectrum of tert-butyl(1,4-dioxo-1,4-dihydronaphthalen-2-yl)carbamate is shown in the attached manual. Figure 1 】

[0248] Step 3: Preparation of Naph-13

[0249] In a 250mL round-bottom flask, after adding a magnetic bar, weigh tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate (5mmol, 1.36g) and add it to the round-bottom flask. Add 80mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver sulfate (1.0mmol, 311.8mg) and nonanoic acid (15mmol, 2.37g). After stirring at room temperature for ten minutes, potassium persulfate (7.5mmol, 2.03g) is dissolved in 40mL of a mixed solvent of acetonitrile: water (3:1), added dropwise into the reaction system, and the temperature is raised to 95°C for 20 hours.

[0250] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether:ethyl acetate=16:1). After evaporating the solvent, 0.79 g of a yellow solid was obtained with a yield of 41%.

[0251] 1H NMR (400MHz, CDCl3) δ8.10–8.05 (m, 2H), 7.73–7.66 (m, 2H), 7.06 (brs, 1H), 2.78–2.60 (m, 2H), 1.51 (s, 9H), 1.44–1.07 (m, 14H), 0.86 (t, J=6.8Hz, 3H). [1HNMR spectrum of Naph-13 is shown in the appendix of the manual Figure 2 】

[0252] Example 5: Preparation of Compound Naph-14

[0253] Step: Preparation of Naph-14

[0254] In a 250mL round-bottom flask, after adding a magnetic bar, weigh tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate (5mmol, 1.36g) and add it to the round-bottom flask. Add 80mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver sulfate (1.0mmol, 311.8mg) and dodecanoic acid (15mmol, 3.00g). After stirring at room temperature for ten minutes, potassium persulfate (7.5mmol, 2.03g) is dissolved in 40mL of a mixed solvent of acetonitrile: water (3:1), added dropwise into the reaction system, and the temperature is raised to 95°C for 20 hours.

[0255] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 0.75 g of a yellow solid was obtained with a yield of 33%.

[0256] 1H NMR (400MHz, CDCl3) δ8.10 (dt, J = 7.7, 1.0Hz, 2H), 7.79-7.67 (m, 3H), 2.34 (t, J = 7.6Hz, 2H), 1.71-1.61 (m, 2H), 1.54 (s, 9H), 1.49-1.10 (m, 16H), 0.88 (t, J = 6.8Hz, 3H). [1H NMR spectrum of Naph-14 is shown in the appendix of the manual Figure 3 】

[0257] Example 6: Preparation of Compound Naph-16

[0258] Step: Preparation of Naph-16

[0259] In a 250mL round-bottom flask, after adding a magnetic bar, weigh tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate (5mmol, 1.36g) and add it to the round-bottom flask. Add 80mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver sulfate (1.0mmol, 311.8mg) and phenylbutyric acid (15mmol, 2.46g). After stirring at room temperature for ten minutes, potassium persulfate (7.5mmol, 2.03g) is dissolved in 40mL of a mixed solvent of acetonitrile: water (3:1), added dropwise into the reaction system, and the temperature is raised to 95°C for 20 hours.

[0260] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 0.99 g of a yellow solid was obtained with a yield of 51%.

[0261] 1H NMR (400MHz, CDCl3) δ8.09–8.04 (m, 2H), 7.73–7.66 (m, 2H), 7.27–7.10 (m, 5H), 7.08 (brs, 1H), 2.85–2.60 (m, 4H), 1.98–1.83 (m, 2H), 1.50 (s, 9H). [1H NMR spectrum of Naph-16 is shown in the appendix of the manual Figure 4 】

[0262] Example 7: Preparation of Compound Naph-17

[0263] Step 1: Preparation of Naph-17

[0264] In a 250mL round-bottom flask, after adding a magnetic bar, weigh tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate (5mmol, 1.36g) and add it to the round-bottom flask. Add 80mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it. Then add silver sulfate (1.0mmol, 311.8mg) and 3-benzoyl propionic acid (15mmol, 2.67g). After stirring at room temperature for ten minutes, potassium persulfate (7.5mmol, 2.03g) is dissolved in 40mL of a mixed solvent of acetonitrile: water (3:1), added dropwise into the reaction system, and the temperature is raised to 95°C for 20 hours.

[0265] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether:ethyl acetate=16:1). After the solvent was evaporated, 0.43 g of a yellow solid was obtained with a yield of 21%.

[0266] 1H NMR (400MHz, CDCl3) δ8.11–8.05 (m, 2H), 8.01–7.94 (m, 2H), 7.75–7.66 (m, 3H), 7.57–7.53 (m, 1H), 7.44 (dd, J = 8.3, 7.0 Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 1.50 (s, 9H). [1H NMR spectrum of Naph-17 is shown in the appendix of the specification Figure 5 】

[0267] Example 8: Preparation of Compound Naph-19

[0268] Step: Preparation of Naph-19

[0269] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-13 (1 mmol, 399 mg) and add it to the round-bottom flask, add 10 mL of DCM to dissolve it, then add TFA (3 mmol, 229.7 mg) and keep the reaction at room temperature.

[0270] After the TLC reaction was completed, water was added to quench, and the product was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate and saturated brine and then dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 4:1). After the solvent was evaporated, 0.25 g of an orange-red solid was obtained with a yield of 84%.

[0271] 1H NMR (400MHz, CDCl3) δ8.08 (d, J = 7.6Hz, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.68 (t, J = 7.5Hz, 1H), 7.59 (t, J = 7.5Hz, 1H), 5.00 (brs, 2H), 2.52–2.43 (m, 2H), 1.50 (dd, J = 10.9, 5.1Hz, 2H), 1.38–1.24 (m, 12H), 0.87 (t, J = 6.8Hz, 3H). [1H NMR spectrum of Naph-19 is shown in the appendix of the specification Figure 6 】

[0272] Example 9: Preparation of Compound Naph-20

[0273] Step 1: In a 250 mL round-bottom flask, after adding a magnetic bar, weigh tert-butyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) carbamate (5 mmol, 1.36 g) and add it to the round-bottom flask, add 80 mL of a mixed solvent of acetonitrile: water (3:1) to dissolve it, then add silver sulfate (1.0 mmol, 311.8 mg) and tridecanoic acid (15 mmol, 3.21 g), stir at room temperature for ten minutes, and then dissolve potassium persulfate (7.5 mmol, 2.03 g) in 40 mL of a mixed solvent of acetonitrile: water (3:1), add it dropwise into the reaction system, and heat to 95 ° C for 20 hours.

[0274] After the TLC reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After evaporating the solvent, 0.73 g of a yellow solid was obtained with a yield of 33%.

[0275] Step 2: Preparation of Naph-20

[0276] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh the product obtained in step 1 (1 mmol, 441 mg) and add it to the round-bottom flask, add 10 mL of DCM to dissolve, then add TFA (3 mmol, 229.7 mg) and keep the reaction at room temperature.

[0277] After the TLC reaction was completed, water was added to quench, and the product was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate and saturated brine and then dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 4:1). After the solvent was evaporated, 0.27 g of an orange-red solid was obtained with a yield of 79%.

[0278] 1H NMR (400MHz, CDCl3) δ8.08 (d, J = 7.6Hz, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.71-7.64 (m, 1H), 7.61-7.58 (m, 1H), 5.00 (brs, 2H), 2.57-2.39 (m, 2H), 1.52-1.23 (m, 20H), 0.87 (t, J = 5.6Hz, 3H). [1H NMR spectrum of Naph-20 is shown in the appendix of the manual Figure 7 】

[0279] Example 10: Preparation of Compound Naph-21

[0280] Step: Preparation of Naph-21

[0281] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-20 (1 mmol, 341 mg) and K2CO3 (2 mmol, 276.4 mg) and add them to the round-bottom flask, add 10 mL of DMF to dissolve, then add iodomethane (2 mmol, 283.88 mg) to the reaction flask, and heat to 60 °C for reaction.

[0282] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 0.245 g of an orange-red solid was obtained with a yield of 69%.

[0283] 1H NMR (400MHz, CDCl3) δ8.07 (d, J = 7.7Hz, 1H), 7.98 (d, J = 7.6Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.56 (t, J = 7.5Hz, 1H), 5.91 (brs, 1H), 3.22 (d, J = 5.5Hz, 3H), 2.78–2.68 (m, 2H), 1.53–1.25 (m, 20H), 0.87 (d, J = 7.0Hz, 3H). [1H NMR spectrum of Naph-21 is shown in the appendix of the specification Figure 8 】

[0284] Example 11: Preparation of Compound Naph-44

[0285] Step 1: Preparation of 2-hydroxynaphthoquinone

[0286] Acylation: In a 100 mL round-bottom flask, add a magnetic particle, weigh naphthoquinone (20 mmol, 3.16 g) and add it to the round-bottom flask. Add 15 mL of acetic anhydride to dissolve it. Place the round-bottom flask in an ice bath and stir for ten minutes. Then, add sulfuric acid (7.5 mmol, 735.6 mg) dropwise into the round-bottom flask and keep the reaction in an ice bath for 2 hours.

[0287] After the TLC reaction was completed, 30 mL of cold water was added to quench, the temperature was lowered to crystallize, the mixture was filtered, washed with petroleum ether, and dried to obtain 5.43 g of brown solid acylate with a yield of 90%.

[0288] Hydrolysis and acidification: After adding a magnetic bar to a 100 mL round-bottom flask, weigh sodium methoxide (30 mmol, 1.62 g) and add it to the round-bottom flask. Add 50 mL of anhydrous methanol to dissolve it and stir it in an ice bath for ten minutes. Then add the acylate (15 mmol, 4.53 g) dropwise into the round-bottom flask and keep it warm in an ice bath for 4 hours.

[0289] The generated solid was filtered and washed with methanol. The obtained solid was dissolved in 90°C hot water and filtered while hot. The filtrate was acidified to pH 1 with concentrated hydrochloric acid, cooled, crystallized under ice bath conditions, filtered, and then washed with water until neutral. The obtained solid was vacuum dried at 70°C for 8 hours to obtain 2.14 g of yellow solid 2-hydroxy-naphthoquinone with a yield of 82%.

[0290] 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H,OH),8.02–7.97(m,1H),7.96–7.92(m,1H),7.89–7.75(m,2H),6.17(s,1H).

[0291] Step 2: Preparation of Naph-44

[0292] In a 100 mL round-bottom flask, after adding a magnetic bar, weigh 2-hydroxynaphthoquinone (5 mmol, 870.8 mg), L-proline (1 mmol, 115.1 mg) and dihydropyridine (5.25 mmol, 1.33 g) and add them to the round-bottom flask, add 50 mL of DCM to dissolve, then add n-butyraldehyde (10 mmol, 721.1 mg) to the round-bottom flask and react at room temperature for 6 hours.

[0293] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 0.876 g of a yellow solid was obtained with a yield of 76%.

[0294] 1H NMR (400MHz, CDCl3) δ8.11 (dt, J = 7.6, 2.0Hz, 1H), 8.06 (dt, J = 7.6, 2.0Hz, 1H), 7.76-7.71 (m, 1H), 7.68-7.65 (m, 1H), 7.33 (brs, 1H), 2.62-2.57 (m, 2H), 1.51 (qd, J = 8.0, 6.9, 4.1Hz, 2H), 1.40 (qd, J = 7.4, 2.7Hz, 2H), 0.93 (t, J = 7.3Hz, 3H). [1HNMR spectrum of Naph-44 is shown in the appendix of the specification Fig. 9 】

[0295] Example 12: Preparation of Compound Naph-45

[0296] Step: Preparation of Naph-45

[0297] In a 100 mL round-bottom flask, after adding a magnetic bar, weigh 2-hydroxynaphthoquinone (5 mmol, 870.8 mg), L-proline (1 mmol, 115.1 mg) and dihydropyridine (5.25 mmol, 1.33 g) and add them to the round-bottom flask, add 50 mL of DCM to dissolve, then add n-hexanal (10 mmol, 1.0 g) to the round-bottom flask and keep the reaction at room temperature for 6 hours.

[0298] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 0.94 g of a yellow solid was obtained with a yield of 73%.

[0299] 1H NMR (400MHz, CDCl3) δ8.11 (dd, J = 7.6, 1.3Hz, 1H), 8.06 (dd, J = 7.5, 1.4Hz, 1H), 7.74 (td, J = 7.6, 1.4Hz, 1H), 7.67 (td, J = 7.5, 1.3Hz, 1H), 7.32 (brs, 1H), 2.62–2.56 (m, 2H), 1.52 (td, J = 7.5, 7.0, 2.4Hz, 2H), 1.39–1.28 (m, 6H), 0.89–0.84 (m, 3H). [1H NMR spectrum of Naph-45 is shown in the attached manual Fig.10 】

[0300] Example 13: Preparation of Compound Naph-46

[0301] Step: Preparation of Naph-46

[0302] In a 100 mL round-bottom flask, after adding a magnetic bar, weigh 2-hydroxynaphthoquinone (5 mmol, 870.8 mg), L-proline (1 mmol, 115.1 mg) and dihydropyridine (5.25 mmol, 1.33 g) and add them to the round-bottom flask, add 50 mL of DCM to dissolve, then add n-octanal (10 mmol, 1.28 g) to the round-bottom flask and keep the reaction at room temperature for 6 hours.

[0303] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 1.02 g of a yellow solid was obtained with a yield of 71%.

[0304] 1H NMR (400MHz, CDCl3) δ8.11 (d, J = 7.6Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 7.74 (t, J = 7.5Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.32 (s, 1H), 2.59 (t, J = 7.8Hz, 2H), 1.53 (t, J = 7.7Hz, 2H), 1.38–1.25 (m, 10H), 0.86 (t, J = 6.7Hz, 3H). [1H NMR spectrum of Naph-46 is shown in the attached manual Fig.11 】

[0305] Example 14: Preparation of Compound Naph-48

[0306] Step: Preparation of Naph-48

[0307] In a 100 mL round-bottom flask, after adding a magnetic bar, weigh 2-hydroxynaphthoquinone (5 mmol, 870.8 mg), L-proline (1 mmol, 115.1 mg) and dihydropyridine (5.25 mmol, 1.33 g) and add them to the round-bottom flask, add 50 mL of DCM to dissolve, then add dodecanal (10 mmol, 1.84 g) to the round-bottom flask and keep the reaction at room temperature for 7 hours.

[0308] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 1.45 g of a yellow solid was obtained with a yield of 85%.

[0309] 1H NMR (400MHz, CDCl3) δ8.11 (dd, J = 7.8, 1.2Hz, 1H), 8.07 (dd, J = 7.6, 1.3Hz, 1H), 7.74 (td, J = 7.5, 1.4Hz, 1H), 7.67 (td, J = 7.5, 1.4Hz, 1H), 7.31 (s, 1H), 2.61–2.57 (m, 2H), 1.53 (t, J = 7.9Hz, 2H), 1.37–1.24 (m, 18H), 0.87 (t, J = 6.9Hz, 3H). [1H NMR spectrum of Naph-48 is shown in the attached manual Fig.12 】

[0310] Example 15: Preparation of Compound Naph-51

[0311] Step: Preparation of Naph-51

[0312] In a 100 mL round-bottom flask, after adding a magnetic bar, weigh 2-hydroxynaphthoquinone (5 mmol, 870.8 mg), L-proline (1 mmol, 115.1 mg) and dihydropyridine (5.25 mmol, 1.33 g) and add them to the round-bottom flask, add 50 mL of DCM to dissolve, then add citronellal (10 mmol, 1.54 g) to the round-bottom flask and react at room temperature for 8 hours.

[0313] After the TLC reaction was completed, water was added to quench, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 0.936 g of a yellow solid was obtained with a yield of 60%.

[0314] 1H NMR (400MHz, CDCl3) δ8.11 (dd, J=7.7, 1.3Hz, 1H), 8.07 (dd, J=7.6, 1.4Hz, 1H), 7. 74(td,J=7.6,1.4Hz,1H),7.67(td,J=7.5,1.4Hz,1H),7.31(brs,1H),5.12–5.08( m,1H),2.65–2.54m,2H),2.06–1.91(m,2H),1.66(s,3H),1.59(s,3H),1.54–1.48 (m,2H),1.43–1.33(m,2H),1.22–1.16(m,1H),0.97(d,J=6.5Hz,3H).[1H of Naph-51 NMR spectrum see the instructions Fig.13 】

[0315] Example 16: Preparation of Compound Naph-52

[0316] Step: Preparation of Naph-52

[0317] In a 100 mL round-bottom flask, after adding a magnetic bar, 2-hydroxynaphthoquinone (5 mmol, 870.8 mg), L-proline (1 mmol, 115.1 mg) and dihydropyridine (5.25 mmol, 1.33 g) were weighed and added to the round-bottom flask, and 50 mL of DCM was added to dissolve, and then undecenal (10 mmol, 1.68 g) was added to the round-bottom flask, and the reaction was kept at room temperature for 8 hours.

[0318] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 1.40 g of a yellow solid was obtained with a yield of 86%.

[0319] 1H NMR (400MHz, CDCl3) δ8.11 (d, J = 7.6Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 7.76-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.31 (s, 1H), 5.84-5.76 (m, 1H), 5.00-4.96 (m, 1H), 4.93-4.90 (m, 1H), 2.62-2.56 (m, 2H), 2.02 (q, J = 7.1Hz, 2H), 1.56-1.50 (m, 2H), 1.38-1.25 (m, 12H). [1H NMR spectrum of Naph-52 is shown in the attached manual Fig.14 】

[0320] Example 17: Preparation of Compound Naph-58

[0321] Step: Preparation of Naph-58

[0322] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and add it to the round-bottom flask. Add 25 mL of DCM to dissolve it. Then, add propionyl chloride (2 mmol, 185.0 mg) and Et3N (2 mmol, 202.4 mg) to the reaction system and keep the reaction at room temperature for 8 hours.

[0323] After the TLC reaction was completed, water was added to quench the reaction, and the product was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 256.6 mg of a light yellow liquid was obtained. The yield was 75%.

[0324] 1H NMR (400MHz, CDCl3) δ8.11–8.06 (m, 2H), 7.88–7.55 (m, 2H), 2.71 (q, J = 7.5Hz, 2H), 2.54 (t, J = 7.8Hz, 2H), 1.53–1.22 (m, 15H), 0.87 (t, J = 6.8Hz, 3H). [1H NMR spectrum of Naph-58 is shown in the appendix of the manual Fig.15 】

[0325] Example 18: Preparation of Compound Naph-59

[0326] Step: Preparation of Naph-59

[0327] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and add it to the round-bottom flask. Add 25 mL of DCM to dissolve it. Then, add butyryl chloride (2 mmol, 201.1 mg) and Et3N (2 mmol, 202.4 mg) to the reaction system and keep the reaction at room temperature for 8 hours.

[0328] After the TLC reaction was completed, water was added to quench the reaction, and the product was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 156.7 mg of a light yellow liquid was obtained. The yield was 44%.

[0329] 1H NMR (400MHz, CDCl3) δ8.11–8.06 (m, 2H), 7.75–7.69 (m, 2H), 2.65 (t, J = 7.4 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H), 1.87–1.80 (m, 2H), 1.50–1.24 (m, 12H), 1.09 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H). [1H NMR spectrum of Naph-59 is shown in the appendix of the specification Fig.16 】

[0330] Example 19: Preparation of Compound Naph-60

[0331] Step: Preparation of Naph-60

[0332] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and add it to the round-bottom flask. Add 25 mL of DCM to dissolve it. Then add isovaleryl chloride (2 mmol, 241.1 mg) and Et3N (2 mmol, 202.4 mg) to the reaction system and keep the reaction at room temperature for 7 hours.

[0333] After the TLC reaction was completed, water was added to quench the reaction, and the product was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 251.7 mg of a light yellow liquid was obtained. The yield was 68%.

[0334] 1H NMR (400MHz, CDCl3) δ8.12–8.06 (m, 2H), 7.75–7.69 (m, 2H), 2.55–2.52 (m, 4H), 2.32–2.24 (m, 1H), 1.49–1.24 (m, 12H), 1.11 (d, J = 6.7 Hz, 6H), 0.87 (t, J = 6.8 Hz, 3H). [1H NMR spectrum of Naph-60 is shown in the appendix of the manual Fig.17 】

[0335] Example 20: Preparation of Compound Naph-62

[0336] Step: Preparation of Naph-62

[0337] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and add it to the round-bottom flask. Add 25 mL of DCM to dissolve it. Then, add 4-chlorobutyryl chloride (2 mmol, 282.0 mg) and Et3N (2 mmol, 202.4 mg) to the reaction system and keep the reaction at room temperature for 8 hours.

[0338] After the TLC reaction was completed, water was added to quench the reaction, and the product was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 335.5 mg of a light yellow liquid was obtained. The yield was 86%.

[0339] 1H NMR (400MHz, CDCl3) δ8.18–8.00 (m, 2H), 7.75–7.70 (m, 2H), 3.72 (t, J = 6.2Hz, 2H), 2.89 (t, J = 7.1Hz, 2H), 2.54 (t, J = 7.8Hz, 2H), 2.34–2.20 (m, 2H), 1.50–1.23 (m, 12H), 0.86 (t, J = 6.8Hz, 3H). [1H NMR spectrum of Naph-62 is shown in the appendix of the specification Fig.18 】

[0340] Example 21: Preparation of Compound Naph-63

[0341] Step: Preparation of Naph-63

[0342] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and add it to the round-bottom flask. Add 25 mL of DCM to dissolve it. Then add trifluoropropionyl chloride (2 mmol, 293.0 mg) and Et3N (2 mmol, 202.4 mg) to the reaction system and keep the reaction at room temperature for 10 hours.

[0343] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 194.1 mg of a yellow solid was obtained with a yield of 49%.

[0344] 1H NMR (400MHz, CDCl3) δ8.15–8.08 (m, 2H), 7.78–7.73 (m, 2H), 3.56 (q, J = 9.8 Hz, 2H), 2.55 (t, J = 7.8 Hz, 2H), 1.49–1.25 (m, 12H), 0.87 (t, J = 6.8 Hz, 3H). [1H NMR spectrum of Naph-63 is shown in the appendix of the manual Fig.19 】

[0345] Example 22: Preparation of Compound Naph-70

[0346] Step: Preparation of Naph-70

[0347] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-44 (1 mmol, 230.1 mg) and K2CO3 (2 mmol, 276.4 mg) and add them to the round-bottom flask, add 10 mL of DMF to dissolve, then add iodomethane (2 mmol, 283.88 mg) to the reaction flask, and heat to 60 °C for reaction.

[0348] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 16:1). After the solvent was evaporated, 202.6 mg of a yellow solid was obtained with a yield of 83%.

[0349] 1H NMR (400MHz,CDCl3)δ8.07–8.00(m,2H),7.70–7.65(m,2H),4.11(s,3H),2.60–2.55(m,2H),1.47–1.36(m,4H),0.94–0.91(m,3H). [1H NMR spectrum of Naph-70 is shown in the appendix of the manual Fig. 20 】

[0350] Example 23: Preparation of Compound Naph-71

[0351] Step: Preparation of Naph-71

[0352] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and K2CO3 (2 mmol, 276.4 mg) and add them to the round-bottom flask, add 10 mL of DMF to dissolve, then add iodomethane (2 mmol, 283.88 mg) to the reaction flask, and heat to 60 °C for reaction.

[0353] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether:ethyl acetate=16:1). After the solvent was evaporated, 243 mg of a yellow solid was obtained. The yield was 81%.

[0354] 1H NMR (400MHz,CDCl3)δ8.08–8.00(m,2H),7.70–7.65(m,2H),4.11(s,3H),2.60–2.53(m,2H),1.45–1.25(m,12H),0.86(t,J=6.7Hz,3H). [1H NMR spectrum of Naph-71 is shown in the appendix of the manual Fig.21 】

[0355] Example 24: Preparation of Compound Naph-73

[0356] Step: Preparation of Naph-73

[0357] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-48 (1 mmol, 342.2 mg) and K2CO3 (1.2 mmol, 165.8 mg) and add them to the round-bottom flask, add 10 mL of DMF to dissolve, then add bromopentanol (2 mmol, 334.08 mg) to the reaction flask and keep the reaction at room temperature for 12 hours.

[0358] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 4:1). After the solvent was evaporated, 115.6 mg of a yellow solid was obtained with a yield of 27%.

[0359] 1H NMR (400MHz, CDCl3) δ8.07–8.02 (m, 2H), 7.71–7.66 (m, 2H), 4.35 (t, J=6.4Hz, 2H), 3.46–3.40 (m, 3H), 2.62–2.55 (m, 2H), 1.97–1.78 (m, 6H), 1.65–1.30 (m, 20H), 0.87 (t, J=6.8Hz, 3H). [1H NMR spectrum of Naph-73 is shown in the appendix of the specification Fig. 22 】

[0360] Example 25: Preparation of Compound Naph-74

[0361] Step: Preparation of Naph-74

[0362] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-46 (1 mmol, 286.1 mg) and K2CO3 (1.2 mmol, 165.8 mg) and add them to the round-bottom flask, add 10 mL of DMF to dissolve, then add ethyl bromoacetate (2 mmol, 334.08 mg) to the reaction flask and keep the reaction at room temperature for 12 hours.

[0363] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether: ethyl acetate = 8:1). After the solvent was evaporated, 294.03 mg of a yellow solid was obtained. The yield was 79%.

[0364] 1H NMR (400MHz, CDCl3) δ8.05 (dd, J = 7.3, 1.8Hz, 1H), 7.99 (dd, J = 7.3, 1.9Hz, 1H), 7.71-7.64 (m, 2H), 5.08 (s, 2H), 4.24 (q, J = 7.1Hz, 2H), 2.69-2.63 (m, 2H), 1.49 (dd, J = 10.7, 4.8Hz, 2H), 1.38-1.25 (m, 13H), 0.86 (t, J = 6.8Hz, 3H). [1H NMR spectrum of Naph-74 is shown in the attached manual Fig.23 】

[0365] Example 26: Preparation of Compound Naph-75

[0366] Step: Preparation of Naph-75

[0367] In a 50 mL round-bottom flask, after adding a magnetic bar, weigh Naph-48 (1 mmol, 342.2 mg) and K2CO3 (1.2 mmol, 165.8 mg) and add them to the round-bottom flask, add 10 mL of DMF to dissolve, then add ethyl bromoacetate (2 mmol, 334.08 mg) to the reaction flask and keep the reaction at room temperature for 12 hours.

[0368] After the TLC reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried. After concentration, it was purified by column chromatography (petroleum ether:ethyl acetate=8:1). After the solvent was evaporated, 355.5 mg of a yellow solid was obtained with a yield of 83%.

[0369] 1H NMR (400MHz, CDCl3) δ8.06 (dd, J = 7.1, 1.9Hz, 1H), 8.00 (dt, J = 7.3, 2.3Hz, 1H), 7.72-7.63 (m, 2H), 5.08 (s, 2H), 4.24 (q, J = 7.1Hz, 2H), 2.71-2.63 (m, 2H), 1.51-1.47 (m, 2H), 1.36-1.24 (m, 21H), 0.89-0.85 (m, 3H). [1H NMR spectrum of Naph-75 is shown in the appendix of the manual Fig.24 】

[0370] The present invention is not limited to the above embodiments. Any simple or equivalent changes or modifications made to the above embodiments based on the technical essence of the present invention are within the technical scope of the present invention.

[0371] The in vitro anti-rabbit itch mite activity assay method and assay results of the compounds of the present invention:

[0372] Source of parasites: Natural mites were collected from the ears of New Zealand rabbits with mites as the test objects;

[0373] Compound sample treatment: Weigh the compound, prepare it into a 1 mg / mL stock solution with DMSO, and then dilute it with distilled water to 100 μg / mL, 50 μg / mL, 20 μg / mL, 10 μg / mL, 5 μg / mL, and 1 μg / mL solutions;

[0374] The specific determination method is as follows:

[0375] Place a 0.45 μm microporous filter membrane with a diameter of 50 mm in a 60 mm dish and add 350 μL of the drug solution;

[0376] Pick 20 mites per dish with an insect picker, repeat 3 times per group, place the mites in a dish containing the drug solution, incubate at 28℃ for 24 hours, record the number of dead mites in each dish, and calculate the mortality rate;

[0377] At the same time, a blank control group and a positive control group were set up, that is, 1% DMSO, amitraz and ivermectin solutions were added respectively.

[0378] Mortality rate = number of mites killed / total number of mites × 100%;

[0379] Corrected mortality rate = (mortality rate of mites in the compound group - mortality rate of mites in the blank control group) / (1 - mortality rate of mites in the blank control group) × 100%;

[0380] Test results: Some test results on rabbit itch mites are as follows:

[0381] At a concentration of 100 μg / mL, after 24 hours of drug action, the mortality rates of Naph-05, Naph-11, Naph-13, Naph-14, Naph-17, Naph-19, Naph-20, Naph-21, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, Naph-71, Naph-72, Naph-73, Naph-74, Naph-75, Naph-77, ivermectin, and amitraz were all above 90%.

[0382] At a concentration of 50 μg / mL, after 24 hours of drug action, the mortality rates of Naph-05, Naph-13, Naph-14, Naph-17, Naph-19, Naph-20, Naph-21, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, Naph-71, Naph-72, Naph-73, Naph-74, Naph-75, and ivermectin were all above 90%.

[0383] At a concentration of 20 μg / mL, after 24 hours of drug action, the mortality rates of Naph-13, Naph-14, Naph-17, Naph-19, Naph-20, Naph-21, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 90%.

[0384] At a concentration of 10 μg / mL, 24 hours after the drug action, the mortality rates of Naph-19, Naph-20, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 90%.

[0385] At a concentration of 5 μg / mL, 24 hours after the drug action, the mortality rates of Naph-19, Naph-20, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 85%.

[0386] At a concentration of 1 μg / mL, 24 hours after the drug action, the mortality rates of Naph-19, Naph-20, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 85%.

[0387] The in vitro anti-canine scabies activity assay method and assay results of the compounds of the present invention are as follows:

[0388] Source of parasites: Take a dog naturally infected with scabies, scrape the affected part, and detect the scabies under a microscope. Put the scraped skin tissue of the affected part in a glass dish, cover it with a lid, and put it in a 37℃ water bath. After 1 hour, take out the dish and collect the scabies crawling out of the tissue as the test object.

[0389] Compound sample treatment: Weigh the compound, prepare it into a 1 mg / mL stock solution with DMSO, and then dilute it with distilled water to 100 μg / mL, 50 μg / mL, 20 μg / mL, 10 μg / mL, 5 μg / mL, and 1 μg / mL solutions;

[0390] The specific determination method is as follows:

[0391] Place a 0.45 μm, 50 mm diameter microporous organic filter membrane in a 60 mm dish and add 350 μL of the drug solution;

[0392] Ten mites were picked from each dish with an insect picking needle, with three replicates per group. The mites were placed in a dish containing the drug solution and incubated in a 28°C incubator for 24 hours. The number of dead mites in each dish was recorded and the mortality rate was calculated.

[0393] At the same time, a blank control group and a positive control group were set up, that is, 1% DMSO, amitraz and ivermectin solutions were added respectively for treatment.

[0394] Mortality rate = number of mites killed / total number of mites × 100%;

[0395] Corrected mortality rate = (mortality rate of mites in the compound group - mortality rate of mites in the blank control group) / (1 - mortality rate of mites in the blank control group) × 100%;

[0396] Test results: Some test results of canine scabies are as follows:

[0397] At a concentration of 100 μg / mL, after 24 hours of drug action, the mortality rates of Naph-05, Naph-11, Naph-13, Naph-14, Naph-17, Naph-19, Naph-20, Naph-21, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, Naph-71, Naph-72, Naph-73, Naph-74, Naph-75, Naph-77, ivermectin, and amitraz were all above 90%.

[0398] At a concentration of 50 μg / mL, after 24 hours of drug action, the mortality rates of Naph-05, Naph-13, Naph-14, Naph-17, Naph-19, Naph-20, Naph-21, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, Naph-71, Naph-72, Naph-73, Naph-74, Naph-75, and ivermectin were all above 90%.

[0399] At a concentration of 20 μg / mL, after 24 hours of drug action, the mortality rates of Naph-13, Naph-14, Naph-17, Naph-19, Naph-20, Naph-21, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 90%.

[0400] At a concentration of 10 μg / mL, 24 hours after the drug action, the mortality rates of Naph-19, Naph-20, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 90%.

[0401] At a concentration of 5 μg / mL, 24 hours after the drug action, the mortality rates of Naph-19, Naph-20, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 85%.

[0402] At a concentration of 1 μg / mL, 24 hours after the drug action, the mortality rates of Naph-19, Naph-20, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 85%.

[0403] The in vitro anti-haemaphysalis longicornis activity assay method and assay results of the compounds of the present invention are as follows:

[0404] Source of parasites: Long-horned ticks were subcultured and fed on the back of rabbits during the parasitic period. During the non-parasitic period, they were cultured in an incubator with a humidity of 70% and a temperature of 25°C. The blood-filled nymphs were taken as the test objects.

[0405] Compound sample treatment: Weigh the compound, prepare it into a 1 mg / mL stock solution with DMSO, and then dilute it with distilled water to 2500 μg / mL, 250 μg / mL, and 25 μg / mL solutions;

[0406] The specific determination method is as follows:

[0407] The drug was used to treat the blood-filled nymphs of the long-horned tick by dipping, with each tick being dipped for 5 minutes;

[0408] Each group contained 10-15 ticks, and each group was repeated three times. After incubation in a 70% relative humidity, 28°C incubator for 48 hours, the number of dead ticks was recorded and the mortality rate was calculated;

[0409] At the same time, a blank control group and a positive control group were set up, which were treated with 10% DMSO and ivermectin solution respectively.

[0410] Mortality rate = number of dead ticks / total number of ticks × 100%;

[0411] Corrected mortality rate = (tick mortality rate in compound group - tick mortality rate in blank control group) / (1 - tick mortality rate in blank control group) × 100%;

[0412] Test results: Some test results of Haemaphysalis longicornis are as follows:

[0413] At a concentration of 2500 μg / mL, after 48 hours of drug action, the mortality rates of Naph-05, Naph-19, Naph-20, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-58, Naph-60, Naph-63, and ivermectin were all above 90%.

[0414] At a concentration of 250 μg / mL, after 48 hours of drug action, the mortality rates of Naph-19, Naph-20, Naph-30, Naph-45, Naph-47, Naph-51, Naph-52, Naph-63, and ivermectin were all above 80%.

[0415] At a concentration of 25 μg / mL, after 48 hours of drug action, the mortality rates of Naph-19, Naph-20, Naph-47, Naph-51, Naph-52, Naph-63, and ivermectin were all above 60%.

[0416] Evaluation and implementation method of the compound of the present invention for the treatment of clinical rabbit ear mites:

[0417] Evaluation criteria for sick rabbits and the degree and scoring criteria for infection of rabbit itch mites: sick rabbits can be diagnosed with rabbit ear itch mite disease based on clinical symptoms, autopsy changes, and microscopic examination of worms; on the 0th, 3rd, and 7th days of the experiment, the ear inflammatory exudate and scabs were examined, and the presence of mites was examined microscopically, and the degree of infection was scored: no exudate or mites 0 point; ear canal exudate but no mites 0.5 point; ear canal with a small amount of scab and mites 1 point; external auditory canal full of scab and mites 2 points; ear canal and proximal 1 / 4 of the auricle with scab and mites 3 points; auricle 1 / 2 full of scab and mites 4 points; auricle 3 / 4 full of scab and mites 5 points; the entire auricle full of scab and mites 6 points.

[0418] Clinical use of the compounds of the present invention:

[0419] Compounds Naph-19, Naph-51, and Naph-71 were prepared into stock solutions with DMSO and then diluted with distilled water into aqueous solutions with a concentration of 250 μg / mL for treatment;

[0420] Ivermectin was used as a positive control, and an aqueous solution containing 0.1% DMSO was used as a blank control;

[0421] Place the drug solution in a 50mL spray bottle and spray it evenly on the affected area every other day. Record the ear inflammatory exudate and scabs, and check for mites under a microscope after one week.

[0422] Evaluation results: Naph-19, Naph-51 and Naph-71 greatly alleviated the clinical symptoms of the sick rabbits after 4 days of use, and part of the scab fell off; one week later, all the scabs of the sick rabbits fell off, there was no inflammatory exudate in the ears, and no worms were found under microscopic examination. The ear mites of the clinically sick rabbits have been cured.

[0423] Evaluation and implementation methods of the compounds of the present invention for the treatment of clinical canine scabies:

[0424] Criteria for judging sick dogs: Use a blunt surgical blade to scrape dandruff from the junction of the dog's affected skin and normal skin until bleeding occurs, and place it on a clean glass slide; examine under a low-power microscope, and if living mites are found, it can be confirmed that the dog has canine scabies.

[0425] Clinical use of the compounds of the present invention:

[0426] Compound Naph-51 was prepared into a stock solution with DMSO and then diluted with distilled water into an aqueous solution with a concentration of 2500 μg / mL for treatment;

[0427] Ivermectin was used as a positive control, and an aqueous solution containing 0.1% DMSO was used as a blank control;

[0428] Place the drug solution in a 50mL spray bottle and spray it evenly on the affected area every other day. Record the scab formation and hair growth, and check for mites under a microscope after 10 days.

[0429] Evaluation results: After 5 days of use, Naph-51 greatly alleviated the clinical symptoms of the sick dogs, and some scabs fell off; after 10 days, all the scabs of the sick dogs fell off, and no worms were found under microscopic examination; after two weeks, the hair of the sick dogs grew normally, and the canine scabies of the clinically sick dogs had been cured.

[0430] In summary, this series of compounds, with their novel structures, exhibit good to excellent antiparasitic activity against ectoparasites; it is particularly worth mentioning that this series of compounds has been introduced into the field of live veterinary drugs, overcoming the technical difficulties that have long plagued technical personnel in this field - namely, how to ensure the compounds' efficient antiparasitic activity while achieving a reasonable balance between their safety and toxicity; in addition, the synthesis process of this series of compounds is simple and the reaction conditions are mild, and a variety of 2,3-disubstituted naphthoquinone compounds can be efficiently prepared.

Claims

1. A 2,3-disubstituted naphthoquinone compound, characterized in that: The general formula of the compound is shown in Formula I, Wherein, X is selected from C, NH, O, S; wherein, when X is selected from C, the X-R1 substituent is an aryl substituent; wherein the aryl substituent is 3-monosubstituted, 4-monosubstituted, 3,4-disubstituted, 3,5-disubstituted; wherein the aryl substituent is one or two of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; When X is selected from NH, the R1 is selected from hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, substituted aryl, substituted benzyl, substituted acyl; When X is selected from O, the R1 is selected from hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, substituted benzyl, substituted acyl; When X is selected from S, the R1 is selected from C1-6 alkyl, substituted aryl, substituted benzyl; The R2 is selected from C1-16 alkyl, substituted aryl, Ra-(CH2)n-, Ra-CO-(CH2)n-.

2. The 2,3-disubstituted naphthoquinone compound according to claim 1, characterized in that: in, The C1-6 alkyl in R1 is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino; Wherein, the C3-6 cycloalkyl in R1 is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl; Wherein, the substituted aryl in R1 is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; Wherein, the substituted benzyl in R1 is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; Wherein, the substituted acyl group in R1 is an acyl group substituted with C1-6 alkyl, an acyl group substituted with C3-6 cycloalkyl, a benzoyl group substituted with an aryl, an acyl group substituted with Ph-(CH2)n- (n=1-4), or an acyl group substituted with tert-butyloxy; wherein, the C1-6 alkyl group is an alkyl substituent with 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino; wherein , the cycloalkyl group is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl; wherein the aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, and 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, and I; Wherein, the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups; The aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I; Wherein, Ra is a substituted aromatic group or a 5-6-membered heterocyclic molecule; wherein the heterocyclic molecule is a monocyclic or cyclic molecule containing one or two of the three heteroatoms of nitrogen, sulfur and oxygen; wherein, the number of CH2, n, is 1-10.

3. The 2,3-disubstituted naphthoquinone compound according to claim 1, characterized in that Two substituents cannot be aryl at the same time.

4. The 2,3-disubstituted naphthoquinone compound according to claim 1, characterized in that The compound is one of the compounds Naph-01 to Naph-80 shown below:

5. Use of any one of the 2,3-disubstituted naphthoquinone compounds of claims 1 to 4, characterized in that: The compound is applied in the field of veterinary medicine for animals, and is specifically used for the prevention and treatment of animal external parasites; the animal external parasites include arthropod parasites such as itch mites, scabies mites, demodex mites and ticks; the animals are one or more of cattle, sheep, pigs, rabbits, cats and dogs.

6. The method for preparing the 2,3-disubstituted naphthoquinone compound according to claims 1-4, characterized in that: The preparation method comprises the following steps: When X is C, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula: The specific preparation steps of the above reaction equation are as follows: S1. Arylation: Dissolving 1,4-naphthoquinone and substituted phenol or substituted aryl boronic acid in a solvent in a certain ratio, reacting them under the catalytic action of a metal catalyst and an additive, and obtaining 2-aryl naphthoquinone after purification; S2, decarboxylation alkylation: Under the catalytic action of metal catalysts and additives, 2-aryl naphthoquinone and corresponding carboxylic acid are dissolved in a solvent in a certain proportion for decarboxylation and alkylation, and the reaction is carried out at a temperature-insulated state, and the target compound is obtained after purification. Wherein, the aromatic substituent R is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the aromatic substituent is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; The substituent Rb is a C1-16 alkyl group, Ra-(CH2)n-, or Ra-CO-(CH2)n-; wherein the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups; In the reaction step S1, the molar ratio of 1,4-naphthoquinone to substituted phenol or substituted aryl boronic acid is 1:1.5-3.0; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 1-10:1; The dosage ratio of 1,4-naphthoquinone to solvent or mixed solvent is 1 mol: 1.5-1.8 L; The metal catalyst is one or two of FeCl3, FeNO2, FeSO4|, Pd(acac)2, Pd(OAc)2, Cu(BF4)2, Cu(OTf)2, [Cp*RhCl2]2, and the molar ratio of the amount to the feed of 1,4-naphthoquinone is 0.1-3.0:1; The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, TBHP, dppben, dppe, dppb, dppp, and dppethy, and the molar ratio of the additive to the feed of 1,4-naphthoquinone is 0.1-5:1; The insulation reaction temperature is 25-75°C, and the insulation reaction time is 10-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:

1. In the reaction step S2, the molar ratio of the 2-aryl naphthoquinone to the corresponding carboxylic acid is 1:3.0-5.0; The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to the 2-aryl naphthoquinone is 0.1-0.5:1; The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to the 2-aryl naphthoquinone is 1.2-2.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The dosage ratio of the 2-aryl naphthoquinone to the solvent or mixed solvent is 1 mol: 1.0-1.3 L; The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:

1.

7. The method for preparing a 2,3-disubstituted naphthoquinone compound according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: When X is NH, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula: The specific preparation steps of the above reaction equation are as follows: A. Preparation of naphthoquinone derivatives, as shown in reaction equation a); S1. Amination: dissolving 1,4-naphthoquinone or 2-aryl naphthoquinone and an amino derivative in a solvent in a certain ratio, reacting them under the catalytic action of a catalyst, and obtaining a naphthoquinone derivative after purification; S2. Boc protection: When Rd = H or BzO-, a 2-aminonaphthoquinone derivative with Re = H is obtained, which is dissolved with Boc2O in a certain ratio, and then reacted in the presence of a catalyst, and then purified to obtain a naphthoquinone derivative. B. Preparation of 2-aminonaphthoquinone derivatives, as shown in reaction equation b); S1. Decarboxylation alkylation: under the catalytic action of metal catalysts and additives, the amino-substituted naphthoquinone derivative and the corresponding carboxylic acid are dissolved in a solvent in a certain ratio for decarboxylation alkylation, the reaction is kept warm, and the naphthoquinone derivative is obtained after purification; S2. Deprotection: When Rf = Boc-, the reaction is carried out under the action of an acidic catalyst and then a 2-aminonaphthoquinone derivative is obtained after purification. C. Preparation of 2,3-disubstituted naphthoquinone derivatives, as shown in reaction equation c); Acylation and alkylation: Under the catalytic action of an alkaline catalyst, 2-amino-3-substituted naphthoquinone derivatives and corresponding acyl chlorides or halogenated hydrocarbons are dissolved in a solvent in a certain proportion to carry out acylation or alkylation reaction, and the reaction is kept warm. After purification, 2,3-disubstituted naphthoquinone derivatives are obtained. Wherein, the substituent Rc is H or substituted aryl; the substituent Rd is H, substituted aryl, substituted benzyl and BzO-; the substituent Re is H, substituted aryl and substituted benzyl; the substituent Rf is Boc-, substituted aryl and substituted benzyl; the substituent Rb is C1-16 alkyl, Ra-(CH2)n-, Ra-CO-(CH2)n-; the substituent Rg is C1-6 alkyl, C3-6 cycloalkyl, substituted aryl, Ph-(CH2)n- (n=1-4); the substituent Rh is C1-6 alkyl and C3-6 cycloalkyl; Wherein, the substituted aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; The substituted benzyl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I; Wherein, the C1-6 alkyl group is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino; Wherein, the C3-6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl; In the reaction step S1.1, the molar ratio of the 1,4-naphthoquinone or 2-aryl naphthoquinone to ammonia water or an amino derivative is 1:1.5-3.0; The catalyst is one of BiCl3, Bi(OTf)3, BF3·OEt2, AcOH, AlCl3, Cu(OAc)2·H2O, CuI, t-BuOK, NaOH, K2CO3, Et3N, iPr2EtN, and the molar ratio of the amount to the feed of 1,4-naphthoquinone is 0.1-1.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, EtOH, HFIP, EtOAc, CHCl3, DMF, DMAC, DMSO, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The ratio of the 1,4-naphthoquinone or 2-aryl naphthoquinone to the solvent or mixed solvent is 1 mol: 0.85-1.0 L; The insulation reaction temperature is 30-90°C, and the insulation reaction time is 10-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In the reaction step S1.2, the molar ratio of the 2-aminonaphthoquinone derivative to Boc2O is 1:1.5-3.0; The catalyst is one of DMAP, Et3N, Pyridine, and iPr2EtN, and the molar ratio of the amount to the 2-aminonaphthoquinone derivative is 0.1-1.5:1; The solvent is one of CH3CN, DCM, THF, and CHCl3; The insulation reaction temperature is 25-90°C, and the insulation reaction time is 5-12 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In the reaction step S2.1, the molar ratio of the amino-substituted naphthoquinone derivative to the corresponding carboxylic acid is 1:3.0-5.0; The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to the amino-substituted naphthoquinone derivative is 0.1-0.5:1; The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to the amino-substituted naphthoquinone derivative is 1.2-2.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The ratio of the amino-substituted naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.0-1.3 L; The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:

1. In the reaction step S2.2, the acid catalyst is one of H2SO4, TFA, H3PO4, HCl, and acetic acid, and the molar ratio of the amount used to the Boc-substituted aminonaphthoquinone derivative is 1.5-3.0:1; The solvent is one of CH3CN, DCM, THF, CHCl3, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The ratio of the Boc-substituted aminonaphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.5-1.8 L; The insulation reaction temperature is 25-30°C, and the insulation reaction time is 1-6 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In the reaction step S3, the molar ratio of the 2-amino-3-substituted naphthoquinone derivative to the corresponding acyl chloride or halogenated hydrocarbon is 1:2.0-3.5; The base catalyst is one of Et3N, Pyridine, iPr2EtN, K2CO3, Na2CO3, NaHCO3, KHCO3, and KH2PO4, and the molar ratio of the base catalyst to the 2-amino-3-substituted naphthoquinone derivative is 1.2-2.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, DMF, DMAC, DMSO, and acetone; The insulation reaction temperature is 30-120°C, and the insulation reaction time is 6-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1.

8. The method for preparing a 2,3-disubstituted naphthoquinone compound according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: When X is O, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula: The specific preparation steps of the above reaction equation are as follows: A. Preparation of 2-hydroxynaphthoquinone, as shown in reaction equation a); S1. Acylation: add 1,4-naphthoquinone and acetic anhydride in a certain proportion, drop a catalyst, keep warm for reaction, crystallize, and filter to obtain an acylate; S2, hydrolysis and acidification: dissolve the acylate and the base in a solvent in a certain proportion, keep the reaction warm for a period of time, filter the generated solid, add it to hot water to dissolve, filter it while hot, cool the filtrate, add acid to acidify, stir it in an ice bath, filter the precipitated solid, wash it with water until it is neutral, and dry it to obtain 2-hydroxy-naphthoquinone. B. Preparation of 2-hydroxy-3-substituted naphthoquinone derivatives, as shown in reaction equation b); S1. Alkylation: dissolving 2-hydroxy-naphthoquinone, a catalyst, an additive and a corresponding aldehyde in a solvent in a certain proportion, keeping the temperature for reaction, adding water to quench after the reaction, separating the organic phase, concentrating it, and purifying it to obtain a 2-hydroxy-3-substituted naphthoquinone derivative; S2. When Ri = substituted aryl, the obtained 2-hydroxy-3-substituted benzyl naphthoquinone derivative is dissolved in a solvent, reacted under the action of an oxidant and an additive, and purified to obtain a 2-hydroxy-3-substituted aryl naphthoquinone derivative; S3. Decarboxylation and alkylation: Under the catalytic action of metal catalysts and additives, 2-hydroxy-naphthoquinone and corresponding carboxylic acids are dissolved in a solvent in a certain ratio for decarboxylation and alkylation, and the reaction is kept warm. After purification, 2-hydroxy-3-substituted naphthoquinone derivatives are obtained. C. Preparation of 2,3-disubstituted naphthoquinone derivatives, as shown in reaction equation c); Acylation and alkylation: Under the catalytic action of an alkaline catalyst, 2-hydroxy-3-substituted naphthoquinone derivatives and corresponding acyl chlorides or halogenated hydrocarbons are dissolved in a solvent in a certain proportion to carry out acylation or alkylation reaction, and the reaction is kept warm. After purification, 2,3-disubstituted naphthoquinone derivatives are obtained. Wherein, the substituent Ri is a substituted aryl, a substituted benzyl and a C1-16 alkyl; the substituent Rb is a C1-16 alkyl, Ra-(CH2)n-, Ra-CO-(CH2)n-; the substituent Rg is a C1-6 alkyl, a C3-6 cycloalkyl, a substituted aryl, Ph-(CH2)n- (n=1-4); the substituent Rh is a C1-6 alkyl and a C3-6 cycloalkyl; Wherein, the substituted aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; The substituted benzyl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I; Wherein, the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups; Wherein, the C1-6 alkyl group is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino; Wherein, the C3-6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane and cyclohexane, and derivatives substituted with different functional groups, and the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, amino, and substituted aryl; In A, the molar ratio of 1,4-naphthoquinone to acetic anhydride in reaction step S1 is 1:6.0-10.0; The catalyst is at least one of protonic acid sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, perchloric acid, phosphoric acid, and nitric acid, and the molar ratio of the catalyst to the 1,4-naphthoquinone is 0.3-1.0:1; The dropping temperature is 10-40°C, and the dropping method is dropwise addition; The insulation reaction temperature is 0-15°C, and the insulation reaction time is 1-2.5 hours; The crystallization method is to add cold water 1-2 times the volume of the solvent into the reaction system, cool down to crystallize, and then filter to obtain the acylated derivative. In A, the molar ratio of the acylated derivative to the base in reaction step S2 is 1:1.2-3.0; The base is at least one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium methoxide, and sodium ethoxide; The solvent is one of dioxane, THF, MeOH, EtOH, nBuOH, iPrOH, HFIP, DMF, and DMSO; The insulation reaction temperature is 0-5°C, and the insulation reaction time is 0.5-4.5 hours; The hot water temperature is 90-100° C., the acidified acid is at least one of concentrated hydrochloric acid, acetic acid, formic acid, perchloric acid, and phosphoric acid, and the acidification degree is pH 1-2; The purification method is to filter by suction, then wash with water whose volume is 5-10 times of the solvent, and vacuum dry at 65-75° C. for 8-12 hours to obtain 2-hydroxy-naphthoquinone. In B, the molar ratio of the 2-hydroxy-naphthoquinone and the corresponding aldehyde in reaction step S1 is 1:1.2-2.0; The catalyst is at least one of L-alanine, L-lysine, L-leucine, L-phenylalanine, L-tryptophan, L-tyrosine, L-proline, L-arginine, L-histidine and L-leucine, and the molar ratio of the catalyst to 2-hydroxy-naphthoquinone is 0.2-0.5:1; The additive is at least one of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid dimethyl ester, 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid didodecyl ester, and the molar ratio of the additive to the 2-hydroxy-naphthoquinone is 1-1.05:1; The solvent is one of CH3CN, dioxane, THF, MeOH, EtOH, iPrOH, DCM, and CHCl3; The insulation reaction temperature is 25-35°C, and the insulation reaction time is 6-8 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In B, the molar ratio of the 2-hydroxy-3-substituted benzyl naphthoquinone derivative and the oxidant in reaction step S2 is 1:1.5-2.5; The oxidant is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, TBHP, and KMnO4; The additive is at least one of NaOH, KOH, LiOH, CsOH, tBuOK and tBuONa, and the molar ratio of the additive to the 2-hydroxy-3-substituted benzyl naphthoquinone derivative is 8.0-16.0:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-5:1; The ratio of the 2-hydroxy-3-substituted benzyl naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.0-1.2 L; The insulation reaction temperature is 25-30°C, and the insulation reaction time is 10-24 hours; The purification method is filtering, acidifying the filtrate with 10-20% HCl aqueous solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In B, the molar ratio of 2-hydroxy-naphthoquinone to the corresponding carboxylic acid in reaction step S3 is 1:3.0-5.0; The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to 2-hydroxy-naphthoquinone is 0.1-0.5:1; The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to 2-hydroxy-naphthoquinone is 1.2-2.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The dosage ratio of the 2-hydroxy-naphthoquinone to the solvent or mixed solvent is 1 mol: 1.0-1.3 L; The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:

1. In C, the molar ratio of the 2-hydroxy-3-substituted naphthoquinone derivative to the corresponding acyl chloride or halogenated hydrocarbon is 1:2.0-3.5; The base catalyst is one of Et3N, Pyridine, iPr2EtN, K2CO3, Na2CO3, NaHCO3, KHCO3, and KH2PO4, and the molar ratio of the base catalyst to the 2-hydroxy-3-substituted naphthoquinone derivative is 1.2-2.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, DMF, DMAC, DMSO, and acetone; The insulation reaction temperature is 30-120°C, and the insulation reaction time is 6-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1.

9. The method for preparing a 2,3-disubstituted naphthoquinone compound according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: When X is S, the general structural formula of the 2,3-disubstituted naphthoquinone compound is Prepared by the following chemical reaction formula: The specific preparation steps of the above reaction equation are as follows: S1. Thioetherification: 1,4-naphthoquinone, a catalyst and corresponding arylthiophenol or thiol are dissolved in a solvent in a certain proportion, and the reaction is carried out at a warm temperature. After purification, a 2-substituted thioether naphthoquinone derivative is obtained. S2, Arylation: According to a certain ratio, a 2-substituted thioether naphthoquinone derivative, a catalyst and a corresponding aryl hydrazine are dissolved in a solvent, and the mixture is heated to react. After purification, a 2-substituted thioether-3-aryl naphthoquinone derivative is obtained. S3, decarboxylation alkylation: Under the catalytic action of metal catalysts and additives, 2-substituted thioether naphthoquinone derivatives and corresponding carboxylic acids are dissolved in a solvent in a certain proportion for decarboxylation and alkylation, and the reaction is carried out at a warm temperature. After purification, 2-substituted thioether-3-substituted naphthoquinone derivatives are obtained. Wherein, the substituent Rj is C1-6 alkyl, substituted aryl and substituted benzyl; the substituent Rb is C1-16 alkyl, Ra-(CH2)n-, Ra-CO-(CH2)n-; Wherein, the C1-6 alkyl group is an alkyl substituent having 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and alkyl derivatives substituted with different functional groups, wherein the functional groups are selected from cyano, halo, alkenyl, alkynyl, trifluoromethyl, hydroxyl, carboxyl, and amino; Wherein, the substituted aryl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, 2,4,6-trisubstituted; wherein the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, I; The substituted benzyl group is 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2,4-disubstituted, 3,4-disubstituted, 3,5-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted; the substituent on the aryl group is one or more of hydroxyl, methyl, methoxy, cyano, nitro, trifluoromethyl, halogen F, Cl, Br, or I; Wherein, the C1-16 alkyl group is an alkyl group with 1 to 16 carbon atoms, an alkyl group containing one or more double bonds, and an alkyl derivative substituted with different functional groups; In the reaction step S1, the molar ratio of the 1,4-naphthoquinone to the corresponding arylthiophenol or thiol is 1:1.2-2.5; The catalyst is at most one of BiCl3, Bi(OTf)3, BF3·OEt2, AcOH, and AlCl3, and the molar ratio of the amount to the feed of 1,4-naphthoquinone is 0.05-0.3:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, EtOH, iPrOH, nBuOH, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The dosage ratio of 1,4-naphthoquinone to solvent or mixed solvent is 1 mol: 0.85-1.0 L; The insulation reaction temperature is 25-35°C, and the insulation reaction time is 10-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In the reaction step S2, the molar ratio of the 2-substituted thioether naphthoquinone derivative to the corresponding aryl hydrazine is 1:2.0-3.5; The catalyst is one of PIDA, PIFA, TBAI, I2, and pyridine, and the molar ratio of the amount to the 2-substituted thioether naphthoquinone derivative is 0.05-0.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, iPrOH, TFE, HFIP, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-5:1; The ratio of the 2-substituted thioether naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.5-1.8 L; The insulation reaction temperature is 25-70°C, and the insulation reaction time is 15-36 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 16.0-1.0:

1. In the reaction step S3, the molar ratio of the 2-substituted thioether naphthoquinone derivative to the corresponding carboxylic acid is 1:3.0-5.0; The metal catalyst is one of AgNO3, Ag2SO4, AgOAc and AgOTf, and the molar ratio of the metal catalyst to the 2-substituted thioether naphthoquinone derivative is 0.1-0.5:1; The additive is at least one of DDQ, K2S2O8, (NH4)2S2O8, H2O2, and TBHP, and the molar ratio of the additive to the 2-substituted thioether naphthoquinone derivative is 1.2-2.5:1; The solvent is one of CH3CN, DCM, dioxane, THF, MeOH, toluene, H2O or a mixed solvent with water, and the ratio of the mixed solvent is organic solvent: water = 2-10:1; The ratio of the 2-substituted thioether naphthoquinone derivative to the solvent or mixed solvent is 1 mol: 1.0-1.3 L; The insulation reaction temperature is 85-95°C, and the insulation reaction time is 5-24 hours; The purification method is column chromatography, and the eluent system is petroleum ether:ethyl acetate, with a volume ratio of 64.0-1.0:1.

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