Preparation method of key intermediate of dibenzo-aza medicine and intermediate of key intermediate of dibenzo-aza medicine

Abstract

The invention provides a method for preparing a key intermediate of a dibenzazepine drug. Specifically, the invention provides a preparation method of a compound as shown in a formula IV, which comprises the following steps: carrying out condensation reaction on o-nitrotoluene and o-chlorobenzaldehyde to obtain a compound as shown in a formula I, then carrying out hydrogenation reduction to obtain a compound as shown in a formula II, and then carrying out intramolecular coupling reaction to obtain a compound as shown in a formula III, and finally, dehydrating to obtain the compound as shown in the formula IV. Compared with a reaction route with harsh reaction conditions and high requirements on reaction equipment in the prior art, the method disclosed by the invention has the advantages of simple reaction route, mild reaction conditions, easiness in industrial production and high product yield. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of raw material drug intermediate synthetic chemistry, and in particular to a method for preparing a key intermediate of a dibenzazepine drug. Background Art

[0002] Dibenzazepines are the most commonly used drugs for the clinical treatment of depression and anticonvulsants, and their raw materials have a global market demand of more than 1,000 tons. For example, carbamazepine is a first-generation dibenzazepine antiepileptic drug (AEDs) and is the first choice for the treatment of epilepsy. Oxcarbazepine is a second-generation AED, which is less toxic and will not be metabolized into toxic epoxides in the liver. Eslicarbazepine acetate produced by Bial-Portela is a third-generation AED, approved for the treatment of partial epileptic seizures in adults, adolescents, and children (4 years and older).

[0003]

[0004] The core structure of this type of dibenzazepine drug is a structure of a nitrogen-containing seven-membered heterocyclic ring with a benzene ring [6-7-6] on both sides, such as iminostilbene (compound shown in formula A) and 5H-dibenzo[B,F]azepine-10(11H)-one (compound shown in formula B). Among them, iminostilbene is a key intermediate for the synthesis of carbamazepine and is also used to synthesize oxcarbazepine and eslicarbazepine acetate, and 5H-dibenzo[B,F]azepine-10(11H)-one can be directly used to synthesize oxcarbazepine and eslicarbazepine acetate.

[0005]

[0006] At present, the main industrial route for producing carbamazepine is to start from o-nitrotoluene, firstly coupling in the presence of sodium methoxide to obtain 2,2'-dinitrobiphenyl, followed by nitro reduction and high-temperature deamination condensation to obtain iminodibenzyl, which is then catalytically dehydrogenated at high temperature (300-400°C) to obtain iminostilbene, which is then chlorinated and aminolyzed to obtain carbamazepine. The process of synthesizing iminostilbene intermediates by this route involves multiple steps of high-temperature and high-pressure reactions, harsh conditions, high requirements for reaction equipment, and high safety risks.

[0007]

[0008] Another route is to first chlorinate and then brominate iminodibenzyl, and then debrominate at high temperature. This route also involves dangerous high-temperature reactions, and the bromination reaction and high-temperature debromination of hydrobromide reactions are highly corrosive to equipment and cause severe pollution.

[0009]

[0010] The literature (Chinese Journal of Pharmaceutical Industry Impurities, 2016, 47, 385) reported a route to obtain iminostilbene from o-nitrotoluene and o-chlorobenzaldehyde through condensation dehydration, nitro reduction, and high-temperature cyclization. However, the high-temperature cyclization reaction conditions of this route are harsh, requiring ultraviolet light irradiation, the reaction temperature is as high as 280-300°C, and the yield is only 56%, making it difficult to industrialize.

[0011]

[0012] The current industrial production route of oxcarbazepine is mainly to start from iminostilbene, react with acetic anhydride to produce 5-acetyl derivatives, and then bromine, methoxylate and hydrolyze to 10-methoxyiminostilbene. The latter is chloroacylated, aminolyzed and hydrolyzed to obtain oxcarbazepine. Its production process inevitably goes through steps with harsh production conditions such as high temperature and high pressure.

[0013] In view of the problems existing in the industrial production of dibenzazepine drugs such as carbamazepine and oxcarbazepine, it is of great significance to develop a method for preparing iminostilbene and 5H-dibenzo[B,F]azepine-10(11H)-one with mild reaction conditions, cost advantages, less waste, and easy industrial production. Summary of the invention

[0014] The purpose of the present invention is to provide a method for producing a key intermediate of dibenzazepine drugs with a novel process route, cheap and readily available raw materials, mild reaction conditions, and easy industrial mass production.

[0015] In the first aspect of the present invention, a method for preparing a compound (iminophthalene) as shown in formula IV is provided.

[0016]

[0017] The method comprises the following steps:

[0018] (i) condensing o-nitrotoluene and o-chlorobenzaldehyde to obtain a compound as shown in formula I;

[0019] (ii) the compound represented by formula I is subjected to reduction reaction to obtain the compound represented by formula II;

[0020] (iii) the compound represented by formula II undergoes an intramolecular coupling reaction to obtain a compound represented by formula III;

[0021] (iv) The compound represented by formula III undergoes a dehydration reaction to obtain a compound represented by formula IV (imidostilbene).

[0022]

[0023] In another preferred embodiment, the step (i) comprises: in a first solvent, in the presence of a first alkaline reagent, condensing o-nitrotoluene and o-chlorobenzaldehyde to obtain a compound as shown in formula I.

[0024] In another preferred embodiment, in the step (i), the first solvent is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, acetone, butanone, methyl isobutyl ketone, isopropyl acetate, isobutyl acetate, or a combination thereof. Preferably, the first solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc) or a combination thereof.

[0025] In another preferred embodiment, in the step (i), the volume of the first solvent is 1 to 20 times the volume of the raw material o-chlorobenzaldehyde, preferably 5 to 10 times the volume.

[0026] In another preferred embodiment, in the step (i), the first alkaline reagent is selected from the following group: sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide, triethylamine, diisopropylethylamine, DABCO, DBU, pyridine, or a combination thereof. Preferably, the first alkaline reagent is one or more of sodium tert-butoxide, sodium ethoxide, and sodium methoxide.

[0027] In another preferred embodiment, in the step (i), the equivalent of the first alkaline reagent is 0.01-5 times the equivalent of the raw material o-chlorobenzaldehyde, preferably 0.05-2.0 times the equivalent, and more preferably 0.1-2.0 times the equivalent, for example 0.05, 0.08, 0.1, 0.2, 0.5, 1.0, 2.0 times the equivalent.

[0028] In another preferred embodiment, in the step (i), the equivalent of the o-nitrotoluene is 1.0-5.0 times the equivalent of the raw material o-chlorobenzaldehyde, and more preferably 1.0-2.0 times the equivalent, for example, 1.0, 1.2, 1.5, 1.8, 2.0 times the equivalent.

[0029] In another preferred embodiment, in the step (i), the condensation reaction is carried out at 20-80°C, more preferably at 20-40°C or 50-80°C.

[0030] In another preferred embodiment, in the step (i), the reaction time of the condensation reaction is 2-20 hours, preferably 5-10 hours, and more preferably 5-7 hours.

[0031] In another preferred embodiment, the step (i) further comprises a post-treatment step. The post-treatment step comprises: after the reaction is completed, ethyl acetate and water are added to extract the reaction system, the organic phases are combined and washed with saturated brine, and then concentrated to dryness and then added with n-heptane for recrystallization.

[0032] In another preferred embodiment, the step (ii) comprises: in a second solvent, under the action of a first catalyst, subjecting the compound as shown in formula I to a reduction reaction, and obtaining a compound as shown in formula II after post-treatment.

[0033] In another preferred embodiment, in the step (ii), a hydrogenation reduction reaction is carried out by hydrogen gas under the action of a first catalyst.

[0034] In another preferred embodiment, in the step (ii), the second solvent is selected from one or more of C1-C8 alcohol solvents, ester solvents, and ether solvents. Among them, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, isobutanol, and n-butanol, the ester solvent is selected from one or more of ethyl acetate, methyl acetate, isopropyl acetate, and n-butyl acetate, and the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether. More preferably, the second solvent is methanol and ethanol.

[0035] In another preferred embodiment, in the step (ii), the first catalyst is a catalyst for hydrogenation reduction reaction.

[0036] In another preferred embodiment, in the step (ii), the first catalyst is selected from one or more of Raney nickel, Pd / C, Ru / C, and Rh / C, such as Pd / C, and more preferably wet Pd / C.

[0037] In another preferred embodiment, in the step (ii), the amount of the compound as shown in formula I and the second solvent is preferably 1-20 times (by mass), more preferably 5-10 times, for example 5 times, 6 times, 10 times.

[0038] In another preferred embodiment, in the step (ii), the hydrogen pressure is 0.1-2.0 MPa, for example 0.3 MPa, 45 psi.

[0039] In another preferred embodiment, in the step (ii), the reduction reaction is carried out at 20-80°C, preferably 30-50°C, and more preferably 40-50°C.

[0040] In another preferred embodiment, in the step (ii), the reaction time of the reduction reaction is 8-24 hours, preferably 10-15 hours.

[0041] In another preferred embodiment, the step (ii) further comprises a post-processing step, wherein the post-processing step comprises: filtering the first catalyst and concentrating it to dryness.

[0042] In another preferred embodiment, the step (iii) comprises: heating the compound represented by formula II in a third solvent in the presence of a second base reagent and a second catalyst to carry out an intramolecular coupling reaction to prepare a compound represented by formula III.

[0043] In another preferred embodiment, the coupling reaction is a CN bond coupling reaction.

[0044] In another preferred embodiment, the coupling reaction is a one-step coupling reaction.

[0045] In another preferred embodiment, in the step (iii), the second catalyst consists of a first copper salt and a first ligand.

[0046] In another preferred embodiment, in the step (iii), the first copper salt is selected from one or more of Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(acac)2, and 8-hydroxyquinoline copper. Preferably, the first copper salt is selected from one or more of Cu2O and Cu(OAc)2.

[0047] In another preferred embodiment, in the step (iii), the first ligand has the structure shown below:

[0048]

[0049] in,

[0050] R a , R b , R c , R d , R e , R g , R h , R i , R j , R keach independently represents H, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-10 membered heterocycloalkyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-13 membered heteroaryl, -(C1-C3 alkylene)-substituted or unsubstituted C6-C14 aryl, -(C1-C3 alkylene)-substituted or unsubstituted 5-13 membered heteroaryl, -NR'R";

[0051] R f is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C6-C10 aryl;

[0052] Each R l are independently H, C1-C6 alkyl;

[0053] R' and R" are each independently H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C6-C14 aryl;

[0054] Here, the "substitution" refers to that one or more (for example, 1, 2, 3, 4) hydrogen atoms on the group are replaced by a group selected from the following group: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl.

[0055] In another preferred embodiment, the heteroaryl group or heterocycloalkyl group contains 1-3 heteroatoms of N, O, or S, and the heteroatoms are optionally oxidized, for example, N is oxidized to N + -O-, S is oxidized to SO and SO2.

[0056] In another preferred embodiment, R a , R b , R c , R d , R e , R g , R h , R i , R j , R k Each is independently a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group.

[0057] In another preferred embodiment, the C6-C14 aryl group includes phenyl, naphthyl, and anthracenyl.

[0058] In another preferred embodiment, the heteroaryl group includes furanyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, pyrazinyl, and imidazolyl.

[0059] In another preferred embodiment, in the step (iii), the first ligand has a structure as shown in the following formula A, formula B, and formula E.

[0060] In another preferred embodiment, in the step (iii), the first ligand is selected from L1-L45, or a combination thereof:

[0061]

[0062] Among them, []2 in the compound means that it is composed of two connected fragments, for example That is That is In another preferred example, in the step (iii), the first ligand is selected from one of the above-mentioned compound L13, compound L22, compound L30, or a combination thereof.

[0063] In another preferred embodiment, in the step (iii), the second alkaline reagent is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcoholate, potassium tert-amyl alcoholate, sodium hydride, sodium amide, tetrabutylammonium hydroxide, triethylamine, tripropylamine, diisopropylethylamine, DABCO, DBU, pyridine, 2-methylpyridine, 2,6-lutidine, and one or more thereof. More preferably, the second alkaline reagent is selected from potassium carbonate, potassium phosphate, and sodium phosphate.

[0064] In another preferred embodiment, in step (iii), the third solvent is selected from one or more of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), cyclopentane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, and ester solvents. The ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, anisole, and diphenyl ether; the ketone solvent is selected from one or more of acetone, butanone, and methyl isobutyl ketone; the alcohol solvent is selected from one or more of C1-C8 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol; the ester solvent is selected from one or more of isopropyl acetate and isobutyl acetate. Preferably, the third solvent is selected from one or more of water, ethanol, isopropanol, n-butanol, DMF, DMSO, and dioxane.

[0065] In another preferred embodiment, in the step (iii), the amount of the first copper salt is 0.1-20 mol% of the compound as shown in formula II, and more preferably 0.5-10 mol%, for example 0.7 mol%, 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%.

[0066] In another preferred embodiment, in the step (iii), the molar ratio of the first copper salt to the second ligand is 1:0.5-5, more preferably 1:0.8-5, and even more preferably 1:0.8-2.

[0067] In another preferred embodiment, in the step (iii), the equivalent of the second alkaline reagent is 0.5 to 20 times the molar equivalent of the compound shown in Formula II, and more preferably 0.7-10 times the molar equivalent, for example 0.7 molar equivalent, 1 molar equivalent, 1.5 molar equivalent, 2 molar equivalent, 2.5 times the molar equivalent, 2.6 molar equivalent.

[0068] In another preferred embodiment, in the step (iii), the volume of the third solvent is 1 to 20 times the volume of the compound represented by Formula II, for example, 10 times the volume.

[0069] In another preferred embodiment, in the step (iii), the coupling reaction is carried out at 60-180°C, preferably 100-130°C.

[0070] In another preferred embodiment, in the step (iii), the coupling reaction is carried out under heating reflux conditions.

[0071] In another preferred embodiment, in the step (iii), the reaction time of the coupling reaction is 2-24 hours, preferably 8-16 hours, such as 10 hours or 16 hours.

[0072] In another preferred embodiment, the step (iii) further comprises a post-treatment step. The post-treatment step comprises: cooling after the reaction is completed, filtering out the solid, concentrating the organic phase, adding water to precipitate the solid, and drying to obtain the product.

[0073] In another preferred embodiment, the step (iv) comprises: in a fourth solvent, in the presence of an acid, subjecting the compound represented by formula III to a dehydration reaction to obtain a compound represented by formula IV.

[0074] In another preferred embodiment, in the step (iv), the fourth solvent is selected from one or more of a benzene solvent, an ether solvent, dichloromethane, dichloroethane, and acetonitrile. The benzene solvent is selected from one or more of toluene, chlorobenzene, and xylene, and the ether solvent is selected from one or more of tetrahydrofuran and 2-methyltetrahydrofuran. More preferably, the fourth solvent is toluene.

[0075] In another preferred embodiment, in step (iv), the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. More preferably, the acid is p-toluenesulfonic acid.

[0076] In another preferred embodiment, in the step (iv), the volume of the fourth solvent is 1 to 10 times the volume of the compound represented by formula III, for example, 6 to 10 times the volume.

[0077] In another preferred embodiment, in the step (iv), the amount of the acid used is 0.1-20 mol% of the compound as shown in formula III, and more preferably 0.5-10 mol%, for example 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%.

[0078] In another preferred embodiment, in the step (iv), the dehydration reaction is carried out at 60-180°C, preferably 100-130°C.

[0079] In another preferred embodiment, in the step (iv), the dehydration reaction is carried out under heating reflux conditions.

[0080] In another preferred embodiment, in the step (iv), the reaction time of the dehydration reaction is 2-24 hours, preferably 5-10 hours, and more preferably 8-10 hours.

[0081] In another preferred embodiment, the step (iv) further comprises a post-treatment step. The post-treatment step comprises: cooling after the reaction is completed, washing once with a sodium bicarbonate aqueous solution and once with water, adding activated carbon for decolorization, and then concentrating and adding n-heptane for crystallization.

[0082] In a second aspect of the present invention, a method for preparing a compound as shown in formula V is provided.

[0083]

[0084] The method comprises the following steps:

[0085] (V) Using the compound represented by Formula III as a reaction raw material, an oxidation reaction is carried out to obtain a compound represented by Formula V.

[0086]

[0087] In another preferred embodiment, the compound represented by formula III is prepared by step (iii) and optionally step (i) and step (ii) described in the first aspect of the present invention.

[0088] In another preferred embodiment, the step (V) comprises: in a fifth solvent, in the presence of a third alkaline reagent, adding Tempo, KBr, and NaClO, and subjecting the compound represented by Formula III to Tempo oxidation to obtain a compound represented by Formula V.

[0089] In another preferred embodiment, in the step (v), the molar equivalent of NaClO is 1-5 times that of the compound shown in formula III, and more preferably 1.5-3 times, for example, 1.1 times, 1.2 times, 1.5 times, and 2 times.

[0090] In another preferred embodiment, in the step (v), the molar equivalent of Tempo is 0.1-10 mol% of the compound represented by formula III, more preferably 0.5-5 mol%, for example 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%.

[0091] In another preferred embodiment, in the step (v), the molar equivalent of KBr is 1-10 mol %, more preferably 5 mol %, of the compound represented by formula III.

[0092] In another preferred embodiment, in step (V), the third alkaline agent is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate. More preferably, the third alkaline agent is sodium bicarbonate.

[0093] In another preferred embodiment, in the step (V), the molar equivalent of the third alkaline reagent is 0.5-5 times, more preferably 0.5-2 times, such as 0.8 times, 1 times, or 1.2 times, of the compound represented by formula III.

[0094] In another preferred embodiment, in the step (v), the third alkaline reagent and NaClO are each independently added to the reaction system in the form of an aqueous solution.

[0095] In another preferred embodiment, in the step (v), the fifth solvent is a mixed solvent of an organic solvent and water.

[0096] In another preferred embodiment, in the fifth solvent, the organic solvent is selected from one or more of dichloromethane, ether solvents, and ester solvents. The ether solvent is selected from one or more of methyl tert-butyl ether and 2-methyltetrahydrofuran, and the ester solvent is selected from one or more of ethyl acetate and isopropyl acetate. More preferably, the organic solvent in the fifth solvent is dichloromethane.

[0097] In another preferred embodiment, in the fifth solvent, the volume ratio of the organic solvent to water is 1:0.5-5, more preferably 1:1-5.

[0098] In another preferred embodiment, in the step (v), the oxidation reaction is carried out at 0-30°C, more preferably 10-30°C, for example 20°C.

[0099] In another preferred embodiment, in the step (v), the reaction time of the oxidation reaction is 2-24 hours, preferably 8-12 hours.

[0100] In another preferred embodiment, the step (V) further comprises a post-treatment step. The post-treatment step comprises: separating the reaction mixture into layers, washing the organic phase twice with water, adding activated carbon for decolorization, and then concentrating and adding n-heptane for crystallization.

[0101] In the third aspect of the present invention, an intermediate is provided, wherein the intermediate has a structure as shown in Formula II:

[0102]

[0103] In a fourth aspect of the present invention, there is provided a method for preparing carbamazepine, the method comprising the steps of:

[0104] The method according to the first aspect of the present invention is used to prepare iminostilbene, and iminostilbene is used to prepare carbamazepine.

[0105] In a fifth aspect of the present invention, there is provided a method for preparing oxcarbazepine, the method comprising the steps of:

[0106] Using the method according to the first aspect of the present invention to prepare iminostilbene, and using iminostilbene to prepare oxcarbazepine;

[0107] Alternatively, 5H-dibenzo[B,F]azepine-10(11H)-one is prepared using the method described in the second aspect of the present invention, and oxcarbazepine is prepared using 5H-dibenzo[B,F]azepine-10(11H)-one.

[0108] In a sixth aspect of the present invention, there is provided a method for preparing eslicarbazepine acetate, the method comprising the steps of:

[0109] Using the method according to the first aspect of the present invention to prepare iminostilbene, and using iminostilbene to prepare eslicarbazepine acetate;

[0110] Alternatively, 5H-dibenzo[B,F]azepine-10(11H)-one is prepared using the method described in the second aspect of the present invention, and eslicarbazepine acetate is prepared using 5H-dibenzo[B,F]azepine-10(11H)-one.

[0111] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0112] After extensive and in-depth research, the inventors have discovered for the first time a simple method for preparing a key intermediate of dibenzazepine drugs. Compared with the reaction routes in the prior art with harsh reaction conditions and high requirements for reaction equipment, the reaction route of the present invention is simple, the reaction conditions are mild, it is easy to industrialize production, and the product yield is high. On this basis, the present invention was completed.

[0113] the term

[0114] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0115] As used herein, the terms "comprise", "include", and "contain" are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the terms include "consisting of", "consisting essentially of".

[0116] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0117] In the present invention, "the compound represented by formula X" is equivalent to "compound X", for example, "the compound represented by formula I" is equivalent to "compound I".

[0118] The term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like."C1-C6 alkyl" includes C1, C2, C3, C4, C5, and C6 alkyl groups.

[0119] The term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, or the like. "C1-C6 alkoxy" includes C1, C2, C3, C4, C5, and C6 alkoxy groups.

[0120] The term "C6-C14 aryl" refers to an aromatic group having 6 to 14 ring carbon atoms, for example, phenyl, naphthyl or anthracenyl.

[0121] The term "5-13 membered heteroaryl" refers to an aromatic group having 5-13 ring atoms and containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. The heteroatoms and carbon atoms on the ring may be optionally oxidized, for example, N is oxidized to N +-O-, S is oxidized to S=O or SO2, C is oxidized to C=O. In addition, the heteroaryl group can be a monocyclic or polycyclic ring (condensed ring, bridged ring), and when the heteroaryl group is a condensed ring, it can include a heteroaryl ring fused with one or more phenyl groups. The heteroaryl group can include pyridine, pyrazine, pyrimidine, thiophene, furan, isoxazole, isothiazole, pyrazole, and imidazole.

[0122] The term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cycloheptyl, or the like.

[0123] The term "3-10 membered heterocyclyl" refers to monocyclic and polycyclic heterocycles (preferably monocyclic heterocycles) having 3-10 ring atoms and 1-3 heteroatoms, such as piperidinyl, tetrahydropyrrolyl, morpholinyl, or similar groups.

[0124] Method for preparing the compound shown in formula IV

[0125] The present invention provides a method for preparing a compound (iminophthalene) as shown in formula IV.

[0126]

[0127] The method specifically comprises the following steps:

[0128] (i) condensing o-nitrotoluene and o-chlorobenzaldehyde to obtain a compound as shown in formula I;

[0129] (ii) the compound represented by formula I is subjected to reduction reaction to obtain the compound represented by formula II;

[0130] (iii) the compound represented by formula II undergoes an intramolecular coupling reaction to obtain a compound represented by formula III;

[0131] (iv) The compound represented by formula III undergoes a dehydration reaction to obtain a compound represented by formula IV (imidostilbene).

[0132]

[0133] The condensation reaction in step (i) is preferably carried out under the following conditions: in a certain amount of solvent, in the presence of a base, at a certain temperature, o-nitrotoluene and o-chlorobenzaldehyde react to obtain a compound as shown in formula I.

[0134] The solvent used in step (i) is selected from one or more of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, acetone, butanone, methyl isobutyl ketone, isopropyl acetate, and isobutyl acetate. Preferably, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc) or a combination thereof.

[0135] The volume of the solvent is 1 to 20 times the volume of the raw material o-chlorobenzaldehyde, preferably 5 to 10 times the volume.

[0136] The base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide, triethylamine, diisopropylethylamine, DABCO, DBU, pyridine, etc., among which sodium tert-butoxide, sodium ethoxide, and sodium methoxide are preferred.

[0137] The equivalent of the base is 0.01-5 times the equivalent of the raw material o-chlorobenzaldehyde, preferably 0.05-2.0 times the equivalent, and more preferably 0.1-2.0 times the equivalent, such as 0.05, 0.08, 0.1, 0.2, 0.5, 1.0, 2.0 times the equivalent.

[0138] The equivalent of the o-nitrotoluene is preferably 1.0-5.0 times the equivalent of the raw material o-chlorobenzaldehyde, more preferably 1.0-2.0 times the equivalent, such as 1.0, 1.2, 1.5, 1.8, 2.0 times the equivalent.

[0139] Wherein, the reaction temperature is preferably 20-80 degrees, more preferably 20-40 degrees or 50-80 degrees.

[0140] Wherein, the reaction time is preferably 2-20 hours, more preferably 5-10 hours, and even more preferably 5-7 hours.

[0141] The method and conditions for the hydrogenation reaction in step (ii) are conventional methods and conditions for hydrogenation reactions in this field. The present invention particularly prefers the following method and conditions: in an organic solvent, in the presence of a catalyst, the compound shown in Formula I is subjected to a hydrogenation reaction. After the reaction is completed, simple filtration is performed, and the solvent is concentrated to obtain a compound shown in Formula II.

[0142] The organic solvent is preferably one or more of C1-C8 alcohol solvents, ester solvents, and ether solvents. The alcohol solvent is preferably one or more of methanol, ethanol, isopropanol, isobutanol, and n-butanol. The ester solvent is preferably one or more of ethyl acetate, methyl acetate, isopropyl acetate, and n-butyl acetate. The ether solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether. Methanol and ethanol are more preferred.

[0143] The catalyst is preferably one or more of Raney nickel, Pd / C, Ru / C, and Rh / C, such as Pd / C, and more preferably wet Pd / C.

[0144] The amount of the compound as shown in formula I and the organic solvent is preferably 1-20 times (by mass), for example 6-10 times.

[0145] The hydrogen pressure is preferably 0.1-2.0 MPa, such as 0.3 MPa.

[0146] The temperature of the hydrogenation reaction is preferably 20-80°C, more preferably 30-50°C, and more preferably 40-50°C.

[0147] The reaction time of the hydrogenation reaction is 8-24 hours, preferably 10-15 hours.

[0148] The step (iii) is a metal-catalyzed intramolecular CN bond coupling reaction. The present invention particularly prefers the following conditions: a certain amount of base and catalyst are added to the compound shown in formula II in a solvent, and the reaction is heated to prepare the compound shown in formula III in one step.

[0149] The catalyst consists of copper salt and ligand.

[0150] The copper salt is selected from one or more of Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(acac)2, 8-hydroxyquinoline copper; Cu2O and Cu(OAc)2 are preferred.

[0151] The ligand in the reaction has the structure shown below:

[0152]

[0153] in,

[0154] R a , R b , R c, R d , R e , R g , R h , R i , R j , R k Each is independently H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-10 membered heterocycloalkyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-13 membered heteroaryl, -(C1-C3 alkylene)-substituted or unsubstituted C6-C14 aryl, -(C1-C3 alkylene)-substituted or unsubstituted 5-13 membered heteroaryl, -NR1R2;

[0155] R f is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C6-C10 aryl;

[0156] Each R l are independently H, C1-C6 alkyl;

[0157] R1 and R2 are each independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl;

[0158] Here, the "substitution" refers to that one or more (for example, 1, 2, 3, 4) hydrogen atoms on the group are replaced by a group selected from the following group: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl.

[0159] Preferably, the heteroaryl or heterocycloalkyl contains 1 to 3 heteroatoms of N, O, or S, and the heteroatoms are optionally oxidized, for example, N is oxidized to N + -O-, S is oxidized to SO and SO2.

[0160] Preferably, R a , R b , R c , R d , R e , R g , R h , R i , R j , R k Each is independently a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group.

[0161] Preferably, the ligand has a structure as shown in the following formula A, formula B, and formula E.

[0162] Preferably, the ligand is selected from L1-L45 or a combination thereof:

[0163]

[0164] More preferably, the ligand is selected from one of the above-mentioned compound L13, compound L22, compound L30, or a combination thereof.

[0165] The base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcoholate, potassium tert-amyl alcoholate, sodium hydride, sodium amide, tetrabutylammonium hydroxide, triethylamine, tripropylamine, diisopropylethylamine, DABCO, DBU, pyridine, 2-methylpyridine, and 2,6-lutidine, among which potassium carbonate, potassium phosphate, and sodium phosphate are preferred.

[0166] The solvent includes one or more of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), cyclopentane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, and ester solvents. The ether solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, anisole, and diphenyl ether; the ketone solvent is preferably one or more of acetone, butanone, and methyl isobutyl ketone; the alcohol solvent is preferably one or more of C1-C8 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol; the ester solvent is preferably one or more of isopropyl acetate and isobutyl acetate; the more preferred solvent is one or a combination of water, ethanol, isopropanol, n-butanol, DMF, and DMSO.

[0167] The amount of copper is preferably 0.1-20 mol%, more preferably 0.5-10 mol%, such as 0.7 mol%, 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, based on the compound of formula II.

[0168] The equivalent of the base is preferably 0.5 to 20 times the molar equivalent of the compound shown in Formula II, more preferably 0.7-10 times the molar equivalent, for example 0.7 molar equivalent, 1 molar equivalent, 1.5 molar equivalent, 2 molar equivalent, 2.5 times the molar equivalent, 2.6 molar equivalent.

[0169] The volume of the solvent for the coupling reaction is 1 to 20 times the volume of the compound represented by Formula II, for example, 10 times the volume.

[0170] The reaction temperature of the coupling reaction is 60-180°C, preferably 100-130°C.

[0171] The coupling reaction is carried out under heating reflux conditions.

[0172] The reaction time of the coupling reaction is 2-24 hours, preferably 8-16 hours, such as 10 hours or 16 hours.

[0173] The method and conditions for the dehydration reaction in step 4 are conventional methods and conditions in the art. The present invention particularly prefers the following conditions: the compound shown in formula III reacts in a solvent at a certain temperature in the presence of an acid to obtain a compound shown in formula IV.

[0174] The solvent is preferably one or more of a benzene solvent, an ether solvent, dichloromethane, dichloroethane, acetonitrile and the like. The benzene solvent is preferably one or more of toluene, chlorobenzene, xylene and the like, and the ether solvent is preferably one or more of tetrahydrofuran and 2-methyltetrahydrofuran. Toluene is more preferred.

[0175] The acid is preferably an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, or an organic acid such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and more preferably p-toluenesulfonic acid.

[0176] The volume of the solvent for the dehydration reaction is 0.1 to 10 times the volume of the compound represented by Formula III, for example, 1 to 2 times the volume.

[0177] The amount of the acid is preferably 0.1-20 mol%, more preferably 0.5-10 mol%, such as 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, based on the compound of formula III.

[0178] The reaction temperature of the dehydration reaction is 60-180°C, preferably 100-120°C.

[0179] The dehydration reaction is carried out under heating reflux conditions.

[0180] The reaction time of the dehydration reaction is 2-24 hours, preferably 5-10 hours, and more preferably 8-10 hours.

[0181] Method for preparing the compound shown in formula V

[0182] The present invention also provides a method for preparing the compound shown in Formula V:

[0183]

[0184] Specifically, starting from the compound shown in formula III, an oxidation reaction is carried out through step five to obtain a compound shown in formula V.

[0185]

[0186] The method and conditions for the oxidation reaction in step 5 are conventional methods and conditions in the art, and the present invention particularly prefers the following conditions: in a solvent, under alkaline conditions, Tempo, KBr, and NaClO are added to perform Tempo oxidation on the compound shown in formula III to obtain a compound shown in formula V.

[0187] The molar equivalent of NaClO is 1-5 times that of the compound shown in formula III, preferably 1.5 times.

[0188] The molar equivalent of Tempo is 0.1-10 mol% of the compound shown in Formula III, and more preferably 0.5-5 mol%, such as 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%.

[0189] The molar equivalent of KBr is 1-10 mol % of the compound represented by formula III, and more preferably 5 mol %.

[0190] The alkali is preferably one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate, more preferably sodium bicarbonate.

[0191] The alkali and sodium hypochlorite are added to the reaction system independently in the form of aqueous solution.

[0192] The solvent is a mixed solvent of an organic solvent and water, the organic solvent is preferably one or more of dichloromethane, ether solvents, and ester solvents, the ether solvent is preferably methyl tert-butyl ether and 2-methyltetrahydrofuran, the ester solvent is preferably one or more of ethyl acetate and isopropyl acetate; more preferably dichloromethane.

[0193] The temperature of the oxidation reaction is preferably 0-30°C, more preferably 10-20°C.

[0194] The reaction time of the oxidation reaction is preferably 2-24 hours, more preferably 8-12 hours.

[0195] The main advantages of the present invention include:

[0196] (1) The method of the present invention has simple steps, a simple route, mild reaction conditions, less waste, and is easy to industrialize.

[0197] (2) The method of the present invention has a high yield. The yield of the compound represented by formula IV can reach up to 69% or more, and the yield of the compound represented by formula V can reach up to 73% or more.

[0198] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0199] Example 1 Preparation of Compound I

[0200] Example 1-1

[0201] DMSO (1000 mL), o-chlorobenzaldehyde (8 mol, 1124 g), o-nitrotoluene (8 mol, 1097 g), and sodium methoxide (43 g, 0.8 mol) were added to the reaction flask, and the mixture was stirred at 30-40° C. for 5 hours. Ethyl acetate and water were added to extract the reaction system twice, and the organic phases were combined and washed with saturated brine, concentrated to dryness, and then recrystallized by adding n-heptane to obtain 1910 g of a white solid with a yield of 86%.

[0202] 1 H NMR (500MHz, CDCl3) δ7.87 (dd, J=8.1, 1.3Hz, 1H), 7.54 (dd, J=7.7, 1.7Hz, 1H), 7.50 (td, J=7.5, 1.4Hz, 1H), 7.39 (td, J=7 .8,1.5Hz,1H),7.34–7.27(m,3H),7.23(td,J=7.6,1.8Hz,1H),5.41(t,J=6.3Hz,1H),3.36(d,J=6.4Hz,2H),2.51(s,1H); 13 CNMR (126MHz, CDCl3) δ150.6,141.0,133.1,132.8,132.8,131.8,129.5,129.0,127.8,127.4,127.4,124.7,71.4,39.9.

[0203] Example 1-2

[0204] DMAc (1000 mL), o-chlorobenzaldehyde (8 mmol, 1124.6 g), o-nitrotoluene (9.6 mmol, 1316.5 g), and sodium methoxide (22 g, 0.4 mmol) were added to the reaction flask, and the mixture was stirred at 20-30°C for 10 hours. Ethyl acetate and water were added to extract the reaction system twice, and the organic phases were combined and washed with saturated brine, concentrated to dryness, and then recrystallized by adding n-heptane to obtain 1910 g of a white solid with a yield of 90%.

[0205] Example 2 Preparation of Compound II

[0206] Example 2-1

[0207] Compound I (1100 g, 4 mol), wet Pd / C (110 g), and ethanol (8 L) were added to the reaction flask and reacted at 30-40 °C under a hydrogen pressure of 45 psi for 10 hours. After the reaction, Pd / C was filtered off and the mixture was concentrated to dryness to obtain 892 g of a white solid with a yield of 100%.

[0208] 1 H NMR (500MHz, CDCl3) δ7.63 (dd, J=7.7, 1.7Hz, 1H), 7.37 (dd, J=7.9, 1.3Hz, 1H ),7.31(td,J=7.5,1.3Hz,1H),7.23(td,J=7.6,1.8Hz,1H),7.13–7.04(m,2H) ,6.77(td,J=7.4,1.2Hz,1H),6.74(d,J=7.8Hz,1H),5.36(dd,J=9.5,2.6Hz, 1H),3.57(s,3H),3.04(dd,J=14.4,2.7Hz,1H),2.80(dd,J=14.4,9.5Hz,1H); 13 C NMR (126MHz, CDCl3) δ145.3,141.7,131.7,131.4,129.4,128.6,128.1,127.3,127.1,124.0,119.5,116.7,71.9,40.2.

[0209] Example 2-2

[0210] Compound I (1100 g, 4 mol), wet Pd / C (65 g) and ethanol (8 L) were added to the reaction flask and reacted at 40-50 °C under a hydrogen pressure of 45 psi for 15 hours. After the reaction, Pd / C was filtered off and the mixture was concentrated to obtain 892 g of a white solid with a yield of 100%.

[0211] Example 3 Preparation of Compound III

[0212] Example 3-1

[0213] Compound II (1000 g), copper acetate (36 g), L13 (60 g), potassium phosphate (900 g), and dioxane (5000 g) were added to the reaction flask and heated to reflux for 16 hours. After the reaction, the temperature was cooled to room temperature, the solid was filtered out, the organic phase was concentrated, water was added to precipitate the solid, and the solid was dried to obtain a solid (770 g) with a yield of 90%.

[0214] Example 3-2

[0215] Compound II (1000 g), copper acetate (36 g), L13 (64 g), potassium phosphate (900 g), and DMF (5000 g) were added to the reaction flask and heated to reflux for 16 hours. After the reaction, the temperature was cooled to room temperature, the solid was filtered out, the organic phase was concentrated, water was added to precipitate the solid, and the solid was dried to obtain a solid (550 g) with a yield of 64%.

[0216] Example 3-3

[0217] Compound II (500 g), cuprous oxide (8 g), L22 (30 g), sodium phosphate (300 g), and n-butanol (2500 g) were added to the reaction flask and heated to reflux for 16 hours. After the reaction, the temperature was cooled to room temperature, the solid was filtered out, the organic phase was concentrated, water was added to precipitate the solid, and the solid was dried to obtain a solid (700 g) with a yield of 82%.

[0218] Embodiment 3-4

[0219] Compound II (500 g), cuprous oxide (8 g), L30 (32 g), potassium carbonate (900 g), and DMSO (2500 g) were added to the reaction flask and heated to reflux for 16 hours. After the reaction, the temperature was cooled to room temperature, the solid was filtered out, the organic phase was concentrated, water was added to precipitate the solid, and the solid was dried to obtain a solid (427 g) with a yield of 50%.

[0220] Example 4 Preparation of Compound IV

[0221] Example 4-1

[0222] Compound III (633 g), toluene (500 mL) and p-toluenesulfonic acid (30 g) were added to the reaction flask, heated to reflux for reaction for 5 hours, cooled to room temperature, washed once with sodium bicarbonate aqueous solution and once with water, activated carbon (30 g) was added for decolorization, and then concentrated and added with n-heptane for crystallization to obtain 498 g of a white solid with a yield of 86%.

[0223] Example 4-2

[0224] Compound III (633 g), toluene (500 mL) and p-toluenesulfonic acid (10 g) were added to the reaction flask, heated to reflux for reaction for 10 hours, cooled to room temperature, washed once with aqueous sodium bicarbonate solution and once with water, activated carbon (30 g) was added for decolorization, and then concentrated and added with n-heptane for crystallization to obtain 490 g of a white solid with a yield of 85%.

[0225] Example 5 Preparation of Compound V

[0226] Example 5-1

[0227] Compound III (422 g), dichloromethane (3000 mL), 7% aqueous sodium bicarbonate solution (2000 g), TEMPO (6.3 g), and potassium bromide (24 g) were added to the reaction flask, and 10% aqueous sodium hypochlorite solution (1700 g) was added dropwise at room temperature. The reaction was allowed to proceed for 8 hours, and the layers were separated. The organic phase was washed twice with water, and activated carbon (20 g) was added for decolorization. After concentration, n-heptane was added for crystallization to obtain 380 g of a white solid with a yield of 91%.

[0228] Example 5-2

[0229] Compound III (422 g), dichloromethane (3000 mL), 7% sodium bicarbonate aqueous solution (2000 g), TEMPO (3.2 g), potassium bromide (12 g) were added to the reaction flask, and 10% sodium hypochlorite aqueous solution (1900 g) was added dropwise at room temperature. The reaction was carried out for 12 hours, and the layers were separated. The organic phase was washed twice with water, and activated carbon (20 g) was added for decolorization. Then, it was concentrated and n-heptane was added for crystallization to obtain 368 g of a white solid with a yield of 88%.

[0230] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a compound as shown in formula IV (Iminophthalide), The method comprises the following steps: (i) condensing o-nitrotoluene and o-chlorobenzaldehyde to obtain a compound as shown in formula I; (ii) the compound represented by formula I is subjected to reduction reaction to obtain the compound represented by formula II; (iii) the compound represented by formula II undergoes an intramolecular coupling reaction to obtain a compound represented by formula III; (iv) The compound represented by formula III undergoes a dehydration reaction to obtain a compound represented by formula IV (imidostilbene).

2. The preparation method according to claim 1, characterized in that The step (i) comprises: in a first solvent, in the presence of a first alkaline reagent, condensing o-nitrotoluene and o-chlorobenzaldehyde to obtain a compound as shown in formula I; Furthermore, the step (i) optionally includes one or more features selected from the following group: (1) In the step (i), the first solvent is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, acetone, butanone, methyl isobutyl ketone, isopropyl acetate, isobutyl acetate, or a combination thereof; (2) In the step (i), the first alkaline reagent is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide, triethylamine, diisopropylethylamine, DABCO, DBU, pyridine, or a combination thereof; (3) In the step (i), the equivalent of the o-nitrotoluene is 1.0-5.0 times the equivalent of the raw material o-chlorobenzaldehyde, preferably 1.0-2.0 times the equivalent; (4) In the step (1), the condensation reaction is carried out at 20-80°C, preferably at 20-40°C or 50-80°C.

3. The preparation method according to claim 1, characterized in that: The step (ii) comprises: in a second solvent, under the action of a first catalyst, subjecting the compound represented by formula I to a reduction reaction, and obtaining a compound represented by formula II after post-treatment; Furthermore, the step (ii) optionally includes one or more features selected from the following group: (1) In the step (ii), the second solvent is selected from one or more of C1-C8 alcohol solvents, ester solvents, and ether solvents, wherein the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, isobutanol, and n-butanol; the ester solvent is selected from one or more of ethyl acetate, methyl acetate, isopropyl acetate, and n-butyl acetate; and the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether; (2) In the step (ii), the first catalyst is selected from one or more of Raney nickel, Pd / C, Ru / C, and Rh / C; (3) In the step (ii), a hydrogenation reduction reaction is carried out by hydrogen gas under the action of a first catalyst, and the hydrogen gas pressure is 0.1-2.0 MPa; (4) The post-treatment step comprises: filtering the first catalyst and concentrating it to dryness.

4. The preparation method according to claim 1, characterized in that: The step (iii) comprises: heating the compound represented by formula II in the presence of a second base reagent and a second catalyst in a third solvent to perform an intramolecular coupling reaction to prepare a compound represented by formula III; Furthermore, the step (iii) optionally includes one or more features selected from the following group: (1) In the step (iii), the second alkaline reagent is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcoholate, potassium tert-amyl alcoholate, sodium hydride, sodium amide, tetrabutylammonium hydroxide, triethylamine, tripropylamine, diisopropylethylamine, DABCO, DBU, pyridine, 2-methylpyridine, and 2,6-lutidine; (2) In the step (iii), the third solvent is selected from one or more of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, anisole, diphenyl ether, methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol; (3) In the step (iii), the coupling reaction is carried out under heating reflux conditions.

5. The preparation method according to claim 4, characterized in that: In the step (iii), the second catalyst is composed of a first copper salt and a first ligand; Furthermore, the first copper salt is selected from one or more of Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(acac)2, and 8-hydroxyquinoline copper; The first ligand has the structure shown below: in, R a , R b , R c , R d , R e , R g , R h , R i , R j , R k each independently represents H, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-10 membered heterocycloalkyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-13 membered heteroaryl, -(C1-C3 alkylene)-substituted or unsubstituted C6-C14 aryl, -(C1-C3 alkylene)-substituted or unsubstituted 5-13 membered heteroaryl, -NR'R"; R f is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C6-C10 aryl; Each R l are independently H, C1-C6 alkyl; R' and R" are each independently H, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C6-C14 aryl; Here, the "substituted" refers to that one or more (e.g., 1, 2, 3, 4) hydrogen atoms on the group are replaced by a group selected from the following group: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl.

6. The preparation method according to claim 5, characterized in that: The first ligand is selected from L1-L45, or a combination thereof:

7. The preparation method according to claim 1, characterized in that: The step (iv) comprises: in a fourth solvent, in the presence of an acid, subjecting the compound represented by formula III to a dehydration reaction to obtain a compound represented by formula IV; Furthermore, the step (iv) optionally includes one or more features selected from the following group: (1) In the step (iv), the fourth solvent is selected from one or more of toluene, chlorobenzene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, and acetonitrile; (2) In step (iv), the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; (3) In the step (iv), the dehydration reaction is carried out at 60-180°C, preferably 100-130°C.

8. A method for preparing a compound as shown in formula V, The method comprises the following steps: (V) Using the compound represented by Formula III as a reaction raw material, an oxidation reaction is carried out to obtain a compound represented by Formula V.

9. The preparation method according to claim 8, characterized in that: The step (V) comprises: adding Tempo, KBr and NaClO in the fifth solvent in the presence of a third alkaline reagent to perform Tempo oxidation on the compound represented by Formula III to obtain a compound represented by Formula V; Furthermore, the step (iv) optionally includes one or more features selected from the following group: (1) In the step (v), the third alkaline reagent is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate; (2) In the step (V), the third alkaline reagent and NaClO are each independently added to the reaction system in the form of an aqueous solution; (3) In the step (V), the fifth solvent is a mixed solvent of an organic solvent and water; the organic solvent is selected from one or more of dichloromethane, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, and isopropyl acetate; (4) In the step (v), the oxidation reaction is carried out at 0-30°C, preferably 10-20°C.

10. The preparation method according to claim 9, characterized in that: The compound shown in formula III is prepared by the following method: The method comprises the following steps: Optionally, (i), o-nitrotoluene and o-chlorobenzaldehyde undergo condensation reaction to obtain a compound as shown in formula I; Optionally (ii), the compound shown in formula I is reduced to obtain a compound shown in formula II; and (iii) The compound represented by formula II undergoes an intramolecular coupling reaction to obtain a compound represented by formula III.

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