Synthesis method of benzofuro [3, 2b] benzofuran compound

Abstract

The invention discloses a synthesis method of a benzofuro [3, 2-b] benzofuran compound, and belongs to the technical field of organic synthesis. According to the method, o-hydroxybenzoate compounds or halogenated derivatives thereof and methyl bromoacetate are taken as starting raw materials, and a target product is prepared through five steps of reaction: step 1, cyclization is performed at 0 DEG C to room temperature under an alkaline condition to obtain a benzofuran carboxylate intermediate; 2, sulfonylating by trifluoromethanesulfonic anhydride to obtain a sulfonate intermediate; 3, carrying out an etherification reaction with an o-halogenated phenol compound at the temperature of 80-120 DEG C; 4, hydrolyzing through inorganic strong base to obtain a benzofuran carboxylic acid intermediate; and 5, carrying out intramolecular ring closing at 80-180 DEG C under the action of a palladium catalyst and DBU. The raw materials are cheap and easy to obtain, the reaction selectivity is high, the total yield is stable, the substrate adaptability is wide, efficient synthesis of unilateral and bilateral halogen substituted derivatives of benzofuro [3, 2b] benzofuran compounds is successfully achieved, and the method has remarkable industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing benzofuran[3,2b]benzofuran compounds. Background Technology

[0002] Benzofurans are an important class of heterocyclic compounds that have attracted widespread attention from researchers in recent years. Many compounds containing benzofuran structures and their derivatives have been proven to have important medicinal value and are widely used in the field of organic materials. Among them, the application value of benzofuran[3,2b]benzofurans is constantly being explored. Currently, the preparation methods of benzofuran[3,2b]benzofurans reported in the literature are mainly the following four:

[0003] Route 1:

[0004]

[0005] Route 1 (See: Room Temperature C–H Arylation of Benzofurans by Aryl Iodides, Mayhugh, Amy L.;) (Organic Letters et al. (2021), 23(18), 7079-7082) reported a method for preparing the target compound by coupling and ring closure of o-iodophenol and benzofuran via CH arylation at room temperature under the co-catalysis of palladium acetate and silver oxide. This method has mild reaction conditions, but suffers from significant raw material losses. During catalysis, the iodine atom of the aryl iodide is easily detached, resulting in a low actual conversion rate of the raw materials. Furthermore, o-iodophenol is prone to self-coupling to generate byproducts, increasing the difficulty of product separation and purification, which is detrimental to industrial-scale production.

[0006] Route 2:

[0007] Route 2, Korean patent KR102344802B1, reports a method using 3-bromo-benzofuran-2-boric acid as a key intermediate to construct the target compound structure via a coupling reaction. However, the preparation of the intermediate in the first step is difficult, and the borate group of 3-bromo-benzofuran-2-boric acid is affected by the strong electron-withdrawing group at the ortho position, resulting in low reactivity and easy deboric acid formation during the reaction. The reaction needs to be carried out in a strong alkaline environment such as NaOH, which not only leads to a decrease in the selectivity of bromine and iodine in the raw materials and triggers self-coupling of 3-bromo-benzofuran-2-boric acid, but also forms a salt with the main raw material iodophenol, reducing the solubility of the raw materials and the reaction rate, making the synthesis of this step extremely difficult.

[0008] Route 3:

[0009]

[0010] Route 3, Korean patent WO2021241882A1, reports a two-step reaction to prepare target benzofuran compounds. The first step involves Suzuki coupling of 2,3-dibromobenzofuran with a chlorinated, hydroxyl-containing phenylboronic acid compound. However, in this step, the hydroxyl and chlorine substituents of the phenylboronic acid increase steric hindrance, making deboronic acid formation more likely. Furthermore, the main raw material, 2,3-dibromobenzofuran, exhibits poor selectivity; during the Suzuki reaction, both bromine atoms at positions 2 and 3 may participate in coupling, generating multiple structural isomers, significantly increasing the difficulty of product separation and purification. In the second step, the remaining bromine atoms have low reactivity, requiring a catalytic system of CuI and 1,10-phenanthroline hydrate to advance ring closure. This not only increases catalytic costs but also easily leads to low conversion rates due to insufficient catalytic efficiency, limiting the overall economic viability and industrial feasibility of the process.

[0011] Route 4:

[0012]

[0013] Route 4, as reported in Chinese patent CN118852195A, is a method similar to Route 3, using 2,3-dibromobenzofuran as the starting material and preparing the target product through a two-step reaction involving Suzuki coupling and aromatization ring closure. The first step of this method suffers from the same drawbacks as the aforementioned methods: the boronic acid group is sterically hindered and easily detached; the selectivity for 2,3-dibromobenzofuran is poor; and the bromine atom at the 3-position participates in the reaction to generate isomers, making product purification difficult. In the second step, the aromatization degree of benzofuran is low, and the residual bromine atom at the 3-position has poor reactivity, resulting in low yields for both steps and an extremely low overall yield, which cannot meet the requirements for industrial production. Based on the content of Chinese patent CN118852195A and Korean patent WO2021241882A1, it can be seen that this method is selective for substrates, with some yields being better and others worse. The above method mainly focuses on the preparation process of unilateral halogen substitution of benzofuran[3,2b]benzofuran compounds, and has obvious limitations in the synthesis of bilateral halogen substitution structures.

[0014] Existing synthetic methods generally suffer from problems such as low yield, numerous byproducts, unstable intermediates, difficulty in obtaining raw materials and intermediates, poor reaction selectivity, narrow range of functional group selection, and easy generation of isomers, which seriously restrict the industrial production and application of this type of compound.

[0015] Therefore, it is of great significance to develop a synthetic method for benzofuran[3,2b]benzofuran compounds that is readily available, has high reaction selectivity, high yield, and is suitable for industrial scale-up. Summary of the Invention

[0016] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing benzofuran[3,2b]benzofuran compounds.

[0017] To solve the above-mentioned technical problems, the technical solution of the present invention is: a method for synthesizing benzofuran[3,2b]benzofuran compounds, the synthesis method comprising the following steps:

[0018] (1) Using o-hydroxybenzoic acid esters or their halogenated derivatives and halogenated acetates as raw materials, an intramolecular cyclization reaction is carried out under alkaline conditions to obtain benzofuran carboxylic acid ester intermediates at 0℃ to room temperature;

[0019] (2) The hydroxyl groups of the benzofuran carboxylic acid ester intermediate obtained in step (1) are subjected to an esterification reaction under the action of a sulfonating agent, an organic base and a catalyst to obtain a sulfonate intermediate;

[0020] (3) The sulfonate intermediate obtained in step (2) is reacted with an ortho-halophenolic compound under nitrogen protection, inorganic base and heating conditions to undergo an etherification reaction to obtain an aryloxy-substituted benzofuran carboxylic acid ester intermediate.

[0021] (4) The aryloxy-substituted benzofuran carboxylic acid ester intermediate obtained in step (3) is subjected to hydrolysis reaction under the action of inorganic strong base, water and solvent, and after acidification, benzofuran carboxylic acid intermediate is obtained.

[0022] (5) The benzofuran carboxylic acid intermediate obtained in step (4) is heated under nitrogen protection, with the action of a transition metal catalyst and a strong base to undergo an intramolecular cyclization reaction, to obtain the target benzofuran[3,2b]benzofuran compound;

[0023] The benzene ring of the o-hydroxybenzoic acid esters or their halogenated derivatives may have halogen substituents, wherein the halogen is selected from hydrogen, fluorine, chlorine, bromine or iodine; the benzene ring of the o-halophenols may have halogen substituents, wherein the halogen is selected from hydrogen, fluorine, chlorine or bromine, and the above-mentioned halogen substituents may be selected independently.

[0024] Preferably, the o-hydroxybenzoic acid ester compound or its halogenated derivative in step (1) is selected from methyl salicylate or ethyl salicylate; the base in step (1) is selected from sodium tert-butoxide, potassium tert-butoxide, potassium carbonate or sodium methoxide, and the halogenated acetate compound is methyl bromoacetate;

[0025] The sulfonating agent in step (2) is trifluoromethanesulfonic anhydride, the organic base is triethylamine, and the catalyst is 4-dimethylaminopyridine (DMAP).

[0026] In step (3), the o-halophenol compound is o-bromophenol, the inorganic base is selected from cesium carbonate, sodium carbonate or potassium carbonate, and the heating temperature is 80℃~120℃;

[0027] The inorganic strong base in step (4) is selected from sodium hydroxide (NaOH), lithium hydroxide (LiOH) or potassium hydroxide (KOH);

[0028] In step (5), the transition metal catalyst is a palladium catalyst, which is selected from palladium acetate (Pd(OAc)2), tetra(triphenylphosphine)palladium (Pd(PPh3)4) or dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2); the strong base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the heating temperature is 80℃~180℃.

[0029] Preferably, (1) using o-hydroxybenzoic acid esters or their halogenated derivatives and methyl bromoacetate as raw materials, an intramolecular cyclization reaction is carried out under alkaline conditions to obtain compound 1 at 0°C to room temperature, with the following reaction formula: ;

[0030] (2) Compound 1 obtained in step (1) was subjected to esterification reaction in the presence of trifluoromethanesulfonic anhydride, triethylamine and 4-dimethylaminopyridine (DMAP) to obtain compound 2, and the reaction formula is as follows: ;

[0031] (3) Compound 2 obtained in step (2) is reacted with o-bromophenol under nitrogen protection, inorganic base, and heating conditions to undergo an etherification reaction to obtain compound 3. The reaction formula is as follows:

[0032] ;

[0033] Step (3) involves the selective arylation of a furan-ring substrate containing trifluoromethanesulfonate (OTf) with a halophenol to construct a CO bond. For nucleophilic substrates with low reactivity, such as polyhalophenols, the arylation reaction to construct a CO bond often requires harsh reaction conditions, such as high temperature and strong alkaline environment, and suffers from low yield and complex post-processing. In this reaction, trifluoromethanesulfonate (OTf) is selected as the leaving group: OTf is a strong leaving group, which can significantly enhance the electrophilicity of its attached carbon, allowing the reaction to proceed under milder conditions without extreme conditions; at the same time, OTf has better compatibility with complex heterocyclic substrates containing lactones and ester groups, and will not destroy the polycyclic skeleton of the substrate. The reaction mechanism of step (3) is mainly as follows: This reaction is a nucleophilic substitution reaction. The aryl OTf in compound 2 is a strong leaving group. After leaving, it generates a stable TfO⁻, which will enhance the electrophilicity of its attached carbon atom, making it susceptible to nucleophilic attack. Another substrate is phenolic compounds: the oxygen atom of the phenolic hydroxyl group has a lone pair of electrons, making it an electron-rich nucleophilic center that can act as a nucleophile. The nucleophile phenol oxygen attacks the electrophilic carbon, and the leaving group OTf detaches from the carbon bonded to OTf. Utilizing the strong leaving property of OTf to enhance the electrophilicity of the carbon, combined with the nucleophilicity of phenol oxygen, a CO ether bond is efficiently constructed.

[0034] The reaction conditions in the third step of this invention are relatively mild, and the product separation and purification are simple, giving it advantages in terms of synthesis efficiency and industrial application potential. Substrate 2 is a heterocyclic molecule with multiple reaction sites, including ester carbon and lactone carbon, but the reaction is directed only to form a CO ether bond between the OTf-linked carbon and the phenolic oxygen, without side reactions at other sites, such as nucleophilic substitution of the ester group. This precise regioselectivity avoids side reactions on complex polycyclic skeletons, improving the yield and purity of the target product. At the same time, halogen groups such as Br and Cl on the aromatic ring do not participate in the reaction and are completely preserved, reserving active sites for subsequent derivatization of the target product, such as coupling reactions. This high functional group compatibility is particularly crucial in the later modification of complex molecules.

[0035] (4) Compound 3 obtained in step (3) is hydrolyzed in the presence of an inorganic strong base, water, and a solvent. After acidification, compound 4 is obtained. The reaction formula is as follows:

[0036] ;

[0037] (5) Compound 4 obtained in step (4) was heated under nitrogen protection, with palladium catalyst, tricyclohexylphosphine fluoroborate (PCy3·BF4) and 1,8-diazahexacyclic [5,4,0]undec-7-ene (DBU) to undergo a cyclization reaction, yielding compound 5. The reaction formula is as follows:

[0038] .

[0039] Step (5) is a decarboxylation and ring-closure reaction. Instead of the existing method using hydroxyl group ring closure, it employs a carboxyl group-occupied, synergistic process of decarboxylation and nucleophilic cyclization. The reaction mechanism is: activation of the palladium catalyst, decarboxylation and cyclization, and reductive elimination. After decarboxylation of compound 4, the original carboxyl site is converted into a Pd-bound aryl carbon, providing an electrophilic aryl carbon site. Simultaneously, the decarboxylation process promotes intramolecular nucleophilic cyclization through the entropy increase effect of CO2 release. This not only enhances the aromatization of benzofuran, increasing reactivity and yield, but also increases the stability of the benzofuran ring, making it less prone to ring-opening, oxidation, and other side reactions under acidic or alkaline conditions. The fifth step, decarboxylation and ring closure, proceed simultaneously, simplifying the reaction steps and reducing isomerization. Palladium catalysis achieves synergistic driving of decarboxylation and cyclization, avoiding byproducts from stepwise reactions.

[0040] Preferably, the specific operation of step (1) is as follows: under nitrogen protection, the o-hydroxybenzoic acid ester compound or its halogenated derivative, methyl bromoacetate and solvent are mixed evenly, cooled to 0°C in an ice-water bath and then the base reagent is added in batches. The mixture is naturally heated to room temperature and reacted for 2-3 hours. After quenching, extraction, drying and purification, compound 1 is obtained; the molar ratio of o-hydroxybenzoic acid ester compound or its halogenated derivative, methyl bromoacetate and base in step (1) is 1:(1.0~1.2):(3.0~4.0); the solvent used in step (1) is one or more of tetrahydrofuran, acetone or methanol.

[0041] Preferably, the specific operation of step (2) is as follows: under nitrogen protection, compound 1, trifluoromethanesulfonic anhydride, triethylamine, 4-dimethylaminopyridine (DMAP) are mixed with solvent and stirred at room temperature for 2-3 hours. After quenching, extraction, drying and concentration, compound 2 is obtained. The molar ratio of compound 1 to trifluoromethanesulfonic anhydride, triethylamine and 4-dimethylaminopyridine (DMAP) in step (2) is: compound 1: trifluoromethanesulfonic anhydride: triethylamine: 4-dimethylaminopyridine (DMAP) = 1: (1.1-1.3): (2.0-3.0): (0.02-0.05). The solvent used in step (2) is selected from dichloroethane, N,N-dimethylformamide (DMF), toluene or a mixture of toluene and 1,4-dioxane.

[0042] Preferably, the specific operation of step (3) is as follows: under nitrogen protection, compound 2, o-bromophenol, inorganic base and solvent are mixed, heated to 100℃ and reacted for 10 to 12 hours, and compound 3 is obtained by quenching, extraction, drying and purification; the molar ratio of compound 2 to o-bromophenol and inorganic base in step (3) is: compound 2: o-bromophenol: inorganic base = 1: (1.2 to 2.5): (2.5 to 4.0); the solvent used in step (3) is N,N-dimethylformamide (DMF).

[0043] Preferably, the specific operation of step (4) is as follows: Compound 3, inorganic strong base, organic solvent and water are mixed and heated under reflux for 6 to 8 hours. After acidification, the mixture is filtered, washed and dried to obtain compound 4. The molar ratio of compound 3 to inorganic strong base in step (4) is: compound 3: inorganic strong base = 1: (3.0 to 6.0). The molar ratio of water to organic solvent is: water: organic solvent = 1 mL: 5 to 10 mL. The organic solvent used in step (4) is methanol or ethanol.

[0044] Preferably, the specific operation of step (5) is as follows: Under nitrogen protection, compound 4, palladium catalyst, tricyclohexylphosphine fluoroborate (PCy3·BF4), 1,8-diazacyclic [5,4,0]undec-7-ene (DBU) and solvent are mixed, heated to 100-160℃ and reacted for 12-18 hours. After quenching, filtration, washing and purification, compound 5 is obtained; in step (5), compound 4, palladium catalyst, tricyclohexylphosphine fluoroborate (PCy3·BF4) and solvent are reacted. The molar ratio of compound 4 to base is: palladium catalyst: tricyclohexylphosphine fluoroborate (PCy3·BF4): 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) = 1: (0.03~0.06): (0.06~0.12): (1.5~3.0); the solvent used in step (5) is N-methyl-2-pyrrolidone (NMP) or N,N-dimethylformamide (DMF).

[0045] Preferably, the o-hydroxybenzoate compound or its halogenated derivative is... o-Halogenated phenolic compounds Compound 3 Compound 4 Compound 5 In the chemical structure, R1 is selected from H, F, Cl, Br or I; R2 is selected from H, F, Cl or Br.

[0046] Compared with the prior art, the advantages of the present invention are as follows:

[0047] (1) The starting materials of this invention, o-hydroxybenzoic acid esters or their halogenated derivatives, methyl bromoacetate and o-halophenols are all commercially mass-produced products with sufficient market supply and low procurement costs. They can be used directly without complicated pretreatment, which greatly reduces the cost of raw material preparation and procurement, and has outstanding economic feasibility.

[0048] (2) The reaction of each step of the present invention achieves highly selective conversion by precisely controlling the substrate structure, catalyst selection and reaction conditions. The third step precisely constructs CO bonds to avoid multifunctional group competition reaction. The fifth step adopts carboxyl group occupancy strategy to fundamentally eliminate the generation of isomers. The purity of the target product can reach more than 99%.

[0049] (3) The intermediates such as benzofuran carboxylic acid ester and sulfonate ester in the synthetic route of the present invention have stable structures and are not prone to side reactions such as ring-opening oxidation or defunctionalization under reaction conditions such as acid, base and heating, which effectively ensures the conversion rate of each step of the reaction and the overall yield is significantly better than the prior art.

[0050] (4) The present invention has a high tolerance for the substituent positions of the substrate. Whether it is a halogen substituent introduced at different sites on the benzofuran ring or the phenol ring at the ortho, meta, or para positions, or a substituent group with different electronic effects, it can participate smoothly in a series of reactions such as intramolecular ring closure, etherification and coupling. It can efficiently construct benzofuran[3,2b]benzofuran compounds with bilateral multihalogen substitution, which can meet the demand for molecular structure diversity in fields such as organic functional materials and pharmaceutical intermediates. It can also reduce the substrate pre-modification steps and reduce side reactions caused by the restriction of substituent positions. While maintaining high reaction yield and selectivity, it significantly broadens the scope of application of the reaction and provides a flexible and efficient general route for the synthesis of target compounds with various substitution modes.

[0051] (5) The benzene rings of the o-hydroxybenzoic acid esters and o-halophenols of the present invention can be flexibly introduced with halogen substituents such as fluorine, chlorine, bromine, and iodine. A series of benzofuran[3,2b]benzofuran derivatives can be synthesized through simple modification to meet the diverse needs of pharmaceutical, organic materials and other fields for compounds with different substituent structures.

[0052] (6) The reaction process of this invention does not use highly toxic or highly polluting reagents. The solvents are mostly conventional organic solvents that can be recycled. The amount of waste emissions is small, which is in line with the concept of green chemistry. The reaction steps have good repeatability and stable yield, avoiding the problems of high raw material loss and many by-products. It has the technical conditions and cost advantages for large-scale production and has broad application prospects. Attached Figure Description

[0053] (1) Figure 1 , NMR spectra of compounds 1-5 of the present invention;

[0054] (2) Figure 2 , NMR spectra of compounds 2-5 of the present invention;

[0055] (3) Figure 3 , NMR spectra of compounds 3-5 of the present invention;

[0056] (4) Figure 4 , NMR spectra of compounds 4-5 of the present invention;

[0057] (5) Figure 5 The NMR spectrum of compound 5-5 of the present invention. Detailed Implementation

[0058] The specific embodiments of the present invention are described below with reference to examples. The raw materials and reagents used in the present invention are all commercially available.

[0059] Example 1

[0060] A method for synthesizing 3-chlorobenzofuran[3,2-b]benzofuran

[0061] Step 1: Synthesis of Compound 1-1

[0062]

[0063] In a dry three-necked flask, add methyl o-hydroxybenzoate (76.0 g, 0.50 mol), methyl bromoacetate (83.6 g, 0.55 mol), and 1.5 L of tetrahydrofuran (THF). Purge with nitrogen three times continuously, stirring until all reactants are thoroughly mixed. Cool the reaction system to 0°C using an ice-water bath. Add sodium tert-butoxide (144.2 g, 1.50 mol) in 10 batches, 14.4 g per batch, 5 minutes apart. After each addition, allow the mixture to warm to room temperature and react for 2 hours. Monitor the reaction mixture by TLC. After the reactants had reacted completely, a 1 mol / L dilute hydrochloric acid aqueous solution was added to the reaction system to quench the reaction and adjust the pH to <2. Then, ethyl acetate was added for extraction three times, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography with petroleum ether:ethyl acetate = 10:1 as the eluent. 87.5 g of white solid compound 1-1, namely methyl 3-hydroxybenzofuran-2-carboxylic acid, was obtained. LC-MS showed a molecular weight of 192.0, HPLC showed >98%, and the yield was 91.2%.

[0064] Step 2: Synthesis of Compounds 1-2

[0065]

[0066] Under nitrogen protection, compound 1-1 (76.8 g, 0.40 mol) obtained in the first step, trifluoromethanesulfonic anhydride (141.0 g, 0.50 mol), triethylamine (81.0 g, 0.80 mmol), 4-dimethylaminopyridine (DMAP) (1.0 g, 8 mmol) and 2 L of dichloroethane were added to a dry three-necked flask. The mixture was stirred at room temperature for 3 h. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched with 500 mL of water, and then extracted three times with dichloromethane and washed twice with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography with petroleum ether:ethyl acetate = 20:1 as the eluent. 123.7 g of a light yellow oily compound 1-2, namely methyl 3-((trifluoromethanesulfonyl)oxy)benzofuran-2-carboxylate, was obtained. LC-MS showed a molecular weight of 324.0, HPLC showed >97%, and the yield was 95.5%.

[0067] Step 3: Synthesis of compounds 1-3

[0068]

[0069] Under nitrogen protection, compounds 1-2 (64.8 g, 0.20 mol) obtained in step 2, 2-bromo-4-chlorophenol (61.8 g, 0.30 mol), cesium carbonate (195.5 g, 0.60 mol), and 2 L of N,N-dimethylformamide (DMF) were added to a dry three-necked flask. The mixture was heated to 100 °C and reacted for 12 h. TLC was monitored until the reaction of the starting material was complete. After cooling to room temperature, 500 mL of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, washed twice with water, dried with anhydrous sodium sulfate, filtered off the drying agent, removed the solvent under reduced pressure, and purified by column chromatography. The eluent was petroleum ether:ethyl acetate = 20:1, yielding 57.2 g of oily compound 1-3, namely methyl 3-(2-bromo-4-chlorophenoxy)benzofuran-2-carboxylate. LC-MS showed a molecular weight of 381.9, HPLC > 98%, and a yield of 75.3%.

[0070] Step 4: Synthesis of compounds 1-4

[0071]

[0072] Compound 1-3 (38.0 g, 0.10 mol) obtained in step 3, KOH (16.8 g, 0.30 mol), 20 mL of water, and 200 mL of ethanol were added to a 500 mL three-necked flask. The mixture was heated to 60 °C under reflux for 6 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid aqueous solution was added to adjust the pH to <2. The mixture was filtered, and the filter cake was washed with water, ethanol, and n-hexane, respectively. The mixture was then dried under vacuum to obtain 34.7 g of white solid powder compound 1-4, namely 3-(2-bromo-4-chlorophenoxy)benzofuran-2-carboxylic acid. LC-MS showed a molecular weight of 367.9, HPLC showed >98%, and the yield was 94.8%.

[0073] Step 5: Synthesis of compounds 1-5

[0074]

[0075] Under nitrogen protection, the compounds obtained in step four (1-418.3 g, 0.05 mol), palladium acetate (0.28 g, 1.50 mmol), tricyclohexylphosphine fluoroborate (molecular weight 368.24) (1.1 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol) and 400 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times and continuously introduced. The mixture was heated to 160 °C in an oil bath and reacted for 18 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, water was added to quench the reaction. The mixture was filtered, and the filter cake was the main crude product. The content of the target product in the filtrate was extremely low. After concentration, the mixture could be combined with the filter cake for purification. The filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 10.3 g of white solid powder compound 1-5, namely 3-chlorobenzofuran[3,2-b]benzofuran. LC-MS showed a molecular weight of 242.0, HPLC > 99%, and a yield of 85.1%.

[0076] NMR spectrum as follows Figure 1 As shown: 1H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.88 (s, 1H), 7.64–7.57 (m,3H), 7.51 (d, J = 10.6 Hz, 2H);

[0077] 13C NMR (125 MHz, DMSO-d6) δ158.93, 157.51, 146.46, 146.18, 132.96,132.53, 130.75, 128.06, 125.02, 122.90, 122.12, 119.32, 113.62, 112.29.

[0078] Example 2: Synthesis of 3-fluorobenzofuran[3,2-b]benzofuran

[0079] Step 1: Synthesis of Compound 2-1

[0080]

[0081] In a dry three-necked flask, add methyl o-hydroxybenzoate (76.0 g, 0.50 mol), methyl bromoacetate (83.6 g, 0.55 mol), and 1.5 L of [unspecified substance]. Tetrahydrofuran (THF) was purged with nitrogen three times and continuously, and the mixture was stirred until all the raw materials were homogeneous. The reaction system was cooled to 0°C using an ice-water bath. Sodium tert-butoxide (144.2 g, 1.50 mol) was added in 10 batches of 14.4 g each, with a 5-minute interval between each batch. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 2 hours. TLC was monitored until the reaction was complete. The reaction was quenched with 1 mol / L dilute hydrochloric acid solution and the pH was adjusted to <2. Ethyl acetate was then added for extraction three times, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography with petroleum ether:ethyl acetate = 10:1 as the eluent. 86.4 g of white solid compound 2-1, namely methyl 3-hydroxybenzofuran-2-carboxylic acid, was obtained. LC-MS showed a molecular weight of 192.0, HPLC showed >98%, and the yield was 90%.

[0082] Step 2: Synthesis of Compound 2-2

[0083]

[0084] Under nitrogen protection, compound 2-1 (76.8 g, 0.40 mol) obtained in the first step, trifluoromethanesulfonic anhydride (141.0 g, 0.50 mol), triethylamine (81.0 g, 0.80 mol), 4-dimethylaminopyridine (DMAP) (1.0 g, 8 mmol), and 2 L of dichloroethane were added to a dry three-necked flask. The mixture was stirred at room temperature for 3 h. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched with 500 mL of water, and then extracted three times with dichloromethane and washed twice with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography with petroleum ether:ethyl acetate = 20:1 as the eluent. 116.6 g of a light yellow oil 2-2, namely methyl 3-((perfluorobutylsulfonyl)oxy)benzofuran-2-carboxylate, was obtained. LC-MS showed a molecular weight of 324.0, HPLC showed >98%, and the yield was 90%.

[0085] Step 3: Synthesis of Compounds 2-3

[0086]

[0087] Under nitrogen protection, compound 2-2 (64.8 g, 0.20 mol) obtained in step two, 2-bromo-4-fluorophenol (57.0 g, 0.30 mol), cesium carbonate (195.5 g, 0.60 mol), and 2 L of N,N-dimethylformamide (DMF) were added to a dry three-necked flask. The mixture was heated to 100 °C and reacted for 12 h. TLC was monitored until the reaction of the starting material was complete. After cooling to room temperature, 500 mL of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, washed twice with water, dried with anhydrous sodium sulfate, filtered off the drying agent, removed the solvent under reduced pressure, and purified by column chromatography. The eluent was petroleum ether:ethyl acetate = 20:1, yielding 52.8 g of oily compound 2-3, namely methyl 3-(2-bromo-4-fluorophenoxy)benzofuran-2-carboxylate. LC-MS showed a molecular weight of 364.0, HPLC > 98%, and a yield of 72.5%.

[0088] Step 4: Synthesis of compounds 2-4

[0089]

[0090] Compound 2-3 (36.4 g, 0.10 mol) obtained in step 3, KOH (16.8 g, 0.30 mol), 30 mL of water, and 300 mL of ethanol were added to a 1000 mL three-necked flask. The mixture was heated to 60 °C under reflux for 5 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid aqueous solution was added to adjust the pH to <2. The mixture was filtered, and the filter cake was washed with water, ethanol, and n-hexane, respectively. The mixture was then dried under vacuum to obtain 33.2 g of white solid powder compound 2-4, namely 3-(2-bromo-4-fluorophenoxy)benzofuran-2-carboxylic acid. LC-MS showed a molecular weight of 350.0, HPLC showed >98%, and the yield was 95%.

[0091] Step 5: Synthesis of compounds 2-5

[0092]

[0093] Under nitrogen protection, compound 2-4 (17.5 g, 0.05 mol) obtained in step four, palladium acetate (0.28 g, 1.50 mmol), tricyclohexylphosphine fluoroborate (molecular weight 368.24) (1.1 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol) and 300 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times and continuously introduced. The oil bath temperature was raised to 160 °C and the reaction was carried out for 15 h. TLC was used to monitor the reaction until the reactants were completely reacted. After the reaction solution was cooled to room temperature, water was added to quench the reaction. The mixture was filtered, and the filter cake was the main crude product. The content of the target product in the filtrate was extremely low. After concentration, the mixture could be combined with the filter cake for purification. The filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 9.7 g of white solid powder compound 2-5, namely 3-fluorodibenzofuran[3,2-b]benzofuran. LC-MS showed a molecular weight of 226.0, HPLC > 99%, and a yield of 86%.

[0094] NMR spectrum as follows Figure 2 As shown:

[0095] 1H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.50 (s, 1H), 7.26 (s, 1H);

[0096] 13C NMR (125 MHz, DMSO-d6) δ 159.39, 158.93, 155.76, 146.19, 145.25,132.96, 128.06, 125.02, 122.49, 120.00, 118.18, 113.29, 111.29, 110.60.

[0097] Example 3: Synthesis of 2,8-dichlorobenzofuran[3,2-b]benzofuran

[0098] Step 1: Synthesis of Compound 3-1

[0099]

[0100] In a dry three-necked flask, add methyl 4-chloro-2-hydroxybenzoate (74.4 g, 0.40 mol), methyl bromoacetate (66.9 g, 0.44 mol), and 1.5 L of [unspecified substance]. Tetrahydrofuran (THF) was purged with nitrogen three times and continuously. The mixture was stirred until all the raw materials were homogeneous. The reaction system was cooled to 0°C using an ice-water bath. Sodium tert-butoxide (115.3 g, 1.20 mol) was added in 10 batches of 11.5 g each, with a 5-minute interval between each batch. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 2 hours. TLC was monitored until the reaction was complete. The reaction was quenched with 1 mol / L dilute hydrochloric acid solution and the pH was adjusted to <2. Ethyl acetate was then added to extract the mixture three times. The organic phase was washed twice with water and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography with a petroleum ether:ethyl acetate ratio of 8:1 as the eluent. 70.1 g of white solid compound 3-1, namely methyl 6-chloro-3-hydroxybenzofuran-2-carboxylate, was obtained. LC-MS showed a molecular weight of 226.0, HPLC showed >98%, and the yield was 77.5%.

[0101] Step 2: Synthesis of Compound 3-2

[0102]

[0103] Under nitrogen protection, compound 3-1 (67.8 g, 0.30 mol) obtained in the first step, trifluoromethanesulfonic anhydride (101.6 g, 0.36 mol), triethylamine (75.9 g, 0.75 mol), 4-dimethylaminopyridine (DMAP) (1.1 g, 9 mmol) and 2LDMF were added to a dry three-necked flask. The mixture was stirred at room temperature for 3 h. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched with 500 mL of water, and then extracted three times with ethyl acetate. The organic phase was washed twice with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed by concentration under reduced pressure. The mixture was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 95.6 g of a light yellow oily compound 3-2, namely methyl 6-chloro-3-((perfluorobutylsulfonyl)oxy)benzofuran-2-carboxylate. LC-MS showed a molecular weight of 358.0, HPLC > 98%, and the yield was 89%.

[0104] Step 3: Synthesis of Compound 3-3

[0105]

[0106] Under nitrogen protection, compound 3-2 (71.6 g, 0.20 mol) obtained in step 2, 2-bromo-4-chlorophenol (61.8 g, 0.30 mol), cesium carbonate (195.5 g, 0.60 mol), and 2 L of N,N-dimethylformamide (DMF) were added to a dry three-necked flask. The mixture was heated to 100 °C and reacted for 12 h. TLC was monitored until the reaction of the starting material was complete. After cooling to room temperature, 500 mL of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phase was washed twice with water. The organic phase was dried with anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography. The eluent was petroleum ether:ethyl acetate = 20:1, yielding 60.4 g of oily compound 3-3, namely methyl 3-(2-bromo-4-chlorophenoxy)-6-chlorobenzofuran-2-carboxylate. LC-MS showed a molecular weight of 415.9, HPLC > 98%, and the yield was 73%.

[0107] Step 4: Synthesis of compounds 3-4

[0108]

[0109] Compound 3-3 (41.4 g, 0.10 mol) obtained in step 3, LiOH (7.2 g, 0.30 mol), 30 mL of water, and 300 mL of methanol were added to a 1000 mL three-necked flask. The mixture was heated to 60 °C under reflux for 5 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid aqueous solution was added to adjust the pH to <2. The mixture was filtered, and the filter cake was washed with water, methanol, and n-hexane, respectively. The mixture was then dried under vacuum to obtain 38.4 g of white solid powder compound 3-4, namely 3-(2-bromo-4-chlorophenoxy)-6-chlorobenzofuran-2-carboxylic acid. LC-MS showed a molecular weight of 401.9, HPLC showed >98%, and the yield was 96%.

[0110] Step 5: Synthesis of compounds 3-5

[0111]

[0112] Under nitrogen protection, compounds 3-4 (20.0 g, 0.05 mol) obtained in step four, palladium acetate (0.28 g, 1.50 mmol), tricyclohexylphosphine fluoroborate (molecular weight 368.24) (1.1 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol) and 300 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times and continuously introduced. The mixture was heated to 160 °C in an oil bath and reacted for 15 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, water was added to quench the reaction. The mixture was filtered, and the filter cake was the main crude product. The content of the target product in the filtrate was extremely low. After concentration, the mixture could be combined with the filter cake for purification. The filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 12.0 g of white solid powder compound 3-5, namely 2,8-dichlorobenzofuran[3,2-b]benzofuran. LC-MS showed a molecular weight of 276.0, HPLC > 99%, and a yield of 87%.

[0113] NMR spectrum as follows Figure 3 As shown:

[0114] 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 7.35 (d, J = 5.3 Hz, 2H);

[0115] 13C NMR (125 MHz, DMSO-d6) δ 157.51, 155.21, 146.53, 145.46, 136.67,132.53, 130.75, 129.62, 124.69, 122.94, 119.32, 117.92, 113.52, 112.29.

[0116] Example 4: Synthesis of 2,8-dibromobenzofuran[3,2-b]benzofuran

[0117] Step 1: Synthesis of Compound 4-1

[0118]

[0119] In a dry three-necked flask, add methyl 4-bromo-2-hydroxybenzoate (92.0 g, 0.40 mol), methyl bromoacetate (66.9 g, 0.44 mol), and 1.5 L of [unspecified substance]. Tetrahydrofuran (THF) was purged with nitrogen three times and continuously, and the mixture was stirred until all the raw materials were homogeneous. The reaction system was cooled to 0°C using an ice-water bath. Sodium tert-butoxide (115.3 g, 1.20 mol) was added in 10 batches of 11.5 g each, with a 5-minute interval between each batch. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 2 hours. TLC was monitored until the reaction was complete. The reaction was quenched with 1 mol / L dilute hydrochloric acid solution and the pH was adjusted to <2. Ethyl acetate was then added for extraction three times, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography with a petroleum ether:ethyl acetate ratio of 8:1 as the eluent. 75.6 g of white solid compound 4-1, namely methyl 6-bromo-3-hydroxybenzofuran-2-carboxylate, was obtained. LC-MS showed a molecular weight of 270.0, HPLC showed >98%, and the yield was 70%.

[0120] Step 2: Synthesis of Compound 4-2

[0121]

[0122] Under nitrogen protection, compound 4-1 (67.5 g, 0.25 mol) obtained in the first step, trifluoromethanesulfonic anhydride (84.6 g, 0.30 mol), triethylamine (75.9 g, 0.75 mol), 4-dimethylaminopyridine (DMAP) (0.9 g, 7.5 mmol), and 2LDMF were added to a dry three-necked flask. The mixture was stirred at room temperature for 3 h. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched with 500 mL of water, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed by concentration under reduced pressure. The mixture was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 90.2 g of a light yellow oily compound 4-2, namely methyl 6-bromo-3-((perfluorobutylsulfonyl)oxy)benzofuran-2-carboxylate. LC-MS showed a molecular weight of 403.9, HPLC > 98%, and the yield was 89.8%.

[0123] Step 3: Synthesis of Compound 4-3

[0124]

[0125] Under nitrogen protection, compound 4-2 (80.4 g, 0.20 mol) obtained in step 2, 2,4-dibromophenol (74.9 g, 0.30 mol), cesium carbonate (195.5 g, 0.60 mol), and 3 L of N,N-dimethylformamide (DMF) were added to a dry three-necked flask. The mixture was heated to 100 °C and reacted for 12 h. TLC was monitored until the reaction of the starting material was complete. After cooling to room temperature, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phase was washed twice with water. The organic phase was dried with anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography. The eluent was petroleum ether:ethyl acetate = 20:1, yielding 75.3 g of oily compound 4-3, namely methyl 3-(2,4-dibromophenoxy)-6-bromobenzofuran-2-carboxylate. LC-MS showed a molecular weight of 503.8, HPLC > 98%, and the yield was 75%.

[0126] Step 4: Synthesis of compound 4-4

[0127]

[0128] Compound 4-3 (50.2 g, 0.10 mol) obtained in step 3, LiOH (7.2 g, 0.30 mol), 40 mL of water, and 400 mL of methanol were added to a 1000 mL three-necked flask. The mixture was heated to 60 °C under reflux for 5 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid aqueous solution was added to adjust the pH to <2. The mixture was filtered, and the filter cake was washed with water, methanol, and n-hexane, respectively. After vacuum drying, 45.7 g of white solid powder compound 4-4, namely 3-(2,4-dibromophenoxy)-6-bromobenzofuran-2-carboxylic acid, was obtained. LC-MS showed a molecular weight of 489.8, HPLC showed >98%, and the yield was 93.6%.

[0129] Step 5: Synthesis of compounds 4-5

[0130]

[0131] Under nitrogen protection, compound 4-4 (24.4 g, 0.05 mol) obtained in step four, palladium acetate (0.28 g, 1.50 mmol), tricyclohexylphosphine fluoroborate (molecular weight 368.24) (1.1 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol) and 400 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times and continuously introduced. The oil bath temperature was raised to 160 °C and the reaction was carried out for 15 h. TLC was used to monitor the reaction until the reactants were completely reacted. After the reaction solution was cooled to room temperature, water was added to quench the reaction. The mixture was filtered, and the filter cake was the main crude product. The content of the target product in the filtrate was extremely low. After concentration, the mixture could be combined with the filter cake for purification. The filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 15.9 g of white solid powder compound 4-5, namely 2,8-dibromobenzofuran[3,2-b]benzofuran. LC-MS showed a molecular weight of 365.9, HPLC > 99%, and a yield of 87.6%.

[0132] NMR spectrum as follows Figure 4 As shown:

[0133] 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H),7.61 – 7.55 (m, 3H);

[0134] 13C NMR (125 MHz, DMSO-d6) δ 157.22, 156.05, 146.38, 145.36, 134.24,130.19, 127.27, 124.35, 123.36, 119.55, 118.74, 117.47, 113.08, 112.13.

[0135] Example 5: Synthesis of 2-bromo-8-chloro-benzofuran[3,2-b]benzofuran

[0136] Step 1: Synthesis of Compound 5-1

[0137]

[0138] In a dry three-necked flask, add methyl 4-bromo-2-hydroxybenzoate (92.0 g, 0.40 mol), methyl bromoacetate (66.9 g, 0.44 mol), and 1.5 L of [unspecified substance]. Tetrahydrofuran (THF) was purged with nitrogen three times and continuously, and the mixture was stirred until all the raw materials were homogeneous. The reaction system was cooled to 0°C using an ice-water bath. Sodium tert-butoxide (115.3 g, 1.20 mol) was added in 10 batches of 11.5 g each, with a 5-minute interval between each batch. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 2 hours. TLC was monitored until the reaction was complete. The reaction was quenched with 1 mol / L dilute hydrochloric acid solution and the pH was adjusted to <2. Ethyl acetate was then added to extract the mixture three times, and the organic phase was washed twice with water. The mixture was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography with a petroleum ether:ethyl acetate ratio of 8:1 as the eluent, yielding 79.4 g of a white solid compound 5-1, namely methyl 6-bromo-3-hydroxybenzofuran-2-carboxylate. LC-MS showed a molecular weight of 270.0, HPLC showed >98%, and the yield was 73.5%.

[0139] Step 2: Synthesis of Compound 5-2

[0140]

[0141] Under nitrogen protection, compound 5-1 (67.5 g, 0.25 mol) obtained in the first step, trifluoromethanesulfonic anhydride (84.6 g, 0.30 mol), triethylamine (75.9 g, 0.75 mol), 4-dimethylaminopyridine (DMAP) (0.9 g, 7.5 mmol) and 2 L DMF were added to a dry three-necked flask. The mixture was stirred at room temperature for 3 h. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched with 500 mL of water, and then extracted three times with ethyl acetate. The organic phase was washed twice with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed by concentration under reduced pressure. The mixture was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 88.4 g of a light yellow oily compound 5-2, namely methyl 6-bromo-3-((perfluorobutylsulfonyl)oxy)benzofuran-2-carboxylate. LC-MS showed a molecular weight of 403.9, HPLC > 98%, and a yield of 88%.

[0142] Step 3: Synthesis of Compound 5-3

[0143]

[0144] Under nitrogen protection, compound 5-2 (80.4 g, 0.20 mol) obtained in step 2, 2-bromo-4-chlorophenol (61.8 g, 0.30 mol), cesium carbonate (195.5 g, 0.60 mol), and 2 L of N,N-dimethylformamide (DMF) were added to a dry three-necked flask. The mixture was heated to 100 °C and reacted for 12 h. TLC was monitored until the reaction of the starting material was complete. After cooling to room temperature, 500 mL of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phase was washed twice with water. The organic phase was dried with anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography. The eluent was petroleum ether:ethyl acetate = 20:1, yielding 68.7 g of oily compound 5-3, namely methyl 3-(2-bromo-4-chlorophenoxy)-6-bromobenzofuran-2-carboxylate. LC-MS showed a molecular weight of 459.8, HPLC > 98%, and the yield was 75%.

[0145] Step 4: Synthesis of compound 5-4

[0146]

[0147] Compound 5-3 (45.8 g, 0.10 mol) obtained in step 3, LiOH (7.2 g, 0.30 mol), 40 mL of water, and 400 mL of methanol were added to a 1000 mL three-necked flask. The mixture was heated to 60 °C under reflux for 5 h. The reaction was monitored by TLC until the reactants were completely reacted. After the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid aqueous solution was added to adjust the pH to <2. The mixture was filtered, and the filter cake was washed with water, methanol, and n-hexane, respectively. The mixture was then dried under vacuum to obtain 42.3 g of white solid powder compound 5-4, namely 3-(2-bromo-4-chlorophenoxy)-6-bromobenzofuran-2-carboxylic acid. LC-MS showed a molecular weight of 445.8, HPLC showed >98%, and the yield was 95.3%.

[0148] Step 5: Synthesis of compound 5-5

[0149]

[0150] Under nitrogen protection, compound 5-4 (22.2 g, 0.05 mol) obtained in step four, palladium acetate (0.28 g, 1.50 mmol), tricyclohexylphosphine fluoroborate (molecular weight 368.24) (1.1 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol) and 400 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times and continuously introduced. The mixture was heated to 160 °C in an oil bath and reacted for 15 h. TLC was used to monitor the reaction until the reactants were completely reacted. After the reaction solution was cooled to room temperature, water was added to quench the reaction. The mixture was filtered, and the filter cake was the main crude product. The content of the target product in the filtrate was extremely low. After concentration, the mixture could be combined with the filter cake for purification. The filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent, yielding 13.8 g of white solid powder compound 5-5, namely 2-bromo-8-chloro-benzofuran[3,2-b]benzofuran. LC-MS showed a molecular weight of 321.9, HPLC > 99%, and a yield of 86.5%.

[0151] NMR spectrum as follows Figure 5 As shown:

[0152] 1H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J = 15.5 Hz, 2H), 7.62 – 7.55(m, 3H), 7.52 (s, 1H);

[0153] 13C NMR (125 MHz, DMSO-d6) δ 157.51, 156.05, 146.53, 145.46, 132.53,130.75, 130.19, 124.35, 123.36, 122.90, 119.32, 117.47, 113.08, 112.29.

[0154] Comparative Example 1:

[0155] Compared to the second step of Example 1, the triethylamine was replaced with other organic bases in the reaction, while the other operating steps were the same as the second step of Example 1, resulting in a significantly reduced yield.

[0156] Under nitrogen protection, compound 1-1 (76.8 g, 0.40 mol), trifluoromethanesulfonic anhydride (141.0 g, 0.50 mol), morpholine (69.7 g, 0.80 mol), DMAP (1.0 g, 8 mmol), and 2 L of dichloroethane were added to a dry three-necked flask. The mixture was stirred at room temperature for 3 h, and the reaction was quenched with water. The mixture was then extracted three times with dichloromethane and washed twice with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography. The eluent was petroleum ether:ethyl acetate = 20:1, and the yield was 40%.

[0157] Comparative Example 2

[0158] Compared with step 5 of Example 1, PCy3·BF4 was replaced with other ligands in the reaction, and the other operation steps were the same as step 5 of Example 1.

[0159] Under nitrogen protection, compounds 1-4 (18.3 g, 0.05 mol), palladium acetate (0.28 g, 1.50 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos) (1.4 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol), and 400 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times continuously, and the mixture was heated to 160 °C in an oil bath for 18 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was quenched with water. The mixture was filtered, and the filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate as the eluent (15:1), yielding 35.1%.

[0160] Comparative Example 3

[0161] Compared to step 5 of Example 1, Pd(OAc)2 was replaced with other palladium catalysts in the reaction, while the other operating steps were the same as step 5 of Example 1.

[0162] Under nitrogen protection, compounds 1-4 (18.3 g, 0.05 mol), Pd(dppf)Cl2 (1.1 g, 1.50 mmol), tricyclohexylphosphine fluoroborate (molecular weight 368.24) (1.1 g, 3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.2 g, 0.10 mol), and 400 mL of N-methyl-2-pyrrolidone (NMP) were added to a 1 L three-necked flask. Nitrogen was purged three times continuously, and the mixture was heated to 160 °C in an oil bath for 18 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was quenched with water. The mixture was filtered, and the filter cake was washed with water, ethanol, and n-hexane, respectively. The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether:ethyl acetate = 15:1 as the eluent. The HPLC yield was < 80%, and the yield was 64%.

[0163] Through comparative experiments of Examples 1-4 and Comparative Examples 1-3, the following core conclusions can be drawn: After replacing triethylamine with morpholine in step (2) of Comparative Example 1, the reaction yield dropped sharply from 95.5% in Example 1 to 40%, proving that triethylamine can effectively regulate the alkalinity of the reaction system and avoid hydrolysis of trifluoromethanesulfonic anhydride or substrate side reactions. It is a key reagent to ensure the efficient progress of sulfonation reaction.

[0164] In Comparative Example 2, after replacing the tricyclohexylphosphonoborate (PCy3・BF4) in step (5) with XPhos, the cyclization reaction yield decreased from 85.1% in Example 1 to 35.1%, indicating that PCy3・BF4 has a stronger synergistic effect with the palladium catalyst, which can effectively activate the CH bond of the substrate and promote the efficient advancement of the decarboxylation cyclization reaction.

[0165] In Comparative Example 3, after replacing palladium acetate (Pd(OAc)2) in step (5) with Pd(dppf)Cl2, the HPLC purity of the product dropped to below 80%, and the yield dropped to 64%, which was much lower than the 99% purity and 85.1% yield of Example 1. This proves that palladium acetate has better catalytic selectivity in this decarboxylation and cyclization system and can reduce side reactions such as isomerization.

[0166] The target product yields in Examples 1-4 were all maintained above 85%, with a purity of ≥99%, and were compatible with substrates with single-sided and double-sided halogen substitutions. In contrast, the comparative examples showed a significant drop in yield or failure to meet purity standards due to the substitution of a single reagent or catalyst. This further verifies the rationality of the selected raw material combination, reaction conditions, and reagent selection in this invention. The process stability and industrial application potential are significantly better than the alternative solutions.

[0167] This invention verifies the synthetic feasibility of benzofurano[3,2b]benzofuran compounds and their bilaterally substituted derivatives through four sets of examples 1-4. Based on the experimental data, the following conclusions are drawn:

[0168] In Examples 1-4, the yield of each of the five steps was maintained above 70%, with the yield of the critical third step etherification reaction being 72.5%-75% and the yield of the fifth step cyclization reaction being 85.1%-87.6%. The total yield of the target product was significantly improved compared with the prior art, and the HPLC purity of the products was ≥99%, with no isomer impurities generated. This solved the core defects of the prior art, namely low yield and difficulty in purifying isomers.

[0169] Example 1: R1=H, R2=Cl; Example 2: R1=H, R2=F; Example 3: R1=Cl, R2=Cl; Example 4: R1=Br, R2=Br. These examples verified the substrate adaptability for unilateral halogen substitution, bilateral substitution with different halogens, and bilateral substitution with the same halogen. All substituted substrates were able to successfully complete the five-step reaction without any reaction stagnation or surge in side reactions caused by the ortho, meta, or para positions of the substituents or electronic effects. This demonstrates that the tolerance of this method to the substituent positions of the substrate is significantly better than that of existing technologies that can only achieve unilateral substitution.

[0170] All Examples 1-4 do not require extreme low temperatures; the reaction temperatures are concentrated between 0℃ and 160℃. The solvents and catalysts are all commercially available mass-produced products. The post-processing only involves routine operations such as extraction, filtration, and column chromatography. Verified by three parallel experiments, the yield fluctuation of each step is ≤3%, and the repeatability is good, meeting the requirements of industrial production for mild conditions and simple operation.

[0171] In Examples 1-4, the halogen functional groups such as F, Cl, and Br contained in the substrates did not undergo dehalogenation or coupling side reactions during the reaction process and were completely retained in the target product, reserving active sites for subsequent derivatization modifications and solving the problem of narrow functional group selection in the prior art.

[0172] The raw materials of this invention are inexpensive and readily available, the reaction has high selectivity, the overall yield is stable, and the substrate adaptability is wide. It has successfully achieved the efficient synthesis of single-sided and double-sided substituted derivatives of benzofuran[3,2b]benzofuran compounds, and has significant industrial application value.

[0173] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

[0174] Many other changes and modifications can be made without departing from the concept and scope of this invention. It should be understood that this invention is not limited to the specific embodiments, and the scope of this invention is defined by the appended claims.

Claims

1. A method for synthesizing benzofuran[3,2b]benzofuran compounds, characterized in that: The synthesis method includes the following steps: (1) Using o-hydroxybenzoic acid esters or their halogenated derivatives and halogenated acetates as raw materials, an intramolecular cyclization reaction is carried out under alkaline conditions to obtain benzofuran carboxylic acid ester intermediates at 0℃ to room temperature; (2) The hydroxyl groups of the benzofuran carboxylic acid ester intermediate obtained in step (1) are subjected to an esterification reaction under the action of a sulfonating agent, an organic base and a catalyst to obtain a sulfonate intermediate; (3) The sulfonate intermediate obtained in step (2) is reacted with an ortho-halophenolic compound under nitrogen protection, inorganic base and heating conditions to undergo an etherification reaction to obtain an aryloxy-substituted benzofuran carboxylic acid ester intermediate. (4) The aryloxy-substituted benzofuran carboxylic acid ester intermediate obtained in step (3) is subjected to hydrolysis reaction under the action of inorganic strong base, water and solvent, and after acidification, benzofuran carboxylic acid intermediate is obtained. (5) The benzofuran carboxylic acid intermediate obtained in step (4) is heated under nitrogen protection, with the action of a transition metal catalyst and a strong base to undergo an intramolecular cyclization reaction, to obtain the target benzofuran[3,2b]benzofuran compound; The benzene ring of the o-hydroxybenzoic acid esters or their halogenated derivatives may have halogen substituents selected from hydrogen, fluorine, chlorine, bromine or iodine; the benzene ring of the o-halophenols may have halogen substituents selected from hydrogen, fluorine, chlorine or bromine.

2. The method for synthesizing benzofuran[3,2b]benzofuran compounds according to claim 1, characterized in that, In step (1), the o-hydroxybenzoic acid ester compound or its halogenated derivative is selected from methyl salicylate or ethyl salicylate; the base in step (1) is selected from sodium tert-butoxide, potassium tert-butoxide, potassium carbonate or sodium methoxide, and the halogenated acetate compound is methyl bromoacetate; The sulfonating agent in step (2) is trifluoromethanesulfonic anhydride, the organic base is triethylamine, and the catalyst is 4-dimethylaminopyridine (DMAP). In step (3), the o-halophenol compound is o-bromophenol, the inorganic base is selected from cesium carbonate, sodium carbonate or potassium carbonate, and the heating temperature is 80℃~120℃; The inorganic strong base in step (4) is selected from sodium hydroxide (NaOH), lithium hydroxide (LiOH) or potassium hydroxide (KOH); In step (5), the transition metal catalyst is a palladium catalyst, which is selected from palladium acetate (Pd(OAc)2), tetra(triphenylphosphine)palladium (Pd(PPh3)4) or dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2); the strong base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the heating temperature is 80℃~180℃.

3. The method for synthesizing benzofuran[3,2b]benzofuran compounds according to claim 2, characterized in that, (1) Using o-hydroxybenzoic acid esters or their halogenated derivatives and methyl bromoacetate as raw materials, an intramolecular cyclization reaction occurs under alkaline conditions, yielding compound 1 at 0°C to room temperature. The reaction formula is as follows: ; (2) Compound 1 obtained in step (1) was subjected to esterification reaction in the presence of trifluoromethanesulfonic anhydride, triethylamine and 4-dimethylaminopyridine (DMAP) to obtain compound 2, and the reaction formula is as follows: ; (3) Compound 2 obtained in step (2) is reacted with o-bromophenol under nitrogen protection, inorganic base, and heating conditions to undergo an etherification reaction to obtain compound 3. The reaction formula is as follows: ； (4) Compound 3 obtained in step (3) is hydrolyzed in the presence of an inorganic strong base, water, and a solvent. After acidification, compound 4 is obtained. The reaction formula is as follows: ； (5) Compound 4 obtained in step (4) was heated under nitrogen protection, with palladium catalyst, tricyclohexylphosphine fluoroborate (PCy3·BF4) and 1,8-diazahexacyclic [5,4,0]undec-7-ene (DBU) to undergo a cyclization reaction, yielding compound 5. The reaction formula is as follows: 。 4. The method for synthesizing benzofuran[3,2b]benzofuran compounds according to claim 3, characterized in that, The specific operation of step (1) is as follows: Under nitrogen protection, o-hydroxybenzoic acid esters or their halogenated derivatives, methyl bromoacetate and solvent are mixed evenly, cooled to 0°C in an ice-water bath and then the base reagent is added in batches. The mixture is naturally heated to room temperature and reacted for 2-3 hours. After quenching, extraction, drying and purification, compound 1 is obtained. The molar ratio of o-hydroxybenzoic acid esters or their halogenated derivatives, methyl bromoacetate and base in step (1) is 1:(1.0~1.2):(3.0~4.0). The solvent used in step (1) is one or more of tetrahydrofuran, acetone or methanol.

5. The method for synthesizing a benzofurano[3,2b]benzofuran compound according to claim 3, characterized in that, The specific operation of step (2) is as follows: under nitrogen protection, compound 1, trifluoromethanesulfonic anhydride, triethylamine, 4-dimethylaminopyridine (DMAP) are mixed with solvent and stirred at room temperature for 2-3 hours. After quenching, extraction, drying and concentration, compound 2 is obtained. The molar ratio of compound 1 to trifluoromethanesulfonic anhydride, triethylamine and 4-dimethylaminopyridine (DMAP) in step (2) is: compound 1: trifluoromethanesulfonic anhydride: triethylamine: 4-dimethylaminopyridine (DMAP) = 1: (1.1-1.3): (2.0-3.0): (0.02-0.05). The solvent used in step (2) is selected from dichloroethane, N,N-dimethylformamide (DMF), toluene or a mixture of toluene and 1,4-dioxane.

6. The method for synthesizing a benzofurano[3,2b]benzofuran compound according to claim 3, characterized in that, The specific operation of step (3) is as follows: under nitrogen protection, compound 2, o-bromophenol, inorganic base and solvent are mixed and heated to 100℃ for 10-12 hours. After quenching, extraction, drying and purification, compound 3 is obtained. The molar ratio of compound 2 to o-bromophenol and inorganic base in step (3) is: compound 2: o-bromophenol: inorganic base = 1: (1.2-2.5): (2.5-4.0). The solvent used in step (3) is N,N-dimethylformamide (DMF).

7. The method for synthesizing benzofurano[3,2b]benzofuran compounds according to claim 3, characterized in that, The specific operation of step (4) is as follows: Mix compound 3, inorganic strong base, organic solvent and water, heat and reflux for 6 to 8 hours, and after acidification, filter, wash and dry to obtain compound 4; the molar ratio of compound 3 to inorganic strong base in step (4) is: compound 3: inorganic strong base = 1: (3.0 to 6.0); the molar ratio of water to organic solvent is: water: organic solvent = 1 mL: 5 to 10 mL; the organic solvent used in step (4) is methanol or ethanol.

8. The method for synthesizing benzofuran[3,2b]benzofuran compounds according to claim 3, characterized in that, The specific operation of step (5) is as follows: Under nitrogen protection, compound 4, palladium catalyst, tricyclohexylphosphine fluoroborate (PCy3·BF4), 1,8-diazacyclic [5,4,0]undec-7-ene (DBU) and solvent are mixed and heated to 100-160℃ for 12-18 hours. After quenching, filtration, washing and purification, compound 5 is obtained; in step (5), compound 4, palladium catalyst, tricyclohexylphosphine fluoroborate (PCy3·BF4) and solvent are mixed and heated to 100-160℃ for 12-18 hours. The molar ratio of BF4 and base is: Compound 4: Palladium catalyst: Tricyclohexylphosphine fluoroborate (PCy3·BF4): 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) = 1: (0.03~0.06): (0.06~0.12): (1.5~3.0); The solvent used in step (5) is N-methyl-2-pyrrolidone (NMP) or N,N-dimethylformamide (DMF).

9. The method for synthesizing benzofuran[3,2b]benzofuran compounds according to claim 3, characterized in that, The o-hydroxybenzoate compound or its halogenated derivative o-Halogenated phenolic compounds Compound 3 Compound 4 Compound 5 In the chemical structure, R1 is selected from H, F, Cl, Br or I; R2 is selected from H, F, Cl or Br.

Images