A method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate

Abstract

The present invention relates to the technical field of compound synthesis, and more particularly to a method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate, wherein the preparation method uses compound III as a raw material, adds compound V and a catalyst to react in a solvent R-Ⅰ to obtain a VI-a solution; sulfuric acid is added to the VI-a solution for reaction, and water and an extraction solvent R-Ⅱ are added to the system after the reaction is completed, and after stirring and standing liquid separation, an aqueous phase is obtained; an alkaline solution is added to the aqueous phase to adjust the pH of the aqueous phase, filtered, dried, and a crude compound VI product is obtained; the crude compound VI product is purified using an organic ether solvent to obtain a cyclopropyl-substituted 2H-benzofuran compound intermediate of compound VI after purification. The preparation method provided by the present invention improves the purity and yield of compound VI, and provides a strong guarantee for finally being able to prepare a highly purified compound A.

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, and in particular to a method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate. Background Art

[0002] Pancreatitis is usually caused by a variety of factors. In foreign countries, the main cause of pancreatitis is long-term drinking, while in China, it is mainly due to gallstones causing poor drainage of pancreatic juice, leading to pancreatic inflammation. Therefore, the most common cause in China is biliary obstructive disease.

[0003] Drug treatment for pancreatitis has always been an important research subject in the medical field. In recent years, some new progress has been made in drugs used for pancreatitis. Patent CN114206850A reports a 2H-benzopyran derivative that can be used to treat pancreatitis. Its chemical structure is shown below:

[0004]

[0005] Patent WO2022179577A1 reports that the preparation route of compound A is as follows:

[0006]

[0007] In this preparation route, compound VI is a key intermediate, and its purity and preparation cost have a crucial impact on compound A. The preparation method disclosed in the above patent has the following problems:

[0008] In the process of preparing compound IV from compound II, compound III needs to be separated and purified, which leads to a decrease in yield and significantly increases the production time and the amount of three wastes generated, which is not conducive to the control of subsequent large-scale production costs;

[0009] Since the furan ring is first formed in compound IV, resulting in a decrease in the activity of bromine, the preparation of the intermediate of the cyclopropyl-substituted 2H-benzofuran compound of compound VI needs to react at a high temperature, resulting in a large number of by-product impurities in this step, difficulty in purification, and reduced yield. Post-treatment requires multiple refining and purification with a mixed solvent, and the impurities are not completely dissolved during the refining process, resulting in impurity inclusion and poor purification effect. The purity of the intermediate of the cyclopropyl-substituted 2H-benzofuran compound of compound VI obtained in the end is only about 96%, which is not conducive to the subsequent quality control of compound A;

[0010] The overall yield is low and the production cost is high. The total yield of preparing compound VI from compound I is only about 33%, which greatly increases the preparation cost of compound A. Summary of the invention

[0011] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the object of the present invention is to provide a method for preparing a cyclopropyl substituted 2H-benzofuran compound intermediate.

[0012] In order to achieve the purpose of the present invention, the technical solution adopted by the present invention is:

[0013] A method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate, wherein the cyclopropyl-substituted 2H-benzofuran compound intermediate has the following structural formula:

[0014] ;

[0015] The steps include:

[0016] S100, compound III As raw material, add compound V and a catalyst in a solvent R-Ⅰ to obtain a solution of compound VI-a;

[0017] S200, adding sulfuric acid to the solution of compound VI-a to react, adding water and extraction solvent R-II to the system after the reaction, stirring, standing and separating the liquids to obtain an aqueous phase;

[0018] S300, adding an alkaline solution to the aqueous phase to adjust the pH of the aqueous phase to 7-9, filtering and drying to obtain a crude intermediate compound VI;

[0019] S400, purifying the crude intermediate of the cyclopropyl-substituted 2H-benzofuran compound using an organic ether solvent to obtain a purified intermediate of the cyclopropyl-substituted 2H-benzofuran compound.

[0020] Furthermore, the specific process of S400 is as follows: add an organic ether solvent to the crude product of the cyclopropyl substituted 2H-benzofuran compound intermediate, stir at a temperature of 50°C to 60°C for 1h to 2h, then slowly cool the solution to 5°C to 15°C, stir and crystallize for 1h to 3h, filter and dry to obtain the purified cyclopropyl substituted 2H-benzofuran compound intermediate.

[0021] Further, the catalyst in step S100 includes at least one of bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, diphenylphosphinoferrocenepalladium dichloride and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium dichloride.

[0022] Furthermore, the solvent R-I in step S100 is a water-soluble solvent, and the solvent R-I includes at least one of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide.

[0023] Furthermore, the reaction temperature of step S100 is 30°C to 60°C.

[0024] Furthermore, in step S200, the molar ratio of sulfuric acid to compound III is 2.0:1 to 5.0:1.

[0025] Furthermore, in step S200, the solvent R-II is a fat-soluble solvent, and the solvent R-II includes at least one of ethyl acetate, isopropyl acetate, tert-butyl acetate and dichloromethane.

[0026] Furthermore, the organic ether solvent in step S400 is at least one of methyl tert-butyl ether, isopropyl ether and diethyl ether.

[0027] Furthermore, the preparation process of compound III in step S100 is as follows:

[0028] S110, Compound Ⅰ Under the catalysis of p-toluenesulfonic acid, it reacts with an iodine reagent in a solvent R-Ⅲ to obtain compound II ;

[0029] S120. Compound II reacts with cyclopropylacetylene to obtain compound III.

[0030] Furthermore, the solvent R-III is a water-soluble solvent, and the solvent R-III includes at least one of acetone, acetonitrile, tetrahydrofuran and N,N-dimethylformamide.

[0031] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects:

[0032] The present invention provides a method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate. Compound III is subjected to a coupling reaction to obtain a new compound VI-a, which is then subjected to continuous hydrolysis to obtain a cyclopropyl-substituted 2H-benzofuran compound intermediate compound VI, thereby reducing byproduct impurities caused by degradation of benzofuran, improving the purity and yield of compound VI, and providing a strong guarantee for ultimately preparing a high-purity compound A.

[0033] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0035] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum detection spectrum of compound VI prepared in Example 1 of the present invention.

[0036] Figure 2 It is the liquid phase detection spectrum of compound VI prepared in Example 1 of the present invention.

[0037] Figure 3 H NMR spectrum of compound A prepared in Example 1 of the present invention DETAILED DESCRIPTION

[0038] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described below in conjunction with the drawings in the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0039] In the following examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all available from commercial sources unless otherwise specified.

[0040] Example 1

[0041] The synthetic route of cyclopropyl-substituted 2H-benzofuran intermediate VI is as follows:

[0042]

[0043] Based on the above-mentioned synthetic route of intermediate VI, compound A was prepared. The specific synthetic route is as follows:

[0044]

[0045] 1. Preparation of compound II.

[0046] Under stirring conditions, compound I (4.00 kg, 18.06 mol) and p-toluenesulfonic acid (6.84 kg, 39.73 mol) were added to acetonitrile (20 L), and the mixture was cooled to 0 o C~10o C, N-iodosuccinimide (4.88 kg, 21.67 mol) was added to the system in batches. After the addition was completed, the reaction system was heated to 25 o C, keep warm and stir for 4 hours. After the reaction is completed, 40 L of purified water is added to the reaction system under stirring and keep warm for 2 hours for crystallization. Then, the system is filtered, and the filter cake is rinsed with 8 L of ethanol. The filter cake is collected and dried to obtain 5.40 kg of compound II. The purity of compound II is 99.74% by HPLC, and the yield is 86.1%.

[0047] 2. Preparation of compound III.

[0048] Under stirring conditions, the above-prepared compound II (5.40kg, 15.55mol), triethylamine (1.57kg, 15.55mol), cyclopropylacetylene (1.23kg, 18.65mol), cuprous iodide (0.15kg, 0.78mol) and tetrakistriphenylphosphine palladium (0.36kg, 0.31mol) were added to 1,4-dioxane (27L), and the reaction system was replaced with nitrogen three times, heated to about 25°C, reacted for about 8 hours, and the system was concentrated under reduced pressure. Then, n-heptane (54L) was added to the concentrated filtrate, and the system was heated to about 70°C, stirred for 1 hour, and then the solution was filtered while hot, and the obtained filtrate was stirred and cooled to about 5°C, and kept warm for crystallization for 2 hours. Then the system was filtered and dried to obtain 3.91kg of compound III, and the purity of compound III was 99.21% and the yield was 88.1% as determined by HPLC.

[0049] 3. Preparation of compound VI cyclopropyl-substituted 2H-benzofuran intermediate.

[0050] Under stirring conditions, the above-prepared compound III (3.40 kg, 11.91 mol), compound V (2.58 kg, 11.67 mol), potassium phosphate (3.99 kg, 18.78 mol) and tetrakistriphenylphosphine palladium (0.29 kg, 0.25 mol) were added to 1,4-dioxane (17 L), the system was replaced with nitrogen, heated to about 40 ° C for 6 hours, the system was filtered with diatomaceous earth to remove insoluble matter, and the filtrate was collected to obtain a solution of compound VI-a.

[0051] Sulfuric acid (3.05 kg, 31.09 mol) was added dropwise to the solution of compound VI-a. After the addition was completed, the temperature of the reaction system was controlled at about 30°C, and the reaction was carried out for about 4 hours. 35 kg of purified water and 15 kg of ethyl acetate were added to the system. After stirring for 20 minutes, the solution was allowed to stand for separation, and the lower aqueous phase was retained. Finally, sodium hydroxide solution was added to the aqueous phase to adjust the pH to 7.8, and a large amount of solid was precipitated. After filtering and drying the solid, it was added to methyl tert-butyl ether (24 L), stirred and heated to 55°C for 1 hour, and then the solution was slowly cooled to about 10°C and stirred for crystallization for 2 hours. After filtering and drying, 3.01 kg of compound VI was obtained. The purity of compound VI was 99.45% and the yield was 88.5% as determined by HPLC.

[0052] 1 HNMR (400 MHz, DMSO-d 6 ): 8.17(s, 1H), 7.97(s, 1H), 7.64(s, 1H), 7.59(s,1H), 6.59 (s, 3H), 2.12-2.18(m, 1H), 1.02-1.05(m, 2H), 0.89-0.92(m, 2H), such as Figure 1 As shown;

[0053] The HPLC liquid chromatogram of compound VI is as follows: Figure 2 As shown;

[0054] The total yield of compound VI prepared from compound I is: 67.1%

[0055] 4. Preparation of compound VIII.

[0056] Under stirring conditions, 1.00kg of compound VI and 0.70kg of triethylamine were added to 3.00kg of N-methylpyrrolidone in sequence. After the addition was completed, the system was cooled to about -5°C. Then, 0.65kg of 2,6-difluorobenzoyl chloride was added dropwise to the reaction system, and the addition was completed, and the reaction was kept warm for 2 hours. After the reaction was completed, 2.02kg of di-tert-butyl chloromethyl phosphate and 2.55kg of cesium carbonate were added to the system. After the addition was completed, the system was heated to 53°C for 5 hours. After the reaction was completed, the temperature in the reactor was reduced to about 10°C, and then 15kg of purified water was added to the reactor, stirred and crystallized. After the crystallization was completed, the solvent was removed by filtration, and the filter cake was purified with a mixed solution of ethyl acetate and n-heptane. 1.73kg of compound VIII was obtained, and the purity of compound VIII was 99.1% by HPLC, and the yield was 86.1%.

[0057] 5. Preparation of compound IX.

[0058] Under stirring conditions, the compound VIII prepared above (1.36 kg) was added to acetonitrile (1.70 kg), and then an acidic hydrolysis solution with a pH of 3.0 prepared by mixing a disodium hydrogen phosphate aqueous solution and a citric acid aqueous solution was added, totaling 4.92 kg. After the addition was completed, the reaction solution was heated to 49°C for 18 hours. After the reaction was completed, the temperature in the reactor was lowered to 22°C, and then 5 kg of 2-methyltetrahydrofuran was added to the reactor. After stirring, the reaction mixture was allowed to stand for separation, the lower aqueous phase was discarded, and the upper organic phase was retained. 4 kg of sodium bicarbonate aqueous solution (0.6 M) was added to the organic phase, and after stirring for 10 minutes, the mixture was allowed to stand for separation, and the lower aqueous phase was retained. Then 1.58 kg of potassium hydrogen sulfate was added to the aqueous phase in batches, and after stirring until the solid was completely dissolved, 3.0 kg of 2-methyltetrahydrofuran was added, and after continuing to stir for 15 minutes, the mixture was allowed to stand for separation, and the upper organic phase was retained to obtain a 2-methyltetrahydrofuran solution of compound X.

[0059] Among them, the disodium hydrogen phosphate aqueous solution is prepared by 79.0g of disodium hydrogen phosphate and 2.80kg of purified water; the citric acid aqueous solution is prepared by 232.0g of citric acid and 1.81kg of purified water.

[0060] 6. Preparation of compound A.

[0061] The compound IX 2-methyltetrahydrofuran solution prepared above was added to the reactor, and 13.3 kg of acetone and tromethamine solution were added in sequence under stirring. After the addition was completed, the system was heated to 43 ° C for reaction for 3 hours. After 3 hours of reaction, the reaction solution was fully dissolved, clear and transparent. 10 g of compound A in crystalline form A was added to the reaction solution to induce crystallization. Solids gradually precipitated in the reaction solution, and the reaction solution was stirred and crystallized for 2 hours. Then, the reaction solution was cooled to about 23 ° C, stirred and stirred for 1 hour, and the solvent was filtered out. After the filter cake was dried, 1.38 kg of compound A was obtained. The purity of compound A was 99.92% determined by HPLC, and the yield was 85.0%.

[0062] The tromethamine solution is prepared from 0.5 kg of tromethamine and 1.69 kg of purified water.

[0063] l HNMR(DMSO-d6): 8.87(s, lH), 8.59(s, lH), 7.70(s, 2H), 7.40-7.56 (m,lH), 7.09(s, 2H), 6.64(s, lH), 5.56(d, J=4.4Hz, 2H), 5.3 (s, 12H), 3.31 (s,12H), 2.12-2.22(m, lH), l.02-l.09(m, 2H), 0.91-0.98(m, 2H), such as Figure 3 shown.

[0064] Comparative Example 1

[0065] Comparative Example 1 The process route for preparing compound VI is as follows:

[0066]

[0067] 1. Preparation of compound II.

[0068] Under stirring, trifluoroacetic acid (175ml) and dichloromethane (88ml) were added to the reaction flask, and then compound I (35.0g, 158mmol) was added. The reaction system was then cooled to about 0°C, and N-iodosuccinimide (40.9g, 181.7mmol) was added in batches. After the addition was completed, the system was heated to 20°C for reaction for 16 hours. After the reaction was completed, the supernatant was extracted, and then 70ml of ethanol was added to the reaction flask, and the mixture was filtered after stirring for 0.5 hours to collect the filter cake. The filter cake was added to 140ml of ethanol, stirred at 25°C for 16 hours, and then the filter cake was filtered and collected. After drying, 36.8g of compound II was obtained. The purity of compound II was 99.1% and the yield was 67% by HPLC.

[0069] 2. Preparation of compound III.

[0070] Under stirring conditions, the above-prepared compound II (35 g, 101 mmol), cyclopropylacetylene (8.66 g, 131 mmol), triethylamine (30.53 g, 302 mmol) and cuprous iodide (0.96 g, 5.4 mmol) were added to 2-methyltetrahydrofuran (350 ml), and the system was replaced with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (1.42g) was added to the system, and after nitrogen replacement again, the system was maintained at about 25°C and reacted for 16 hours. After the reaction, the system was filtered with diatomaceous earth, the filter cake was rinsed with 100ml of ethyl acetate, the organic phases were combined, and washed with 1N potassium hydrogen sulfate solution (180ml), saturated sodium bicarbonate solution (180ml) and saturated brine (180ml) in sequence, and then the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, and then the crude product was stirred with 210ml of a mixed solution of n-heptane: ethyl acetate = 20:1 for 1 hour, and the filtrate was concentrated under reduced pressure to obtain 24.3g of compound III. The purity of compound III was determined by HPLC to be 94.2%, and the yield was 84.5%.

[0071] 3. Preparation of compound IV.

[0072] Under stirring, the compound III prepared above (24.0 g, 84 mmol) was added to anhydrous ethanol (240 ml), and then concentrated sulfuric acid (8.24 g, 84 mmol) was added to the system. After the addition was completed, the system was heated to 80°C for reaction for 16 hours. After the reaction was completed, the system was concentrated under reduced pressure, and then 200 ml of ethyl acetate was added for dissolution, and then washed with saturated sodium bicarbonate aqueous solution (100 ml×2) and saturated brine (65 ml×2) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound IV.

[0073] The crude product of compound IV was added to 600 ml of n-heptane and stirred to dissolve, then filtered through a silica gel pad, and the silica gel was rinsed with 400 ml of n-heptane. The filtrates were combined and concentrated under reduced pressure to obtain 18.5 g of compound IV. The purity of compound IV was determined by HPLC to be 95.7%, and the yield was 81.1%.

[0074] 4. Preparation of compound VI.

[0075] Under stirring conditions, the above-prepared compound IV (15.0 g, 55.2 mmol), compound V (20.4 g, 82.9 mmol) and potassium phosphate (29.3 g, 138.1 mmol) were added to 300 ml of ethanol and 30 ml of purified water. After the system was replaced with nitrogen, [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (1.8 g, 2.8 mmol) was added. After the addition was completed, the system was replaced with nitrogen again, and the temperature of the system was raised to about 80°C and the reaction was carried out for 16 hours. After the reaction, 60 ml of purified water was added to the system, and then the system was concentrated under reduced pressure to remove the solvent. Then, 450 ml of a mixed solution of n-heptane: ethyl acetate = 1:1 (volume ratio) was added to the concentrated solid. After stirring at room temperature for 1 hour, it was purified by chromatography column. The filter cake was stirred with 120 ml of a mixed solution of n-heptane: ethyl acetate = 1:1 for 0.5 hours, filtered again, and repeated twice. The filtrate was combined and washed with purified water (100 ml×5) and saturated brine (100 ml×2) in turn. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of compound VI. The crude product of compound VI was stirred with 750 ml of a mixed solution of n-heptane: ethyl acetate = 10:1 (volume ratio) for 16 hours. Then it was filtered, and the filtrate was concentrated under reduced pressure to obtain 11.4 g of compound VI. The purity of compound VI was 96.7% and the yield was 72.2% as determined by HPLC.

[0076] By comparing Example 1 with Comparative Example 1, it can be seen that the method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate provided by the present invention has the following advantages:

[0077] The preparation process provided in Example 1 is to first couple compound III and compound V to obtain a solution of compound VI-a, and then add sulfuric acid to the solution to obtain a cyclopropyl-substituted 2H-benzofuran compound intermediate. The process operation is relatively simple, the loss of compound VI is reduced, and the yield is significantly improved. And because the bromine activity in the structure of compound III is relatively high, the coupling reaction can react normally at a temperature of 30°C to 60°C, so the impurities generated during the reaction are relatively small, the product purity is high, which is conducive to post-processing purification and large-scale production.

[0078] Example 1 For the purification of the crude intermediate of the cyclopropyl-substituted 2H-benzofuran compound, an ether solvent is used for refining and purification, which is simple to operate, and the purity and yield of the product are significantly improved, which is beneficial to quality control and cost control;

[0079] Example 1 In the process of preparing compound II, p-toluenesulfonic acid is used to replace the strong acidic solvent trifluoroacetic acid, and a water-miscible solvent is used to replace dichloromethane. The reaction conditions are mild, the post-treatment is simple, the product can be precipitated by adding water, and the purity and yield of compound II can be significantly improved.

[0080] In Example 1, Compound VI was prepared using Compound I as a raw material, and the total yield was 67.1%. In Comparative Example 1, Compound VI was prepared using Compound I as a raw material, and the total yield was 33.2%.

[0081] In summary, the preparation method provided by the present invention, whether it is the preparation of the key intermediate cyclopropyl-substituted 2H-benzofuran compounds, or the preparation of 2H-benzopyran derivatives for the treatment of pancreatitis by this method, the purity and yield are significantly improved, and the operation is simpler and safer, the amount of three wastes generated is reduced, and it is conducive to large-scale production.

[0082] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a cyclopropyl-substituted 2H-benzofuran compound intermediate, characterized in that: The structural formula of the cyclopropyl-substituted 2H-benzofuran compound intermediate is as follows: ； The preparation method comprises the following steps: S100, compound III As raw material, add compound V and a catalyst in a solvent R-Ⅰ to obtain compound VI-a Solution; The catalyst is selected from at least one of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, diphenylphosphinodiferrocenepalladium dichloride and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium dichloride; The solvent R-Ⅰ is a water-soluble solvent, and the solvent R-Ⅰ is selected from at least one of 1,4-dioxane and tetrahydrofuran; The reaction temperature is 30°C to 60°C; S200, adding sulfuric acid to the solution of compound VI-a to react, adding water and extraction solvent R-II to the system after the reaction, stirring, standing and separating the liquids to obtain an aqueous phase; The molar ratio of sulfuric acid to compound III is 2.0:1 to 5.0:1; The solvent R-II is a fat-soluble solvent, and the solvent R-II is selected from at least one of ethyl acetate, isopropyl acetate, tert-butyl acetate and dichloromethane; S300, adding an alkaline solution to the aqueous phase to adjust the pH of the aqueous phase to 7-9, filtering and drying to obtain a crude intermediate of a cyclopropyl-substituted 2H-benzofuran compound; S400, purifying the crude intermediate compound of the cyclopropyl-substituted 2H-benzofuran compound using an organic ether solvent to obtain a purified intermediate compound of the cyclopropyl-substituted 2H-benzofuran compound.

2. The method for preparing the cyclopropyl-substituted 2H-benzofuran compound intermediate according to claim 1, characterized in that: The S400 process is as follows: add an organic ether solvent to the crude product of the cyclopropyl substituted 2H-benzofuran compound intermediate, stir at a temperature of 50°C to 60°C for 1h to 2h, then slowly cool the solution to 5°C to 15°C, stir and crystallize for 1h to 3h, filter and dry to obtain the purified cyclopropyl substituted 2H-benzofuran compound intermediate.

3. The method for preparing the cyclopropyl-substituted 2H-benzofuran compound intermediate according to claim 2, characterized in that: The organic ether solvent in step S400 is at least one of methyl tert-butyl ether, isopropyl ether and diethyl ether.

4. The method for preparing the cyclopropyl-substituted 2H-benzofuran compound intermediate according to claim 1, characterized in that: The preparation process of compound III in step S100 is as follows: S110, Compound Ⅰ Under the catalysis of p-toluenesulfonic acid, it reacts with an iodine reagent in a solvent R-Ⅲ to obtain compound II ; S120. Compound II reacts with cyclopropylacetylene to obtain compound III.

5. The method for preparing the cyclopropyl-substituted 2H-benzofuran compound intermediate according to claim 4, characterized in that: The solvent R-III is a water-soluble solvent, and the solvent R-III is selected from at least one of acetone, acetonitrile, tetrahydrofuran and N,N-dimethylformamide.

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