Preparation method of cyclopropyl-substituted 2H-benzofuran derivative

Abstract

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a cyclopropyl-substituted 2H-benzofuran derivative, in S100, a compound I, an acid-binding agent I and a compound II are used for preparing an intermediate I. The step effectively avoids generation of an impurity A and improves the purity and yield of the intermediate I; in S200, an intermediate I, an acid-binding agent II and a compound III are used for preparing an intermediate II, the step effectively avoids generation of an impurity B and an impurity C under the conditions of high temperature and strong alkali, and the purity and the yield of the intermediate II are improved; in the step S300, the intermediate II is utilized to prepare the cyclopropyl substituted 2H-benzofuran derivative. Results show that the purity and the yield of the target compound can be remarkably improved by utilizing the preparation method provided by the invention, the quality control of bulk drugs is facilitated, and the production cost can be reduced.

Description

Technical Field

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

[0002] A cyclopropyl-substituted 2H-benzofuran derivative with clinical potential for treating pancreatitis, the structural formula of which is shown below: ; The following preparation route is disclosed in patent document WO2022179577A1: ; In this synthetic route, due to the compound The structural formula contains an acyl chloride structure, which has high activity and is used to prepare intermediates When the partial disubstituted impurity A is generated , the formation of impurity A will lead to the intermediate The purity and yield of the product are reduced and purification is difficult; using intermediates Preparation of another intermediate When the intermediate The amide in the structure is less reactive and therefore is not as active as the compound During the reaction, strong alkali (cesium carbonate, potassium carbonate, etc.) and high temperature conditions are required to complete the reaction. Strong alkali and high temperature conditions will lead to the production of many side reactions, the main of which is impurity B and impurity C , leading to the intermediate The yield and purity of impurities B and C are reduced. The mechanism of generation is as follows: ; Excessive impurities generated during the preparation of intermediates will reduce the purity and yield of the target compound 2H-benzofuran derivative.

[0003] Therefore, there is an urgent need for a preparation method with mild preparation conditions, simple operation, less impurities, and high purity of intermediates and target compounds. Summary of the invention

[0004] 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 derivative.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is: A method for preparing a cyclopropyl-substituted 2H-benzofuran derivative, wherein the structural formula of the cyclopropyl-substituted 2H-benzofuran derivative is as follows: ; The steps include: S100, using compound Ⅰ , acid binding agent Ⅰ and compound Ⅱ , Preparation of intermediate Ⅰ ; Wherein, the acid binding agent I is selected from organic bases; S200, using the intermediate I, acid binding agent II and compound III , Preparation of Intermediate II ; Wherein, the acid binding agent II is selected from an organic base; S300, using the intermediate II to prepare a cyclopropyl-substituted 2H-benzofuran derivative.

[0006] Furthermore, the process of step S100 is as follows: At a temperature of 0 to 30°C, add reaction solvent I to the reaction system, and under stirring, add compound I, acid binding agent I and compound II in sequence. After reacting for 6±0.5h at a temperature of 25 to 35°C, add water to the reaction system, stir evenly, let stand, remove the aqueous phase, obtain an organic phase, dry, concentrate under reduced pressure, add methyl tert-butyl ether, stir and crystallize for 1±0.5h, filter and dry to obtain intermediate I; The process of step S200 is as follows: at a temperature of 0 to 30° C., a reaction solvent II, the intermediate I and an acid binding agent II are added to a reaction system, the temperature is lowered to 0 to 10° C. under stirring conditions, compound III is added dropwise, and after reacting for 3±0.5 h, water is added to the reaction system, the mixture is stirred evenly, and the mixture is allowed to stand, the aqueous phase is removed, an organic phase is obtained, the organic phase is concentrated under reduced pressure, n-heptane and ethyl acetate are added, the mixture is stirred for crystallization for 2±0.5 h, and then filtered and dried to obtain intermediate II; The process of step S300 is as follows: under stirring conditions, acetonitrile, intermediate II and a mixed solution of disodium hydrogen phosphate and citric acid at a pH of 3 are added to the reaction system, the temperature is raised to 45°C, the reaction is carried out for 24±1h, the temperature is lowered to 0-30°C, acetone is added to the reaction system after extraction and concentration, the mixture is stirred and dissolved, the tromethamine solution is added, the temperature is raised to 45±0.5°C, crystallization is carried out for 16±1h, the temperature is lowered to 23±0.5°C, the mixture is kept warm and stirred for 2±0.5h, and then filtered to obtain a filter cake, which is dried to obtain a cyclopropyl-substituted 2H-benzofuran derivative.

[0007] Furthermore, the acid binding agent I and the acid binding agent II are each independently selected from at least one of triethylamine, N,N-diisopropylethylamine and pyridine.

[0008] Furthermore, in step S100, the molar ratio of the acid binding agent I to the compound I is 1:1 to 4:1.

[0009] Furthermore, the reaction solvent I and the reaction solvent II are each independently selected from at least one of dichloromethane, chloroform, tetrahydrofuran and N,N-dimethylformamide.

[0010] Furthermore, the reaction solvent I and the reaction solvent II are both selected from dichloromethane.

[0011] Furthermore, in step S100, the mass ratio of the amount of the reaction solvent I added to the amount of the compound I added is 3:1 to 15:1.

[0012] Furthermore, in step S200, the molar ratio of the acid binding agent II to the intermediate I is 1:1 to 4:1.

[0013] Furthermore, in step S200, the mass ratio of the amount of the reaction solvent II added to the amount of the intermediate I added is 3:1 to 15:1.

[0014] Furthermore, in step S200, the mass ratio of n-heptane and ethyl acetate added is 4:1.

[0015] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: The present invention provides a method for preparing a cyclopropyl-substituted 2H-benzofuran derivative, step S100, using an acid-binding agent I, compound I and compound II to generate intermediate I, this step effectively avoids the generation of impurity A, and improves the purity and yield of intermediate I; step S200, using an acid-binding agent II, intermediate I and compound III to generate intermediate II, this step effectively avoids the generation of impurities B and impurity C under high temperature and strong alkaline conditions, and improves the purity and yield of intermediate II; step S300, using intermediate II to prepare a cyclopropyl-substituted 2H-benzofuran derivative. The results show that the preparation method provided by the present invention can significantly improve the purity (≥99.5%) and yield of the target compound, which is beneficial to the quality control of pharmaceutical raw materials and can reduce its production cost.

[0016] 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

[0017] Figure 1 It is the HPLC chromatogram of intermediate I provided in Example 1 of the present invention.

[0018] Figure 2This is the HNMR spectrum of the intermediate I provided in Example 1 of the present invention.

[0019] Figure 3 It is the HPLC chromatogram of intermediate II provided in Example 1 of the present invention.

[0020] Figure 4 It is the HPLC chromatogram of the cyclopropyl substituted 2H-benzofuran derivative provided in Example 1 of the present invention.

[0021] Figure 5 It is the HNMR spectrum of the cyclopropyl substituted 2H-benzofuran derivative provided in Example 1 of the present invention.

[0022] Figure 6 It is the HPLC chromatogram of the intermediate Ⅰ0 provided in Comparative Example 1 of the present invention.

[0023] Figure 7 It is the HPLC chromatogram of intermediate II provided in Comparative Example 1 of the present invention.

[0024] Figure 8 It is the HPLC chromatogram of the cyclopropyl substituted 2H-benzofuran derivative provided in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme in the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of 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.

[0026] A method for preparing a cyclopropyl-substituted 2H-benzofuran derivative, the synthetic route of which is as follows: .

[0027] In the following examples and comparative examples, the experimental methods used are conventional methods unless otherwise specified, and are carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used are all commercially available unless otherwise specified.

[0028] Example 1 1. Preparation of intermediate Ⅰ, the process is as follows: At room temperature, add the reaction solvent I dichloromethane (8.0 kg) into a 20 L reactor, start stirring, and then add compound I (1.0kg), acid binding agent I triethylamine (0.53kg) and compound II (0.95kg), after the addition, the temperature in the reactor was controlled to be 25°C, after reacting for 6h, purified water (5kg) was added to the reactor, stirred for 20min, the aqueous phase was removed, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, methyl tert-butyl ether (8.5kg) was added, and crystallization was stirred at room temperature for 1h, then filtered and dried to obtain intermediate Ⅰ (1.65kg); the results of its high-performance liquid chromatography (HPLC) test are as follows Figure 1 As shown in Figure 2, its hydrogen nuclear magnetic resonance spectrum (HNMR) is as follows: Figure 2 As shown; Among them, the detection purity of intermediate I was 99.6%, and the yield was 92.8%; 1 HNMR (CDCl3): δ (ppm) 8.40 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.06~8.07 (m, lH), 7.08 (s, 1H), 6.87~6.88 (m, lH), 5.80 (d, J=8.0Hz, 2H), 1.71-1.75(m, lH), 1.02(s, 18H), 0.81-0.84(m, 2H), 0.70-0.71(m, 2H).

[0029] The reaction solvent I is not limited to dichloromethane, but may also be selected from at least one of chloroform, tetrahydrofuran and N,N-dimethylformamide.

[0030] The acid-binding agent I is not limited to triethylamine, and may also be selected from at least one of N,N-diisopropylethylamine and pyridine.

[0031] 2. Preparation of Intermediate II: At room temperature, the reaction solvent II dichloromethane (13.04 kg), the intermediate I obtained above (1.63 kg) and the acid binding agent II triethylamine (0.49 kg) were added to a 20L reactor in sequence, stirring was started, the temperature in the reactor was lowered to 10°C, and then compound III was added dropwise. (0.59kg), after the addition, the temperature in the reactor was controlled at 10°C, after reacting for 3h, purified water (4kg) was added to the reactor, stirred for 20h, the aqueous phase was removed, the organic phase was dried over anhydrous sodium sulfate, and after reduced pressure concentration, n-heptane (8.80kg) and ethyl acetate (2.20kg) were added to the system, stirred at room temperature, crystallized for 2h, and then filtered and dried to obtain intermediate II (1.86kg), HPLC test results are as follows Figure 3 As shown, the purity of intermediate II is 99.2% and the yield is 89.4%; Wherein, the reaction solvent II is not limited to dichloromethane, and may also be selected from at least one of chloroform, tetrahydrofuran and N,N-dimethylformamide, and the reaction solvent II may be the same as or different from the reaction solvent I; The acid binding agent II is not limited to triethylamine, and may also be selected from at least one of N,N-diisopropylethylamine and pyridine. The acid binding agent II may be the same as or different from the acid binding agent I.

[0032] 3. Preparation of cyclopropyl-substituted 2H-benzofuran derivatives, the process is as follows: Under stirring, acetonitrile (15.80 kg) and the intermediate II (1.83 kg) obtained above were added to a 100L reactor, followed by addition of disodium hydrogen phosphate and citric acid buffer (6.65 kg) at a pH of 3 as a hydrolyzing solution. After the addition was completed, the reaction solution was heated to 45°C. After reacting for 24 hours, the solution in the reactor was cooled to room temperature. Ethyl acetate (40.30 kg) and purified water (9.15 kg) were then added to the reactor. The mixture was stirred and extracted. The upper organic phase was retained. A 0.6 M sodium bicarbonate aqueous solution (5.36 kg) was then added to the organic phase. The mixture was separated after stirring, and the lower aqueous phase was retained. Potassium hydrogen sulfate (2.12 kg) was added to the aqueous phase in batches. After stirring until the solid was completely dissolved, ethyl acetate (30.00 kg) was added. After stirring and extracting again, the aqueous phase was discarded, and the upper organic phase was retained. After reduced pressure concentration, acetone (18.30 kg) was added to the system. After stirring and dissolving, tromethamine solution (0.67 kg) and purified water (1.83 kg) were added. After the addition was completed, the system was heated to 45°C and reacted for 16 hours. The reaction solution was cooled to 23°C, stirred and kept warm for 2 hours, and the solvent was removed by filtration to obtain a filter cake. After drying, a cyclopropyl-substituted 2H-benzofuran derivative (1.56 kg) was obtained. The HPLC test results are as follows Figure 4 As shown, HNMR Figure 5 As shown; The purity of the cyclopropyl-substituted 2H-benzofuran derivative was 99.5% and the yield was 70.9%; 1 HNMR (DMSO -d6)δ(ppm): 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=4.0Hz, 2H), 5.3(brs, 12H), 3.31(s, 12H), 2.13-2.20(m, lH), 1.03-1.07(m, 2H), 0.92-0.94(m, 2H).

[0033] Comparative Example 1 According to the technical scheme disclosed in patent WO2022179577, a cyclopropyl-substituted 2H-benzofuran derivative was prepared, and its synthesis route is as follows: .

[0034] 1. Intermediate Ⅰ0 The preparation process is as follows: Under stirring, dichloromethane (200 ml) and compound I were added to the reaction flask. (40.0 g) and pyridine (22.2 g), the system was cooled to 5 °C, and compound III (25.2g) was diluted with dichloromethane (40ml) and added to the system. After the addition was completed, the system was heated to 20°C and reacted for 4h. Then purified water (400ml) was added to the system and stirred for 2h. Then the system was filtered to obtain a filter cake. The filter cake was rinsed with purified water and ethanol, and then dried and slurried with a mixture of methyl tert-butyl ether (150ml) and anhydrous ethanol (50ml) for purification. After filtration and drying, intermediate Ⅰ0 was obtained. (41.1 g), and its HPLC test results are as follows Figure 6 As shown, the purity is 95.6%, the yield is 69.0%, and the content of impurity A is 4.4%.

[0035] 2. Intermediate II The preparation process is as follows: Under stirring, N,N-dimethylacetamide (400 ml) and the intermediate Ⅰ0 prepared above were added to the reaction bottle. (40g), Compound II (60.7g), cesium carbonate (76.7g) and potassium iodide (1.56g), after the addition, the system was heated to 45°C, reacted for 16h, the reaction system was cooled to room temperature, and then purified water (1.6L) and ethyl acetate (500ml) were added to the reaction system. After stirring and extraction, the aqueous phase was extracted once with ethyl acetate (500ml), the ethyl acetate organic phase was combined, and washed with purified water (300ml) and saturated brine (300ml) in sequence, and then the ethyl acetate was dried over anhydrous sodium sulfate, reduced pressure and concentrated to obtain a reddish brown viscous crude product, and then the viscous crude product was first refined with dichloromethane and n-heptane, and then purified by beating with a mixed solution of ethyl acetate and n-heptane to obtain intermediate II (35.9 g), and its HPLC test results are as follows Figure 7 As shown, the purity is 95.3% and the yield is 59.1%.

[0036] 3. Preparation of cyclopropyl-substituted 2H-benzofuran derivatives, the process is as follows: Under room temperature, stirring, acetonitrile (350 ml) and the intermediate II obtained above were added to the reaction bottle in sequence. (35.0g), after stirring and dissolving, add 350ml of a mixed solution of sodium dihydrogen phosphate and citric acid with a pH of 3 as an acidic hydrolyzate. After the addition is completed, the reaction solution is heated to 45°C and reacted for 24h. After the liquid phase detection reaction is completed, the reaction solution is cooled to room temperature, and then ethyl acetate (1.6L) and purified water (1.2L) are added. After stirring, stand and separate the liquids. After the organic phase is washed with purified water (100ml×3), a saturated sodium bicarbonate aqueous solution (400ml) is added to the organic phase. After stirring, stand and separate the liquids, retain the lower aqueous phase, and add a 1M potassium hydrogen sulfate aqueous solution to the aqueous phase in batches to adjust its pH to 4, and then extract with ethyl acetate (800ml×3). The obtained ethyl acetate solution is dried over anhydrous sodium sulfate, decompressed and concentrated to obtain a concentrate. Then, the concentrate was added to acetone (270 ml), stirred and dissolved, tromethamine (8.51 g) was dissolved in purified water (35 ml) and added to the reaction system, and the reaction system was heated to 25°C. After reacting for 16 hours, the filter cake was filtered to obtain a filter cake, which was rinsed with acetone (100 ml) and vacuum dried to obtain a cyclopropyl-substituted 2H-benzofuran derivative (27.3 g). The HPLC test results are as follows: Figure 8 As shown, the purity is 96.7% and the yield is 65.1%.

[0037] It can be seen from Example 1 and Comparative Example 1 that the purity and yield of the cyclopropyl substituted 2H-benzofuran derivative obtained by the preparation method provided by the present invention are higher than those of the cyclopropyl substituted 2H-benzofuran derivative obtained by the preparation method provided by the comparative example, and the preparation method provided by Example 1 effectively avoids the generation of intermediate impurities A, impurity B and impurity C, which is beneficial to improving the quality and safety of the final target compound.

[0038] 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 derivative, characterized in that: The structural formula of the cyclopropyl-substituted 2H-benzofuran derivative is shown below: ； The steps include: S100, using compound Ⅰ , acid binding agent Ⅰ and compound Ⅱ , Preparation of intermediate Ⅰ ; Wherein, the acid binding agent I is selected from an organic base; S200, using the intermediate I, the acid binding agent II and the compound III , Preparation of Intermediate II ; Wherein, the acid binding agent II is selected from an organic base; S300, using the intermediate II to prepare a cyclopropyl-substituted 2H-benzofuran derivative.

2. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 1, characterized in that: The process of step S100 is as follows: At a temperature of 0 to 30°C, add reaction solvent I to the reaction system, and under stirring, add compound I, acid binding agent I and compound II in sequence. After reacting for 6±0.5h at a temperature of 25 to 35°C, add water to the reaction system, stir evenly, let stand, remove the aqueous phase, obtain an organic phase, dry, concentrate under reduced pressure, add methyl tert-butyl ether, stir and crystallize for 1±0.5h, filter and dry to obtain intermediate I; The process of step S200 is as follows: at a temperature of 0 to 30° C., a reaction solvent II, the intermediate I and an acid binding agent II are added to a reaction system, the temperature is lowered to 0 to 10° C. under stirring conditions, compound III is added dropwise, and after reacting for 3±0.5 h, water is added to the reaction system, the mixture is stirred evenly, and the mixture is allowed to stand, the aqueous phase is removed, an organic phase is obtained, the organic phase is concentrated under reduced pressure, n-heptane and ethyl acetate are added, the mixture is stirred for crystallization for 2±0.5 h, and then filtered and dried to obtain intermediate II; The process of step S300 is as follows: under stirring conditions, acetonitrile, intermediate II and a mixed solution of disodium hydrogen phosphate and citric acid at a pH of 3 are added to the reaction system, the temperature is raised to 45°C, the reaction is carried out for 24±1h, the temperature is lowered to 0-30°C, acetone is added to the reaction system after extraction and concentration, the mixture is stirred and dissolved, the tromethamine solution is added, the temperature is raised to 45±0.5°C, crystallization is carried out for 16±1h, the temperature is lowered to 23±0.5°C, the mixture is kept warm and stirred for 2±0.5h, and then filtered to obtain a filter cake, which is dried to obtain a cyclopropyl-substituted 2H-benzofuran derivative.

3. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 1 or 2, characterized in that: The acid binding agent I and the acid binding agent II are each independently selected from at least one of triethylamine, N,N-diisopropylethylamine and pyridine.

4. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 2, characterized in that: The molar ratio of the acid binding agent I to the compound I added in step S100 is 1:1 to 4:

1.

5. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 2, characterized in that: The reaction solvent I and the reaction solvent II are each independently selected from at least one of dichloromethane, chloroform, tetrahydrofuran and N,N-dimethylformamide.

6. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 5, characterized in that: The reaction solvent I and the reaction solvent II are both selected from dichloromethane.

7. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 2, characterized in that: The mass ratio of the amount of the reaction solvent I added in step S100 to the amount of the compound I added is 3:1 to 15:

1.

8. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 2, characterized in that: The molar ratio of the acid binding agent II to the intermediate I added in step S200 is 1:1 to 4:

1.

9. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 2, characterized in that: In step S200, the mass ratio of the amount of the reaction solvent II added to the amount of the intermediate I added is 3:1 to 15:

1.

10. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 2, characterized in that: In step S200, the mass ratio of n-heptane and ethyl acetate added is 4:1.

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